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Taking the Detour
A 60‐year‐old woman presented to a community hospital's emergency department with 4 days of right‐sided abdominal pain and multiple episodes of black stools. She reported nausea without vomiting. She denied light‐headedness, chest pain, or shortness of breath. She also denied difficulty in swallowing, weight loss, jaundice, or other bleeding.
The first priority when assessing a patient with gastrointestinal (GI) bleeding is to ensure hemodynamic stability. Next, it is important to carefully characterize the stools to help narrow the differential diagnosis. As blood is a cathartic, frequent, loose, and black stools suggest vigorous bleeding. It is essential to establish that the stools are actually black, as some patients will mistake dark brown stools for melena. Using a visual aid like a black pen or shoes as a point of reference can help the patient differentiate between dark stool and melena. It is also important to obtain a thorough medication history because iron supplements or bismuth‐containing remedies can turn stool black. The use of any antiplatelet agents or anticoagulants should also be noted. The right‐sided abdominal pain should be characterized by establishing the frequency, severity, and association with eating, movement, and position. For this patient's presentation, increased pain with eating would rapidly heighten concern for mesenteric ischemia.
The patient reported having 1 to 2 semiformed, tarry, black bowel movements per day. The night prior to admission she had passed some bright red blood along with the melena. The abdominal pain had increased gradually over 4 days, was dull, constant, did not radiate, and there were no evident aggravating or relieving factors. She rated the pain as 4 out of 10 in intensity, worst in her right upper quadrant.
Her past medical history was notable for recurrent deep venous thromboses and pulmonary emboli that had occurred even while on oral anticoagulation. Inferior vena cava (IVC) filters had twice been placed many years prior; anticoagulation had been subsequently discontinued. Additionally, she was known to have chronic superior vena cava (SVC) occlusion, presumably related to hypercoagulability. Previous evaluation had identified only hyperhomocysteinemia as a risk factor for recurrent thromboses. Other medical problems included hemorrhoids, gastroesophageal reflux disease, and asthma. Her only surgical history was an abdominal hysterectomy and bilateral oophorectomy many years ago for nonmalignant disease. Home medications were omeprazole, ranitidine, albuterol, and fluticasone‐salmeterol. She denied using nonsteroidal anti‐inflammatory drugs, aspirin, or any dietary supplements. She denied smoking, alcohol, or recreational drug use.
Because melena is confirmed, an upper GI tract bleeding source is most likely. The more recent appearance of bright red blood is concerning for acceleration of bleeding, or may point to a distal small bowel or right colonic source. Given the history of thromboembolic disease and likely underlying hypercoagulability, vascular occlusion is a leading possibility. Thus, mesenteric arterial insufficiency or mesenteric venous thrombosis should be considered, even though the patient does not report the characteristic postprandial exacerbation of pain. Ischemic colitis due to arterial insufficiency typically presents with severe, acute pain, with or without hematochezia. This syndrome is typically manifested in vascular watershed areas such as the splenic flexure, but can also affect the right colon. Mesenteric venous thrombosis is a rare condition that most often occurs in patients with hypercoagulability. Patients present with variable degrees of abdominal pain and often with GI bleeding. Finally, portal venous thrombosis may be seen alongside thromboses of other mesenteric veins or may occur independently. Portal hypertension due to portal vein thrombosis can result in esophageal and/or gastric varices. Although variceal bleeding classically presents with dramatic hematemesis, the absence of hematemesis does not rule out a variceal bleed in this patient.
On physical examination, the patient had a temperature of 37.1C with a pulse of 90 beats per minute and blood pressure of 161/97 mm Hg. Orthostatics were not performed. No blood was seen on nasal and oropharyngeal exam. Respiratory and cardiovascular exams were normal. On abdominal exam, there was tenderness to palpation of the right upper quadrant without rebound or guarding. The spleen and the liver were not palpable. There was a lower midline incisional scar. Rectal exam revealed nonbleeding hemorrhoids and heme‐positive stool without gross blood. Bilateral lower extremities had trace pitting edema, hyperpigmentation, and superficial venous varicosities. On skin exam, there were distended subcutaneous veins radiating outward from around the umbilicus as well as prominent subcutaneous venous collaterals over the chest and lateral abdomen.
The collateral veins over the chest and lateral abdomen are consistent with central venous obstruction from the patient's known SVC thrombus. However, the presence of paraumbilical venous collaterals (caput medusa) is highly suggestive of portal hypertension. This evidence, in addition to the known central venous occlusion and history of thromboembolic disease, raises the suspicion for mesenteric thrombosis as a cause of her bleeding and pain. The first diagnostic procedure should be an esophagogastroduodenoscopy (EGD) to identify and potentially treat the source of bleeding, whether it is portal hypertension related (portal gastropathy, variceal bleed) or from a more common cause (peptic ulcer disease, stress gastritis). If the EGD is not diagnostic, the next step should be to obtain computed tomography (CT) of the abdomen and pelvis with intravenous (IV) and oral contrast. In many patients with GI bleed, a colonoscopy would typically be performed as the next diagnostic study after EGD. However, in this patient, a CT scan is likely to be of higher yield because it could help assess the mesenteric and portal vessels for patency and characterize the appearance of the small intestine and colon. Depending on the findings of the CT, additional dedicated vascular diagnostics might be needed.
Hemoglobin was 8.5 g/dL (12.4 g/dL 6 weeks prior) with a normal mean corpuscular volume and red cell distribution. The white cell count was normal, and the platelet count was 142,000/mm3. The blood urea nitrogen was 27 mg/dL, with a creatinine of 1.1 mg/dL. Routine chemistries, liver enzymes, bilirubin, and coagulation parameters were normal. Ferritin was 15 ng/mL (normal: 15200 ng/mL).
The patient was admitted to the intensive care unit. An EGD revealed a hiatal hernia and grade II nonbleeding esophageal varices with normal=appearing stomach and duodenum. The varices did not have stigmata of a recent bleed and were not ligated. The patient continued to bleed and received 2 U of packed red blood cells (RBCs), as her hemoglobin had decreased to 7.3 g/dL. On hospital day 3, a colonoscopy was done that showed blood clots in the ascending colon but was otherwise normal. The patient had ongoing abdominal pain, melena, and hematochezia, and continued to require blood transfusions every other day.
Esophageal varices were confirmed on EGD. However, no high‐risk stigmata were seen. Findings that suggest either recent bleeding or are risk factors for subsequent bleeding include large size of the varices, nipple sign referring to a protruding vessel from an underlying varix, or red wale sign, referring to a longitudinal red streak on a varix. The lack of evidence for an esophageal, gastric, or duodenal bleeding source correlates with lack of clinical signs of upper GI tract hemorrhage such as hematemesis or coffee ground emesis. Because the colonoscopy also did not identify a bleeding source, the bleeding remains unexplained. The absence of significant abnormalities in liver function or liver inflammation labs suggests that the patient does not have advanced cirrhosis and supports the suspicion of a vascular cause of the portal hypertension. At this point, it would be most useful to obtain a CT scan of the abdomen and pelvis.
The patient continued to bleed, requiring a total of 7 U of packed RBCs over 7 days. On hospital day 4, a repeat EGD showed nonbleeding varices with a red wale sign that were banded. Despite this, the hemoglobin continued to drop. A technetium‐tagged RBC study showed a small area of subumbilical activity, which appeared to indicate transverse colonic or small bowel bleeding (Figure 1). A subsequent mesenteric angiogram failed to show active bleeding.
A red wale sign confers a higher risk of bleeding from esophageal varices. However, this finding can be subjective, and the endoscopist must individualize the decision for banding based on the size and appearance of the varices. It was reasonable to proceed with banding this time because the varices were large, had a red wale sign, and there was otherwise unexplained ongoing bleeding. Because her hemoglobin continued to drop after the banding and a tagged RBC study best localized the bleeding to the small intestine or transverse colon, it is unlikely that the varices are the primary source of bleeding. It is not surprising that the mesenteric angiogram did not show a source of bleeding, because this study requires active bleeding at a sufficient rate to radiographically identify the source.
The leading diagnosis remains an as yet uncharacterized small bowel bleeding source related to mesenteric thrombotic disease. Cross‐sectional imaging with IV contrast to identify significant vascular occlusion should be the next diagnostic step. Capsule endoscopy would be a more expensive and time‐consuming option, and although this could reveal the source of bleeding, it might not characterize the underlying vascular nature of the problem.
Due to persistent abdominal pain, a CT without intravenous contrast was done on hospital day 10. This showed extensive collateral vessels along the chest and abdominal wall with a distended azygos vein. The study was otherwise unrevealing. Her bloody stools cleared, so she was discharged with a plan for capsule endoscopy and outpatient follow‐up with her gastroenterologist. On the day of discharge (hospital day 11), hemoglobin was 7.5 g/dL and she received an eighth unit of packed RBCs. Overt bleeding was absent.
As an outpatient, intermittent hematochezia and melena recurred. The capsule endoscopy showed active bleeding approximately 45 minutes after the capsule exited the stomach. The lesion was not precisely located or characterized, but was believed to be in the distal small bowel.
The capsule finding supports the growing body of evidence implicating a small bowel source of bleeding. Furthermore, the ongoing but slow rate of blood loss makes a venous bleed more likely than an arterial bleed. A CT scan was performed prior to capsule study, but this was done without intravenous contrast. The brief description of the CT findings emphasizes the subcutaneous venous changes; a contraindication to IV contrast is not mentioned. Certainly IV contrast would have been very helpful to characterize the mesenteric arterial and venous vasculature. If there is no contraindication, a repeat CT scan with IV contrast should be performed. If there is a contraindication to IV contrast, it would be beneficial to revisit the noncontrast study with the specific purpose of searching for clues suggesting mesenteric or portal thrombosis. If the source still remains unclear, the next steps should be to perform push enteroscopy to assess the small intestine from the luminal side and magnetic resonance angiogram with venous phase imaging (or CT venogram if there is no contraindication to contrast) to evaluate the venous circulation.
The patient was readmitted 9 days after discharge with persistent melena and hematochezia. Her hemoglobin was 7.2 g/dL. Given the lack of a diagnosis, the patient was transferred to a tertiary care hospital, where a second colonoscopy and mesenteric angiogram were negative for bleeding. Small bowel enteroscopy showed no source of bleeding up to 60 cm past the pylorus. A third colonoscopy was performed due to recurrent bleeding; this showed a large amount of dark blood and clots throughout the entire colon including the cecum (Figure 2). After copious irrigation, the underlying mucosa was seen to be normal. At this point, a CT angiogram with both venous and arterial phases was done due to the high suspicion for a distal jejunal bleeding source. The CT angiogram showed numerous venous collaterals encasing a loop of midsmall bowel demonstrating progressive submucosal venous enhancement. In addition, a venous collateral ran down the right side of the sternum to the infraumbilical area and drained through the encasing collaterals into the portal venous system (Figure 3). The CT scan also revealed IVC obstruction below the distal IVC filter and an enlarged portal vein measuring 18 mm (normal <12 mm).
The CT angiogram provides much‐needed clarity. The continued bleeding is likely due to ectopic varices in the small bowel. The venous phase of the CT angiogram shows thrombosis of key venous structures and evidence of a dilated portal vein (indicating portal hypertension) leading to ectopic varices in the abdominal wall and jejunum. Given the prior studies that suggest a small bowel source of bleeding, jejunal varices are the most likely cause of recurrent GI bleeding in this patient.
The patient underwent exploratory laparotomy. Loops of small bowel were found to be adherent to the hysterectomy scar. There were many venous collaterals from the abdominal wall to these loops of bowel, dilating the veins both in intestinal walls and those in the adjacent mesentery. After clamping these veins, the small bowel was detached from the abdominal wall. On unclamping, the collaterals bled with a high venous pressure. Because these systemic‐portal shunts were responsible for the bleeding, the collaterals were sutured, stopping the bleeding. Thus, partial small bowel resection was not necessary. Postoperatively, her bleeding resolved completely and she maintained normal hemoglobin at 1‐year follow‐up.
COMMENTARY
The axiom common ailments are encountered most frequently underpins the classical stepwise approach to GI bleeding. First, a focused history helps localize the source of bleeding to the upper or lower GI tract. Next, endoscopy is performed to identify and treat the cause of bleeding. Finally, advanced tests such as angiography and capsule endoscopy are performed if needed. For this patient, following the usual algorithm failed to make the diagnosis or stop the bleeding. Despite historical and examination features suggesting that her case fell outside of the common patterns of GI bleeding, this patient underwent 3 upper endoscopies, 3 colonoscopies, a capsule endoscopy, a technetium‐tagged RBC study, 2 mesenteric angiograms, and a noncontrast CT scan before the study that was ultimately diagnostic was performed. The clinicians caring for this patient struggled to incorporate the atypical features of her history and presentation and failed to take an earlier detour from the usual algorithm. Instead, the same studies that had not previously led to the diagnosis were repeated multiple times.
Ectopic varices are enlarged portosystemic venous collaterals located anywhere outside the gastroesophageal region.[1] They occur in the setting of portal hypertension, surgical procedures involving abdominal viscera and vasculature, and venous occlusion. Ectopic varices account for 4% to 5% of all variceal bleeding episodes.[1] The most common sites include the anorectal junction (44%), duodenum (17%33%), jejunum/emleum (5%17%), colon (3.5%14%), and sites of previous abdominal surgery.[2, 3] Ectopic varices can cause either luminal or extraluminal (i.e., peritoneal) bleeding.[3] Luminal bleeding, seen in this case, is caused by venous protrusion into the submucosa. Ectopic varices present as a slow venous ooze, which explains this patient's ongoing requirement for recurrent blood transfusions.[4]
In this patient, submucosal ectopic varices developed as a result of a combination of known risk factors: portal hypertension in the setting of chronic venous occlusion from her hypercoagulability and a history of abdominal surgery (hysterectomy). [5] The apposition of her abdominal wall structures (drained by the systemic veins) to the bowel (drained by the portal veins) resulted in adhesion formation, detour of venous flow, collateralization, and submucosal varix formation.[1, 2, 6]
The key diagnostic study for this patient was a CT angiogram, with both arterial and venous phases. The prior 2 mesenteric angiograms had been limited to the arterial phase, which had missed identifying the venous abnormalities altogether. This highlights an important lesson from this case: contrast‐enhanced CT may have a higher yield in diagnosing ectopic varices compared to repeated endoscopiesespecially when captured in the late venous phaseand should strongly be considered for unexplained bleeding in patients with stigmata of liver disease or portal hypertension.[7, 8] Another clue for ectopic varices in a bleeding patient are nonbleeding esophageal or gastric varices, as was the case in this patient.[9]
The initial management of ectopic varices is similar to bleeding secondary to esophageal varices.[1] Definitive treatment includes endoscopic embolization or ligation, interventional radiological procedures such as portosystemic shunting or percutaneous embolization, and exploratory laparotomy to either resect the segment of bowel that is the source of bleeding or to decompress the collaterals surgically.[9] Although endoscopic ligation has been shown to have a lower rebleeding rate and mortality compared to endoscopic injection sclerotherapy in patients with esophageal varices, the data are too sparse in jejunal varices to recommend 1 treatment over another. Both have been used successfully either alone or in combination with each other, and can be useful alternatives for patients who are unable to undergo laparotomy.[9]
Diagnostic errors due to cognitive biases can be avoided by following diagnostic algorithms. However, over‐reliance on algorithms can result in vertical line failure, a form of cognitive bias in which the clinician subconsciously adheres to an inflexible diagnostic approach.[10] To overcome this bias, clinicians need to think laterally and consider alternative diagnoses when algorithms do not lead to expected outcomes. This case highlights the challenges of knowing when to break free of conventional approaches and the rewards of taking a well‐chosen detour that leads to the diagnosis.
KEY POINTS
- Recurrent, occult gastrointestinal bleeding should raise concern for a small bowel source, and clinicians may need to take a detour away from the usual workup to arrive at a diagnosis.
- CT angiography of the abdomen and pelvis may miss venous sources of bleeding, unless a venous phase is specifically requested.
- Ectopic varices can occur in patients with portal hypertension who have had a history of abdominal surgery; these patients can develop venous collaterals for decompression into the systemic circulation through the abdominal wall.
Disclosure
Nothing to report.
- , , . Updates in the pathogenesis, diagnosis and management of ectopic varices. Hepatol Int. 2008;2:322–334.
- , , . Management of ectopic varices. Hepatology. 1998;28:1154–1158.
- , , , et al. Current status of ectopic varices in Japan: results of a survey by the Japan Society for Portal Hypertension. Hepatol Res. 2010;40:763–766.
- , , . Stomal Varices: Management with decompression TIPS and transvenous obliteration or sclerosis. Tech Vasc Interv Radiol. 2013;16:126–134.
- , , , et al. Jejunal varices as a cause of massive gastrointestinal bleeding. Am J Gastroenterol. 1992;87:514–517.
- , . Ectopic varices in portal hypertension. Clin Gastroenterol. 1985;14:105–121.
- , , , et al. Ectopic varices in portal hypertension: computed tomographic angiography instead of repeated endoscopies for diagnosis. Eur J Gastroenterol Hepatol. 2011;23:620–622.
- , , , et al. ACR appropriateness criteria. Radiologic management of lower gastrointestinal tract bleeding. Reston, VA: American College of Radiology; 2011. Available at: http://www.acr.org/Quality‐Safety/Appropriateness‐Criteria/∼/media/5F9CB95C164E4DA19DCBCFBBA790BB3C.pdf. Accessed January 28, 2015.
- , . Diagnosis and management of ectopic varices. Gastrointest Interv. 2012;1:3–10.
- . Achieving quality in clinical decision making: cognitive strategies and detection of bias. Acad Emerg Med. 2002;9:1184–1204.
A 60‐year‐old woman presented to a community hospital's emergency department with 4 days of right‐sided abdominal pain and multiple episodes of black stools. She reported nausea without vomiting. She denied light‐headedness, chest pain, or shortness of breath. She also denied difficulty in swallowing, weight loss, jaundice, or other bleeding.
The first priority when assessing a patient with gastrointestinal (GI) bleeding is to ensure hemodynamic stability. Next, it is important to carefully characterize the stools to help narrow the differential diagnosis. As blood is a cathartic, frequent, loose, and black stools suggest vigorous bleeding. It is essential to establish that the stools are actually black, as some patients will mistake dark brown stools for melena. Using a visual aid like a black pen or shoes as a point of reference can help the patient differentiate between dark stool and melena. It is also important to obtain a thorough medication history because iron supplements or bismuth‐containing remedies can turn stool black. The use of any antiplatelet agents or anticoagulants should also be noted. The right‐sided abdominal pain should be characterized by establishing the frequency, severity, and association with eating, movement, and position. For this patient's presentation, increased pain with eating would rapidly heighten concern for mesenteric ischemia.
The patient reported having 1 to 2 semiformed, tarry, black bowel movements per day. The night prior to admission she had passed some bright red blood along with the melena. The abdominal pain had increased gradually over 4 days, was dull, constant, did not radiate, and there were no evident aggravating or relieving factors. She rated the pain as 4 out of 10 in intensity, worst in her right upper quadrant.
Her past medical history was notable for recurrent deep venous thromboses and pulmonary emboli that had occurred even while on oral anticoagulation. Inferior vena cava (IVC) filters had twice been placed many years prior; anticoagulation had been subsequently discontinued. Additionally, she was known to have chronic superior vena cava (SVC) occlusion, presumably related to hypercoagulability. Previous evaluation had identified only hyperhomocysteinemia as a risk factor for recurrent thromboses. Other medical problems included hemorrhoids, gastroesophageal reflux disease, and asthma. Her only surgical history was an abdominal hysterectomy and bilateral oophorectomy many years ago for nonmalignant disease. Home medications were omeprazole, ranitidine, albuterol, and fluticasone‐salmeterol. She denied using nonsteroidal anti‐inflammatory drugs, aspirin, or any dietary supplements. She denied smoking, alcohol, or recreational drug use.
Because melena is confirmed, an upper GI tract bleeding source is most likely. The more recent appearance of bright red blood is concerning for acceleration of bleeding, or may point to a distal small bowel or right colonic source. Given the history of thromboembolic disease and likely underlying hypercoagulability, vascular occlusion is a leading possibility. Thus, mesenteric arterial insufficiency or mesenteric venous thrombosis should be considered, even though the patient does not report the characteristic postprandial exacerbation of pain. Ischemic colitis due to arterial insufficiency typically presents with severe, acute pain, with or without hematochezia. This syndrome is typically manifested in vascular watershed areas such as the splenic flexure, but can also affect the right colon. Mesenteric venous thrombosis is a rare condition that most often occurs in patients with hypercoagulability. Patients present with variable degrees of abdominal pain and often with GI bleeding. Finally, portal venous thrombosis may be seen alongside thromboses of other mesenteric veins or may occur independently. Portal hypertension due to portal vein thrombosis can result in esophageal and/or gastric varices. Although variceal bleeding classically presents with dramatic hematemesis, the absence of hematemesis does not rule out a variceal bleed in this patient.
On physical examination, the patient had a temperature of 37.1C with a pulse of 90 beats per minute and blood pressure of 161/97 mm Hg. Orthostatics were not performed. No blood was seen on nasal and oropharyngeal exam. Respiratory and cardiovascular exams were normal. On abdominal exam, there was tenderness to palpation of the right upper quadrant without rebound or guarding. The spleen and the liver were not palpable. There was a lower midline incisional scar. Rectal exam revealed nonbleeding hemorrhoids and heme‐positive stool without gross blood. Bilateral lower extremities had trace pitting edema, hyperpigmentation, and superficial venous varicosities. On skin exam, there were distended subcutaneous veins radiating outward from around the umbilicus as well as prominent subcutaneous venous collaterals over the chest and lateral abdomen.
The collateral veins over the chest and lateral abdomen are consistent with central venous obstruction from the patient's known SVC thrombus. However, the presence of paraumbilical venous collaterals (caput medusa) is highly suggestive of portal hypertension. This evidence, in addition to the known central venous occlusion and history of thromboembolic disease, raises the suspicion for mesenteric thrombosis as a cause of her bleeding and pain. The first diagnostic procedure should be an esophagogastroduodenoscopy (EGD) to identify and potentially treat the source of bleeding, whether it is portal hypertension related (portal gastropathy, variceal bleed) or from a more common cause (peptic ulcer disease, stress gastritis). If the EGD is not diagnostic, the next step should be to obtain computed tomography (CT) of the abdomen and pelvis with intravenous (IV) and oral contrast. In many patients with GI bleed, a colonoscopy would typically be performed as the next diagnostic study after EGD. However, in this patient, a CT scan is likely to be of higher yield because it could help assess the mesenteric and portal vessels for patency and characterize the appearance of the small intestine and colon. Depending on the findings of the CT, additional dedicated vascular diagnostics might be needed.
Hemoglobin was 8.5 g/dL (12.4 g/dL 6 weeks prior) with a normal mean corpuscular volume and red cell distribution. The white cell count was normal, and the platelet count was 142,000/mm3. The blood urea nitrogen was 27 mg/dL, with a creatinine of 1.1 mg/dL. Routine chemistries, liver enzymes, bilirubin, and coagulation parameters were normal. Ferritin was 15 ng/mL (normal: 15200 ng/mL).
The patient was admitted to the intensive care unit. An EGD revealed a hiatal hernia and grade II nonbleeding esophageal varices with normal=appearing stomach and duodenum. The varices did not have stigmata of a recent bleed and were not ligated. The patient continued to bleed and received 2 U of packed red blood cells (RBCs), as her hemoglobin had decreased to 7.3 g/dL. On hospital day 3, a colonoscopy was done that showed blood clots in the ascending colon but was otherwise normal. The patient had ongoing abdominal pain, melena, and hematochezia, and continued to require blood transfusions every other day.
Esophageal varices were confirmed on EGD. However, no high‐risk stigmata were seen. Findings that suggest either recent bleeding or are risk factors for subsequent bleeding include large size of the varices, nipple sign referring to a protruding vessel from an underlying varix, or red wale sign, referring to a longitudinal red streak on a varix. The lack of evidence for an esophageal, gastric, or duodenal bleeding source correlates with lack of clinical signs of upper GI tract hemorrhage such as hematemesis or coffee ground emesis. Because the colonoscopy also did not identify a bleeding source, the bleeding remains unexplained. The absence of significant abnormalities in liver function or liver inflammation labs suggests that the patient does not have advanced cirrhosis and supports the suspicion of a vascular cause of the portal hypertension. At this point, it would be most useful to obtain a CT scan of the abdomen and pelvis.
The patient continued to bleed, requiring a total of 7 U of packed RBCs over 7 days. On hospital day 4, a repeat EGD showed nonbleeding varices with a red wale sign that were banded. Despite this, the hemoglobin continued to drop. A technetium‐tagged RBC study showed a small area of subumbilical activity, which appeared to indicate transverse colonic or small bowel bleeding (Figure 1). A subsequent mesenteric angiogram failed to show active bleeding.
A red wale sign confers a higher risk of bleeding from esophageal varices. However, this finding can be subjective, and the endoscopist must individualize the decision for banding based on the size and appearance of the varices. It was reasonable to proceed with banding this time because the varices were large, had a red wale sign, and there was otherwise unexplained ongoing bleeding. Because her hemoglobin continued to drop after the banding and a tagged RBC study best localized the bleeding to the small intestine or transverse colon, it is unlikely that the varices are the primary source of bleeding. It is not surprising that the mesenteric angiogram did not show a source of bleeding, because this study requires active bleeding at a sufficient rate to radiographically identify the source.
The leading diagnosis remains an as yet uncharacterized small bowel bleeding source related to mesenteric thrombotic disease. Cross‐sectional imaging with IV contrast to identify significant vascular occlusion should be the next diagnostic step. Capsule endoscopy would be a more expensive and time‐consuming option, and although this could reveal the source of bleeding, it might not characterize the underlying vascular nature of the problem.
Due to persistent abdominal pain, a CT without intravenous contrast was done on hospital day 10. This showed extensive collateral vessels along the chest and abdominal wall with a distended azygos vein. The study was otherwise unrevealing. Her bloody stools cleared, so she was discharged with a plan for capsule endoscopy and outpatient follow‐up with her gastroenterologist. On the day of discharge (hospital day 11), hemoglobin was 7.5 g/dL and she received an eighth unit of packed RBCs. Overt bleeding was absent.
As an outpatient, intermittent hematochezia and melena recurred. The capsule endoscopy showed active bleeding approximately 45 minutes after the capsule exited the stomach. The lesion was not precisely located or characterized, but was believed to be in the distal small bowel.
The capsule finding supports the growing body of evidence implicating a small bowel source of bleeding. Furthermore, the ongoing but slow rate of blood loss makes a venous bleed more likely than an arterial bleed. A CT scan was performed prior to capsule study, but this was done without intravenous contrast. The brief description of the CT findings emphasizes the subcutaneous venous changes; a contraindication to IV contrast is not mentioned. Certainly IV contrast would have been very helpful to characterize the mesenteric arterial and venous vasculature. If there is no contraindication, a repeat CT scan with IV contrast should be performed. If there is a contraindication to IV contrast, it would be beneficial to revisit the noncontrast study with the specific purpose of searching for clues suggesting mesenteric or portal thrombosis. If the source still remains unclear, the next steps should be to perform push enteroscopy to assess the small intestine from the luminal side and magnetic resonance angiogram with venous phase imaging (or CT venogram if there is no contraindication to contrast) to evaluate the venous circulation.
The patient was readmitted 9 days after discharge with persistent melena and hematochezia. Her hemoglobin was 7.2 g/dL. Given the lack of a diagnosis, the patient was transferred to a tertiary care hospital, where a second colonoscopy and mesenteric angiogram were negative for bleeding. Small bowel enteroscopy showed no source of bleeding up to 60 cm past the pylorus. A third colonoscopy was performed due to recurrent bleeding; this showed a large amount of dark blood and clots throughout the entire colon including the cecum (Figure 2). After copious irrigation, the underlying mucosa was seen to be normal. At this point, a CT angiogram with both venous and arterial phases was done due to the high suspicion for a distal jejunal bleeding source. The CT angiogram showed numerous venous collaterals encasing a loop of midsmall bowel demonstrating progressive submucosal venous enhancement. In addition, a venous collateral ran down the right side of the sternum to the infraumbilical area and drained through the encasing collaterals into the portal venous system (Figure 3). The CT scan also revealed IVC obstruction below the distal IVC filter and an enlarged portal vein measuring 18 mm (normal <12 mm).
The CT angiogram provides much‐needed clarity. The continued bleeding is likely due to ectopic varices in the small bowel. The venous phase of the CT angiogram shows thrombosis of key venous structures and evidence of a dilated portal vein (indicating portal hypertension) leading to ectopic varices in the abdominal wall and jejunum. Given the prior studies that suggest a small bowel source of bleeding, jejunal varices are the most likely cause of recurrent GI bleeding in this patient.
The patient underwent exploratory laparotomy. Loops of small bowel were found to be adherent to the hysterectomy scar. There were many venous collaterals from the abdominal wall to these loops of bowel, dilating the veins both in intestinal walls and those in the adjacent mesentery. After clamping these veins, the small bowel was detached from the abdominal wall. On unclamping, the collaterals bled with a high venous pressure. Because these systemic‐portal shunts were responsible for the bleeding, the collaterals were sutured, stopping the bleeding. Thus, partial small bowel resection was not necessary. Postoperatively, her bleeding resolved completely and she maintained normal hemoglobin at 1‐year follow‐up.
COMMENTARY
The axiom common ailments are encountered most frequently underpins the classical stepwise approach to GI bleeding. First, a focused history helps localize the source of bleeding to the upper or lower GI tract. Next, endoscopy is performed to identify and treat the cause of bleeding. Finally, advanced tests such as angiography and capsule endoscopy are performed if needed. For this patient, following the usual algorithm failed to make the diagnosis or stop the bleeding. Despite historical and examination features suggesting that her case fell outside of the common patterns of GI bleeding, this patient underwent 3 upper endoscopies, 3 colonoscopies, a capsule endoscopy, a technetium‐tagged RBC study, 2 mesenteric angiograms, and a noncontrast CT scan before the study that was ultimately diagnostic was performed. The clinicians caring for this patient struggled to incorporate the atypical features of her history and presentation and failed to take an earlier detour from the usual algorithm. Instead, the same studies that had not previously led to the diagnosis were repeated multiple times.
Ectopic varices are enlarged portosystemic venous collaterals located anywhere outside the gastroesophageal region.[1] They occur in the setting of portal hypertension, surgical procedures involving abdominal viscera and vasculature, and venous occlusion. Ectopic varices account for 4% to 5% of all variceal bleeding episodes.[1] The most common sites include the anorectal junction (44%), duodenum (17%33%), jejunum/emleum (5%17%), colon (3.5%14%), and sites of previous abdominal surgery.[2, 3] Ectopic varices can cause either luminal or extraluminal (i.e., peritoneal) bleeding.[3] Luminal bleeding, seen in this case, is caused by venous protrusion into the submucosa. Ectopic varices present as a slow venous ooze, which explains this patient's ongoing requirement for recurrent blood transfusions.[4]
In this patient, submucosal ectopic varices developed as a result of a combination of known risk factors: portal hypertension in the setting of chronic venous occlusion from her hypercoagulability and a history of abdominal surgery (hysterectomy). [5] The apposition of her abdominal wall structures (drained by the systemic veins) to the bowel (drained by the portal veins) resulted in adhesion formation, detour of venous flow, collateralization, and submucosal varix formation.[1, 2, 6]
The key diagnostic study for this patient was a CT angiogram, with both arterial and venous phases. The prior 2 mesenteric angiograms had been limited to the arterial phase, which had missed identifying the venous abnormalities altogether. This highlights an important lesson from this case: contrast‐enhanced CT may have a higher yield in diagnosing ectopic varices compared to repeated endoscopiesespecially when captured in the late venous phaseand should strongly be considered for unexplained bleeding in patients with stigmata of liver disease or portal hypertension.[7, 8] Another clue for ectopic varices in a bleeding patient are nonbleeding esophageal or gastric varices, as was the case in this patient.[9]
The initial management of ectopic varices is similar to bleeding secondary to esophageal varices.[1] Definitive treatment includes endoscopic embolization or ligation, interventional radiological procedures such as portosystemic shunting or percutaneous embolization, and exploratory laparotomy to either resect the segment of bowel that is the source of bleeding or to decompress the collaterals surgically.[9] Although endoscopic ligation has been shown to have a lower rebleeding rate and mortality compared to endoscopic injection sclerotherapy in patients with esophageal varices, the data are too sparse in jejunal varices to recommend 1 treatment over another. Both have been used successfully either alone or in combination with each other, and can be useful alternatives for patients who are unable to undergo laparotomy.[9]
Diagnostic errors due to cognitive biases can be avoided by following diagnostic algorithms. However, over‐reliance on algorithms can result in vertical line failure, a form of cognitive bias in which the clinician subconsciously adheres to an inflexible diagnostic approach.[10] To overcome this bias, clinicians need to think laterally and consider alternative diagnoses when algorithms do not lead to expected outcomes. This case highlights the challenges of knowing when to break free of conventional approaches and the rewards of taking a well‐chosen detour that leads to the diagnosis.
KEY POINTS
- Recurrent, occult gastrointestinal bleeding should raise concern for a small bowel source, and clinicians may need to take a detour away from the usual workup to arrive at a diagnosis.
- CT angiography of the abdomen and pelvis may miss venous sources of bleeding, unless a venous phase is specifically requested.
- Ectopic varices can occur in patients with portal hypertension who have had a history of abdominal surgery; these patients can develop venous collaterals for decompression into the systemic circulation through the abdominal wall.
Disclosure
Nothing to report.
A 60‐year‐old woman presented to a community hospital's emergency department with 4 days of right‐sided abdominal pain and multiple episodes of black stools. She reported nausea without vomiting. She denied light‐headedness, chest pain, or shortness of breath. She also denied difficulty in swallowing, weight loss, jaundice, or other bleeding.
The first priority when assessing a patient with gastrointestinal (GI) bleeding is to ensure hemodynamic stability. Next, it is important to carefully characterize the stools to help narrow the differential diagnosis. As blood is a cathartic, frequent, loose, and black stools suggest vigorous bleeding. It is essential to establish that the stools are actually black, as some patients will mistake dark brown stools for melena. Using a visual aid like a black pen or shoes as a point of reference can help the patient differentiate between dark stool and melena. It is also important to obtain a thorough medication history because iron supplements or bismuth‐containing remedies can turn stool black. The use of any antiplatelet agents or anticoagulants should also be noted. The right‐sided abdominal pain should be characterized by establishing the frequency, severity, and association with eating, movement, and position. For this patient's presentation, increased pain with eating would rapidly heighten concern for mesenteric ischemia.
The patient reported having 1 to 2 semiformed, tarry, black bowel movements per day. The night prior to admission she had passed some bright red blood along with the melena. The abdominal pain had increased gradually over 4 days, was dull, constant, did not radiate, and there were no evident aggravating or relieving factors. She rated the pain as 4 out of 10 in intensity, worst in her right upper quadrant.
Her past medical history was notable for recurrent deep venous thromboses and pulmonary emboli that had occurred even while on oral anticoagulation. Inferior vena cava (IVC) filters had twice been placed many years prior; anticoagulation had been subsequently discontinued. Additionally, she was known to have chronic superior vena cava (SVC) occlusion, presumably related to hypercoagulability. Previous evaluation had identified only hyperhomocysteinemia as a risk factor for recurrent thromboses. Other medical problems included hemorrhoids, gastroesophageal reflux disease, and asthma. Her only surgical history was an abdominal hysterectomy and bilateral oophorectomy many years ago for nonmalignant disease. Home medications were omeprazole, ranitidine, albuterol, and fluticasone‐salmeterol. She denied using nonsteroidal anti‐inflammatory drugs, aspirin, or any dietary supplements. She denied smoking, alcohol, or recreational drug use.
Because melena is confirmed, an upper GI tract bleeding source is most likely. The more recent appearance of bright red blood is concerning for acceleration of bleeding, or may point to a distal small bowel or right colonic source. Given the history of thromboembolic disease and likely underlying hypercoagulability, vascular occlusion is a leading possibility. Thus, mesenteric arterial insufficiency or mesenteric venous thrombosis should be considered, even though the patient does not report the characteristic postprandial exacerbation of pain. Ischemic colitis due to arterial insufficiency typically presents with severe, acute pain, with or without hematochezia. This syndrome is typically manifested in vascular watershed areas such as the splenic flexure, but can also affect the right colon. Mesenteric venous thrombosis is a rare condition that most often occurs in patients with hypercoagulability. Patients present with variable degrees of abdominal pain and often with GI bleeding. Finally, portal venous thrombosis may be seen alongside thromboses of other mesenteric veins or may occur independently. Portal hypertension due to portal vein thrombosis can result in esophageal and/or gastric varices. Although variceal bleeding classically presents with dramatic hematemesis, the absence of hematemesis does not rule out a variceal bleed in this patient.
On physical examination, the patient had a temperature of 37.1C with a pulse of 90 beats per minute and blood pressure of 161/97 mm Hg. Orthostatics were not performed. No blood was seen on nasal and oropharyngeal exam. Respiratory and cardiovascular exams were normal. On abdominal exam, there was tenderness to palpation of the right upper quadrant without rebound or guarding. The spleen and the liver were not palpable. There was a lower midline incisional scar. Rectal exam revealed nonbleeding hemorrhoids and heme‐positive stool without gross blood. Bilateral lower extremities had trace pitting edema, hyperpigmentation, and superficial venous varicosities. On skin exam, there were distended subcutaneous veins radiating outward from around the umbilicus as well as prominent subcutaneous venous collaterals over the chest and lateral abdomen.
The collateral veins over the chest and lateral abdomen are consistent with central venous obstruction from the patient's known SVC thrombus. However, the presence of paraumbilical venous collaterals (caput medusa) is highly suggestive of portal hypertension. This evidence, in addition to the known central venous occlusion and history of thromboembolic disease, raises the suspicion for mesenteric thrombosis as a cause of her bleeding and pain. The first diagnostic procedure should be an esophagogastroduodenoscopy (EGD) to identify and potentially treat the source of bleeding, whether it is portal hypertension related (portal gastropathy, variceal bleed) or from a more common cause (peptic ulcer disease, stress gastritis). If the EGD is not diagnostic, the next step should be to obtain computed tomography (CT) of the abdomen and pelvis with intravenous (IV) and oral contrast. In many patients with GI bleed, a colonoscopy would typically be performed as the next diagnostic study after EGD. However, in this patient, a CT scan is likely to be of higher yield because it could help assess the mesenteric and portal vessels for patency and characterize the appearance of the small intestine and colon. Depending on the findings of the CT, additional dedicated vascular diagnostics might be needed.
Hemoglobin was 8.5 g/dL (12.4 g/dL 6 weeks prior) with a normal mean corpuscular volume and red cell distribution. The white cell count was normal, and the platelet count was 142,000/mm3. The blood urea nitrogen was 27 mg/dL, with a creatinine of 1.1 mg/dL. Routine chemistries, liver enzymes, bilirubin, and coagulation parameters were normal. Ferritin was 15 ng/mL (normal: 15200 ng/mL).
The patient was admitted to the intensive care unit. An EGD revealed a hiatal hernia and grade II nonbleeding esophageal varices with normal=appearing stomach and duodenum. The varices did not have stigmata of a recent bleed and were not ligated. The patient continued to bleed and received 2 U of packed red blood cells (RBCs), as her hemoglobin had decreased to 7.3 g/dL. On hospital day 3, a colonoscopy was done that showed blood clots in the ascending colon but was otherwise normal. The patient had ongoing abdominal pain, melena, and hematochezia, and continued to require blood transfusions every other day.
Esophageal varices were confirmed on EGD. However, no high‐risk stigmata were seen. Findings that suggest either recent bleeding or are risk factors for subsequent bleeding include large size of the varices, nipple sign referring to a protruding vessel from an underlying varix, or red wale sign, referring to a longitudinal red streak on a varix. The lack of evidence for an esophageal, gastric, or duodenal bleeding source correlates with lack of clinical signs of upper GI tract hemorrhage such as hematemesis or coffee ground emesis. Because the colonoscopy also did not identify a bleeding source, the bleeding remains unexplained. The absence of significant abnormalities in liver function or liver inflammation labs suggests that the patient does not have advanced cirrhosis and supports the suspicion of a vascular cause of the portal hypertension. At this point, it would be most useful to obtain a CT scan of the abdomen and pelvis.
The patient continued to bleed, requiring a total of 7 U of packed RBCs over 7 days. On hospital day 4, a repeat EGD showed nonbleeding varices with a red wale sign that were banded. Despite this, the hemoglobin continued to drop. A technetium‐tagged RBC study showed a small area of subumbilical activity, which appeared to indicate transverse colonic or small bowel bleeding (Figure 1). A subsequent mesenteric angiogram failed to show active bleeding.
A red wale sign confers a higher risk of bleeding from esophageal varices. However, this finding can be subjective, and the endoscopist must individualize the decision for banding based on the size and appearance of the varices. It was reasonable to proceed with banding this time because the varices were large, had a red wale sign, and there was otherwise unexplained ongoing bleeding. Because her hemoglobin continued to drop after the banding and a tagged RBC study best localized the bleeding to the small intestine or transverse colon, it is unlikely that the varices are the primary source of bleeding. It is not surprising that the mesenteric angiogram did not show a source of bleeding, because this study requires active bleeding at a sufficient rate to radiographically identify the source.
The leading diagnosis remains an as yet uncharacterized small bowel bleeding source related to mesenteric thrombotic disease. Cross‐sectional imaging with IV contrast to identify significant vascular occlusion should be the next diagnostic step. Capsule endoscopy would be a more expensive and time‐consuming option, and although this could reveal the source of bleeding, it might not characterize the underlying vascular nature of the problem.
Due to persistent abdominal pain, a CT without intravenous contrast was done on hospital day 10. This showed extensive collateral vessels along the chest and abdominal wall with a distended azygos vein. The study was otherwise unrevealing. Her bloody stools cleared, so she was discharged with a plan for capsule endoscopy and outpatient follow‐up with her gastroenterologist. On the day of discharge (hospital day 11), hemoglobin was 7.5 g/dL and she received an eighth unit of packed RBCs. Overt bleeding was absent.
As an outpatient, intermittent hematochezia and melena recurred. The capsule endoscopy showed active bleeding approximately 45 minutes after the capsule exited the stomach. The lesion was not precisely located or characterized, but was believed to be in the distal small bowel.
The capsule finding supports the growing body of evidence implicating a small bowel source of bleeding. Furthermore, the ongoing but slow rate of blood loss makes a venous bleed more likely than an arterial bleed. A CT scan was performed prior to capsule study, but this was done without intravenous contrast. The brief description of the CT findings emphasizes the subcutaneous venous changes; a contraindication to IV contrast is not mentioned. Certainly IV contrast would have been very helpful to characterize the mesenteric arterial and venous vasculature. If there is no contraindication, a repeat CT scan with IV contrast should be performed. If there is a contraindication to IV contrast, it would be beneficial to revisit the noncontrast study with the specific purpose of searching for clues suggesting mesenteric or portal thrombosis. If the source still remains unclear, the next steps should be to perform push enteroscopy to assess the small intestine from the luminal side and magnetic resonance angiogram with venous phase imaging (or CT venogram if there is no contraindication to contrast) to evaluate the venous circulation.
The patient was readmitted 9 days after discharge with persistent melena and hematochezia. Her hemoglobin was 7.2 g/dL. Given the lack of a diagnosis, the patient was transferred to a tertiary care hospital, where a second colonoscopy and mesenteric angiogram were negative for bleeding. Small bowel enteroscopy showed no source of bleeding up to 60 cm past the pylorus. A third colonoscopy was performed due to recurrent bleeding; this showed a large amount of dark blood and clots throughout the entire colon including the cecum (Figure 2). After copious irrigation, the underlying mucosa was seen to be normal. At this point, a CT angiogram with both venous and arterial phases was done due to the high suspicion for a distal jejunal bleeding source. The CT angiogram showed numerous venous collaterals encasing a loop of midsmall bowel demonstrating progressive submucosal venous enhancement. In addition, a venous collateral ran down the right side of the sternum to the infraumbilical area and drained through the encasing collaterals into the portal venous system (Figure 3). The CT scan also revealed IVC obstruction below the distal IVC filter and an enlarged portal vein measuring 18 mm (normal <12 mm).
The CT angiogram provides much‐needed clarity. The continued bleeding is likely due to ectopic varices in the small bowel. The venous phase of the CT angiogram shows thrombosis of key venous structures and evidence of a dilated portal vein (indicating portal hypertension) leading to ectopic varices in the abdominal wall and jejunum. Given the prior studies that suggest a small bowel source of bleeding, jejunal varices are the most likely cause of recurrent GI bleeding in this patient.
The patient underwent exploratory laparotomy. Loops of small bowel were found to be adherent to the hysterectomy scar. There were many venous collaterals from the abdominal wall to these loops of bowel, dilating the veins both in intestinal walls and those in the adjacent mesentery. After clamping these veins, the small bowel was detached from the abdominal wall. On unclamping, the collaterals bled with a high venous pressure. Because these systemic‐portal shunts were responsible for the bleeding, the collaterals were sutured, stopping the bleeding. Thus, partial small bowel resection was not necessary. Postoperatively, her bleeding resolved completely and she maintained normal hemoglobin at 1‐year follow‐up.
COMMENTARY
The axiom common ailments are encountered most frequently underpins the classical stepwise approach to GI bleeding. First, a focused history helps localize the source of bleeding to the upper or lower GI tract. Next, endoscopy is performed to identify and treat the cause of bleeding. Finally, advanced tests such as angiography and capsule endoscopy are performed if needed. For this patient, following the usual algorithm failed to make the diagnosis or stop the bleeding. Despite historical and examination features suggesting that her case fell outside of the common patterns of GI bleeding, this patient underwent 3 upper endoscopies, 3 colonoscopies, a capsule endoscopy, a technetium‐tagged RBC study, 2 mesenteric angiograms, and a noncontrast CT scan before the study that was ultimately diagnostic was performed. The clinicians caring for this patient struggled to incorporate the atypical features of her history and presentation and failed to take an earlier detour from the usual algorithm. Instead, the same studies that had not previously led to the diagnosis were repeated multiple times.
Ectopic varices are enlarged portosystemic venous collaterals located anywhere outside the gastroesophageal region.[1] They occur in the setting of portal hypertension, surgical procedures involving abdominal viscera and vasculature, and venous occlusion. Ectopic varices account for 4% to 5% of all variceal bleeding episodes.[1] The most common sites include the anorectal junction (44%), duodenum (17%33%), jejunum/emleum (5%17%), colon (3.5%14%), and sites of previous abdominal surgery.[2, 3] Ectopic varices can cause either luminal or extraluminal (i.e., peritoneal) bleeding.[3] Luminal bleeding, seen in this case, is caused by venous protrusion into the submucosa. Ectopic varices present as a slow venous ooze, which explains this patient's ongoing requirement for recurrent blood transfusions.[4]
In this patient, submucosal ectopic varices developed as a result of a combination of known risk factors: portal hypertension in the setting of chronic venous occlusion from her hypercoagulability and a history of abdominal surgery (hysterectomy). [5] The apposition of her abdominal wall structures (drained by the systemic veins) to the bowel (drained by the portal veins) resulted in adhesion formation, detour of venous flow, collateralization, and submucosal varix formation.[1, 2, 6]
The key diagnostic study for this patient was a CT angiogram, with both arterial and venous phases. The prior 2 mesenteric angiograms had been limited to the arterial phase, which had missed identifying the venous abnormalities altogether. This highlights an important lesson from this case: contrast‐enhanced CT may have a higher yield in diagnosing ectopic varices compared to repeated endoscopiesespecially when captured in the late venous phaseand should strongly be considered for unexplained bleeding in patients with stigmata of liver disease or portal hypertension.[7, 8] Another clue for ectopic varices in a bleeding patient are nonbleeding esophageal or gastric varices, as was the case in this patient.[9]
The initial management of ectopic varices is similar to bleeding secondary to esophageal varices.[1] Definitive treatment includes endoscopic embolization or ligation, interventional radiological procedures such as portosystemic shunting or percutaneous embolization, and exploratory laparotomy to either resect the segment of bowel that is the source of bleeding or to decompress the collaterals surgically.[9] Although endoscopic ligation has been shown to have a lower rebleeding rate and mortality compared to endoscopic injection sclerotherapy in patients with esophageal varices, the data are too sparse in jejunal varices to recommend 1 treatment over another. Both have been used successfully either alone or in combination with each other, and can be useful alternatives for patients who are unable to undergo laparotomy.[9]
Diagnostic errors due to cognitive biases can be avoided by following diagnostic algorithms. However, over‐reliance on algorithms can result in vertical line failure, a form of cognitive bias in which the clinician subconsciously adheres to an inflexible diagnostic approach.[10] To overcome this bias, clinicians need to think laterally and consider alternative diagnoses when algorithms do not lead to expected outcomes. This case highlights the challenges of knowing when to break free of conventional approaches and the rewards of taking a well‐chosen detour that leads to the diagnosis.
KEY POINTS
- Recurrent, occult gastrointestinal bleeding should raise concern for a small bowel source, and clinicians may need to take a detour away from the usual workup to arrive at a diagnosis.
- CT angiography of the abdomen and pelvis may miss venous sources of bleeding, unless a venous phase is specifically requested.
- Ectopic varices can occur in patients with portal hypertension who have had a history of abdominal surgery; these patients can develop venous collaterals for decompression into the systemic circulation through the abdominal wall.
Disclosure
Nothing to report.
- , , . Updates in the pathogenesis, diagnosis and management of ectopic varices. Hepatol Int. 2008;2:322–334.
- , , . Management of ectopic varices. Hepatology. 1998;28:1154–1158.
- , , , et al. Current status of ectopic varices in Japan: results of a survey by the Japan Society for Portal Hypertension. Hepatol Res. 2010;40:763–766.
- , , . Stomal Varices: Management with decompression TIPS and transvenous obliteration or sclerosis. Tech Vasc Interv Radiol. 2013;16:126–134.
- , , , et al. Jejunal varices as a cause of massive gastrointestinal bleeding. Am J Gastroenterol. 1992;87:514–517.
- , . Ectopic varices in portal hypertension. Clin Gastroenterol. 1985;14:105–121.
- , , , et al. Ectopic varices in portal hypertension: computed tomographic angiography instead of repeated endoscopies for diagnosis. Eur J Gastroenterol Hepatol. 2011;23:620–622.
- , , , et al. ACR appropriateness criteria. Radiologic management of lower gastrointestinal tract bleeding. Reston, VA: American College of Radiology; 2011. Available at: http://www.acr.org/Quality‐Safety/Appropriateness‐Criteria/∼/media/5F9CB95C164E4DA19DCBCFBBA790BB3C.pdf. Accessed January 28, 2015.
- , . Diagnosis and management of ectopic varices. Gastrointest Interv. 2012;1:3–10.
- . Achieving quality in clinical decision making: cognitive strategies and detection of bias. Acad Emerg Med. 2002;9:1184–1204.
- , , . Updates in the pathogenesis, diagnosis and management of ectopic varices. Hepatol Int. 2008;2:322–334.
- , , . Management of ectopic varices. Hepatology. 1998;28:1154–1158.
- , , , et al. Current status of ectopic varices in Japan: results of a survey by the Japan Society for Portal Hypertension. Hepatol Res. 2010;40:763–766.
- , , . Stomal Varices: Management with decompression TIPS and transvenous obliteration or sclerosis. Tech Vasc Interv Radiol. 2013;16:126–134.
- , , , et al. Jejunal varices as a cause of massive gastrointestinal bleeding. Am J Gastroenterol. 1992;87:514–517.
- , . Ectopic varices in portal hypertension. Clin Gastroenterol. 1985;14:105–121.
- , , , et al. Ectopic varices in portal hypertension: computed tomographic angiography instead of repeated endoscopies for diagnosis. Eur J Gastroenterol Hepatol. 2011;23:620–622.
- , , , et al. ACR appropriateness criteria. Radiologic management of lower gastrointestinal tract bleeding. Reston, VA: American College of Radiology; 2011. Available at: http://www.acr.org/Quality‐Safety/Appropriateness‐Criteria/∼/media/5F9CB95C164E4DA19DCBCFBBA790BB3C.pdf. Accessed January 28, 2015.
- , . Diagnosis and management of ectopic varices. Gastrointest Interv. 2012;1:3–10.
- . Achieving quality in clinical decision making: cognitive strategies and detection of bias. Acad Emerg Med. 2002;9:1184–1204.
Isotretinoin Treatment in Patients With Acne Vulgaris: Does It Impact Muscle Strength, Fatigue, and Endurance?
Isotretinoin is a vitamin A derivative that frequently is used in the treatment of acne vulgaris.1,2 Although isotretinoin generally is associated with favorable effects, adverse effects also have been reported.3-5 Musculoskeletal side effects can include myalgia, sacroiliitis, back pain, diffuse idiopathic skeletal hyperostosis, ligament and tendon calcifications, bone resorption, and reduced collagen synthesis.6,7 Elevated creatine kinase (CK) levels also have been reported in 15% to 50% of patients with isotretinoin-induced myalgia.8 However, there are limited data available on the effects of isotretinoin treatment on muscle strength. The objective of this study was to evaluate the impact of isotretinoin on muscle strength, fatigue, and endurance using an isokinetic dynamometer.
Methods
Study Design and Participants
The study followed a pretest-posttest design including 27 patients with acne vulgaris who were treated with oral isotretinoin (age range, 18–40 years) as well as 26 control patients for comparison. Exclusion criteria were renal or liver disease, uncontrolled hypertension, heart failure, malignancy, thyroid and bone disorders (eg, parathyroid disease, osteomalacia), use of drugs that can affect skeletal metabolism (eg, corticosteroids, heparin, anticonvulsants), and history of trauma to and/or surgery of the lower extremities. All patients were informed of the study procedure and informed consent was obtained. The study protocol was approved by the local ethics committee.
Data Collection
Participant demographics and clinical features (eg, sex, age, body mass index [BMI]) were obtained. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month, followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements of the knee muscles were performed on the nondominant side at baseline and at 3-month follow-up. Reports of muscular side effects were noted during the course of treatment.
Isokinetic Evaluation
A calibrated isokinetic dynamometer was used to conduct isokinetic evaluations. After performing 5 submaximal warm-up contractions, concentric peak torque (PT) values of the quadriceps and hamstrings at 60° and 180° per second angular velocities (AVs), hamstring strength to quadriceps strength ratio (H:Q ratio), and muscle fatigue were evaluated. The isokinetic test protocol included 10 repeats at 60° per second, 15 seconds of rest, and 15 repeats at 180° per second.
Statistical Analysis
Data analysis was conducted using SPSS software version 20.0. Data were expressed as mean (standard deviation [SD]). After checking normal distribution with the Kolmogorov-Smirnov test, independent t tests were used to compare the baseline parameters between the treatment and control groups. Paired t tests and Wilcoxon signed rank tests were used to compare baseline and posttreatment values where appropriate. The results were for those who completed treatment. Statistical significance was set at P<.05.
Results
Twenty-seven participants (24 female; 3 male) with newly diagnosed acne vulgaris were enrolled in the treatment group along with 26 controls (23 female; 3 male). One of the participants in the treatment group did not tolerate isotretinoin due to headache and was excluded from the study. The mean (SD) age of the participants was 20.6 (1.6) years for the treatment group and 21.3 (1.5) years for the control group, and the mean (SD) BMI for both groups was 21.8 (2.8) and 21.5 (1.8), respectively. Participant demographics and isokinetic values at baseline are presented in Table 1. No significant differences between the treatment and control groups for participant sex, age, or BMI were noted (P>.05).
Of the 26 participants in the treatment group, 5 reported myalgia and nonspecific back pain. Isokinetic measurements of the treatment group obtained using the dynamometer are shown in Table 2. Although the PT of the hamstring and quadriceps at both 60° and 180° per second AV was decreased at 3-month follow-up, there was no significant difference compared to baseline (P>.05). Additionally, no significant difference in H:Q ratio or muscle fatigue was noted (P>.05), and no significant difference in isokinetic measurements was seen in participants with myalgia (n=5) at 3-month follow-up versus baseline (P>.05).
Comment
This study aimed to investigate the short-term effects of isotretinoin treatment on muscle strength, fatigue, and endurance in patients with acne vulgaris, which has not been widely evaluated in the literature. Although maximal PT of the hamstring and quadriceps in the isotretinoin treatment group was decreased at 3-month follow-up, there was no statistically significant difference in all parameters (ie, PT at 60° and 180° per second, H:Q ratio, muscle fatigue) versus baseline. These findings showed that systemic isotretinoin was not associated with muscle dysfunction in this patient population.
Myalgia, particularly associated with exercise, has been seen in approximately 50% of patients treated with isotretinoin.6 Furthermore, Goulden et al9 reported that patients with higher CK levels might be at an increased risk for developing rhabdomyolysis in the setting of isotretinoin treatment. High CK levels indicate serious muscular cell damage and are usually associated with release of myoglobin from muscular cells.10 In the current study, 5 participants reported myalgia and nonspecific back pain at 3-month follow-up; however, no participants reported muscle weakness. Differences in the isokinetic measurements of participants with myalgia at baseline and at 3-month follow-up were not statistically significant.
Muscles mainly consist of type I (slow oxidative), type IIA (fast oxidative), and type IIB (fast glycolytic) muscle fibers. Type I fibers produce low force and high endurance, type IIB fibers produce high force and low endurance, and type IIA fibers fall in between the two. At low AVs (eg, 60° per second), only type II fibers contract. As the AV increases (eg, 180° per second), only type II fibers contract. Consequently, the observation of a decrease in the isokinetic test parameters at low or high AVs indicate the decrease in type I or type II contracting muscle fibers.11,12 In our study, the isokinetic values did not significantly change. As such, we concluded that isotretinoin treatment did not result in the reduction of muscle fibers in our patient population.
The H:Q ratio is the indicator of muscle balance and dynamic stabilization of the knee. It is calculated by dividing the PT of the hamstrings by the PT of the quadriceps in concentric motion.13 Additionally, muscle fatigue demonstrates the endurance of the contraction of type IIB fibers (anaerobic).14 In our study, isotretinoin treatment did not impact the H:Q ratio or muscle fatigue.
This study included a few important limitations. The sample size was small, particularly concerning the number of participants who reported myalgia. The lack of laboratory evaluations (eg, creatinine kinase) also was a limitation. Finally, the short study period limited the conclusions that could be drawn from the data.
Conclusion
Results from the current study revealed that systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance. Further studies taking into account histologic evaluations with larger sample sizes and long-term follow-up are needed.
1. Yıldızgören MT, Karatas Togral A, Baki AE, et al. Effects of isotretinoin treatment on cartilage and tendon thicknesses: an ultrasonographic study [published online ahead of print July 2, 2014]. Clin Rheumatol. doi:10.1007/s10067-014-2733-9.
2. Karatas Togral A, Yıldızgören MT, Mustu Koryürek Ö, et al. Can isotretinoin induce SAPHO syndrome? West Indian Med J. In press.
3. Yıldızgören MT, Ekiz T, Karatas Togral A. Bilateral sacroiliitis induced by systemic isotretinoin treatment. West Indian Med J. In press.
4. Chapman MS. Vitamin A: history, current uses, and controversies. Semin Cutan Med Surg. 2012;31:11-16.
5. Blasiak RC, Stamey CR, Burkhart CN, et al. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol. 2013;149:1392.
6. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83:191-201.
7. DiGiovanna JJ. Isotretinoin effects on bone. J Am Acad Dermatol. 2001;45:S176-S182.
8. Heudes AM, Laroche L. Muscular damage during isotretinoin treatment. Ann Dermatol Venereol. 1998;125:94-97.
9. Goulden V, Layton AM, Cunliffe WJ. Long term safety of isotretinoin as a treatment for acne vulgaris. Br J Dermatol. 1994;131:360-363.
10. Fiallo P, Tagliapietra AG. Severe acute myopathy induced by isotretinoin. Arch Dermatol. 1996;132:1521-1522.
11. Impellizzeri FM, Bizzini M, Rampinini E, et al. Reliability of isokinetic strength imbalance ratios measured using the Cybex NORM dynamometer.
Clin Physiol Funct Imaging. 2008;28:113-119.
12. Brown LE. Isokinetics in Human Performance. Champaign, IL: Human Kinetics; 2000.
13. Alangari AS, Al-Hazzaa HM. Normal isometric and isokinetic peak torques of hamstring and quadriceps muscles in young adult Saudi males. Neurosciences (Riyadh). 2004;9:165-170.
14. Pincivero DM, Gear WS, Sterner RL, et al. Gender differences in the relationship between quadriceps work and fatigue during high intensity exercise. J Strength Cond Res. 2000;14:202-206.
Isotretinoin is a vitamin A derivative that frequently is used in the treatment of acne vulgaris.1,2 Although isotretinoin generally is associated with favorable effects, adverse effects also have been reported.3-5 Musculoskeletal side effects can include myalgia, sacroiliitis, back pain, diffuse idiopathic skeletal hyperostosis, ligament and tendon calcifications, bone resorption, and reduced collagen synthesis.6,7 Elevated creatine kinase (CK) levels also have been reported in 15% to 50% of patients with isotretinoin-induced myalgia.8 However, there are limited data available on the effects of isotretinoin treatment on muscle strength. The objective of this study was to evaluate the impact of isotretinoin on muscle strength, fatigue, and endurance using an isokinetic dynamometer.
Methods
Study Design and Participants
The study followed a pretest-posttest design including 27 patients with acne vulgaris who were treated with oral isotretinoin (age range, 18–40 years) as well as 26 control patients for comparison. Exclusion criteria were renal or liver disease, uncontrolled hypertension, heart failure, malignancy, thyroid and bone disorders (eg, parathyroid disease, osteomalacia), use of drugs that can affect skeletal metabolism (eg, corticosteroids, heparin, anticonvulsants), and history of trauma to and/or surgery of the lower extremities. All patients were informed of the study procedure and informed consent was obtained. The study protocol was approved by the local ethics committee.
Data Collection
Participant demographics and clinical features (eg, sex, age, body mass index [BMI]) were obtained. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month, followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements of the knee muscles were performed on the nondominant side at baseline and at 3-month follow-up. Reports of muscular side effects were noted during the course of treatment.
Isokinetic Evaluation
A calibrated isokinetic dynamometer was used to conduct isokinetic evaluations. After performing 5 submaximal warm-up contractions, concentric peak torque (PT) values of the quadriceps and hamstrings at 60° and 180° per second angular velocities (AVs), hamstring strength to quadriceps strength ratio (H:Q ratio), and muscle fatigue were evaluated. The isokinetic test protocol included 10 repeats at 60° per second, 15 seconds of rest, and 15 repeats at 180° per second.
Statistical Analysis
Data analysis was conducted using SPSS software version 20.0. Data were expressed as mean (standard deviation [SD]). After checking normal distribution with the Kolmogorov-Smirnov test, independent t tests were used to compare the baseline parameters between the treatment and control groups. Paired t tests and Wilcoxon signed rank tests were used to compare baseline and posttreatment values where appropriate. The results were for those who completed treatment. Statistical significance was set at P<.05.
Results
Twenty-seven participants (24 female; 3 male) with newly diagnosed acne vulgaris were enrolled in the treatment group along with 26 controls (23 female; 3 male). One of the participants in the treatment group did not tolerate isotretinoin due to headache and was excluded from the study. The mean (SD) age of the participants was 20.6 (1.6) years for the treatment group and 21.3 (1.5) years for the control group, and the mean (SD) BMI for both groups was 21.8 (2.8) and 21.5 (1.8), respectively. Participant demographics and isokinetic values at baseline are presented in Table 1. No significant differences between the treatment and control groups for participant sex, age, or BMI were noted (P>.05).
Of the 26 participants in the treatment group, 5 reported myalgia and nonspecific back pain. Isokinetic measurements of the treatment group obtained using the dynamometer are shown in Table 2. Although the PT of the hamstring and quadriceps at both 60° and 180° per second AV was decreased at 3-month follow-up, there was no significant difference compared to baseline (P>.05). Additionally, no significant difference in H:Q ratio or muscle fatigue was noted (P>.05), and no significant difference in isokinetic measurements was seen in participants with myalgia (n=5) at 3-month follow-up versus baseline (P>.05).
Comment
This study aimed to investigate the short-term effects of isotretinoin treatment on muscle strength, fatigue, and endurance in patients with acne vulgaris, which has not been widely evaluated in the literature. Although maximal PT of the hamstring and quadriceps in the isotretinoin treatment group was decreased at 3-month follow-up, there was no statistically significant difference in all parameters (ie, PT at 60° and 180° per second, H:Q ratio, muscle fatigue) versus baseline. These findings showed that systemic isotretinoin was not associated with muscle dysfunction in this patient population.
Myalgia, particularly associated with exercise, has been seen in approximately 50% of patients treated with isotretinoin.6 Furthermore, Goulden et al9 reported that patients with higher CK levels might be at an increased risk for developing rhabdomyolysis in the setting of isotretinoin treatment. High CK levels indicate serious muscular cell damage and are usually associated with release of myoglobin from muscular cells.10 In the current study, 5 participants reported myalgia and nonspecific back pain at 3-month follow-up; however, no participants reported muscle weakness. Differences in the isokinetic measurements of participants with myalgia at baseline and at 3-month follow-up were not statistically significant.
Muscles mainly consist of type I (slow oxidative), type IIA (fast oxidative), and type IIB (fast glycolytic) muscle fibers. Type I fibers produce low force and high endurance, type IIB fibers produce high force and low endurance, and type IIA fibers fall in between the two. At low AVs (eg, 60° per second), only type II fibers contract. As the AV increases (eg, 180° per second), only type II fibers contract. Consequently, the observation of a decrease in the isokinetic test parameters at low or high AVs indicate the decrease in type I or type II contracting muscle fibers.11,12 In our study, the isokinetic values did not significantly change. As such, we concluded that isotretinoin treatment did not result in the reduction of muscle fibers in our patient population.
The H:Q ratio is the indicator of muscle balance and dynamic stabilization of the knee. It is calculated by dividing the PT of the hamstrings by the PT of the quadriceps in concentric motion.13 Additionally, muscle fatigue demonstrates the endurance of the contraction of type IIB fibers (anaerobic).14 In our study, isotretinoin treatment did not impact the H:Q ratio or muscle fatigue.
This study included a few important limitations. The sample size was small, particularly concerning the number of participants who reported myalgia. The lack of laboratory evaluations (eg, creatinine kinase) also was a limitation. Finally, the short study period limited the conclusions that could be drawn from the data.
Conclusion
Results from the current study revealed that systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance. Further studies taking into account histologic evaluations with larger sample sizes and long-term follow-up are needed.
Isotretinoin is a vitamin A derivative that frequently is used in the treatment of acne vulgaris.1,2 Although isotretinoin generally is associated with favorable effects, adverse effects also have been reported.3-5 Musculoskeletal side effects can include myalgia, sacroiliitis, back pain, diffuse idiopathic skeletal hyperostosis, ligament and tendon calcifications, bone resorption, and reduced collagen synthesis.6,7 Elevated creatine kinase (CK) levels also have been reported in 15% to 50% of patients with isotretinoin-induced myalgia.8 However, there are limited data available on the effects of isotretinoin treatment on muscle strength. The objective of this study was to evaluate the impact of isotretinoin on muscle strength, fatigue, and endurance using an isokinetic dynamometer.
Methods
Study Design and Participants
The study followed a pretest-posttest design including 27 patients with acne vulgaris who were treated with oral isotretinoin (age range, 18–40 years) as well as 26 control patients for comparison. Exclusion criteria were renal or liver disease, uncontrolled hypertension, heart failure, malignancy, thyroid and bone disorders (eg, parathyroid disease, osteomalacia), use of drugs that can affect skeletal metabolism (eg, corticosteroids, heparin, anticonvulsants), and history of trauma to and/or surgery of the lower extremities. All patients were informed of the study procedure and informed consent was obtained. The study protocol was approved by the local ethics committee.
Data Collection
Participant demographics and clinical features (eg, sex, age, body mass index [BMI]) were obtained. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month, followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements of the knee muscles were performed on the nondominant side at baseline and at 3-month follow-up. Reports of muscular side effects were noted during the course of treatment.
Isokinetic Evaluation
A calibrated isokinetic dynamometer was used to conduct isokinetic evaluations. After performing 5 submaximal warm-up contractions, concentric peak torque (PT) values of the quadriceps and hamstrings at 60° and 180° per second angular velocities (AVs), hamstring strength to quadriceps strength ratio (H:Q ratio), and muscle fatigue were evaluated. The isokinetic test protocol included 10 repeats at 60° per second, 15 seconds of rest, and 15 repeats at 180° per second.
Statistical Analysis
Data analysis was conducted using SPSS software version 20.0. Data were expressed as mean (standard deviation [SD]). After checking normal distribution with the Kolmogorov-Smirnov test, independent t tests were used to compare the baseline parameters between the treatment and control groups. Paired t tests and Wilcoxon signed rank tests were used to compare baseline and posttreatment values where appropriate. The results were for those who completed treatment. Statistical significance was set at P<.05.
Results
Twenty-seven participants (24 female; 3 male) with newly diagnosed acne vulgaris were enrolled in the treatment group along with 26 controls (23 female; 3 male). One of the participants in the treatment group did not tolerate isotretinoin due to headache and was excluded from the study. The mean (SD) age of the participants was 20.6 (1.6) years for the treatment group and 21.3 (1.5) years for the control group, and the mean (SD) BMI for both groups was 21.8 (2.8) and 21.5 (1.8), respectively. Participant demographics and isokinetic values at baseline are presented in Table 1. No significant differences between the treatment and control groups for participant sex, age, or BMI were noted (P>.05).
Of the 26 participants in the treatment group, 5 reported myalgia and nonspecific back pain. Isokinetic measurements of the treatment group obtained using the dynamometer are shown in Table 2. Although the PT of the hamstring and quadriceps at both 60° and 180° per second AV was decreased at 3-month follow-up, there was no significant difference compared to baseline (P>.05). Additionally, no significant difference in H:Q ratio or muscle fatigue was noted (P>.05), and no significant difference in isokinetic measurements was seen in participants with myalgia (n=5) at 3-month follow-up versus baseline (P>.05).
Comment
This study aimed to investigate the short-term effects of isotretinoin treatment on muscle strength, fatigue, and endurance in patients with acne vulgaris, which has not been widely evaluated in the literature. Although maximal PT of the hamstring and quadriceps in the isotretinoin treatment group was decreased at 3-month follow-up, there was no statistically significant difference in all parameters (ie, PT at 60° and 180° per second, H:Q ratio, muscle fatigue) versus baseline. These findings showed that systemic isotretinoin was not associated with muscle dysfunction in this patient population.
Myalgia, particularly associated with exercise, has been seen in approximately 50% of patients treated with isotretinoin.6 Furthermore, Goulden et al9 reported that patients with higher CK levels might be at an increased risk for developing rhabdomyolysis in the setting of isotretinoin treatment. High CK levels indicate serious muscular cell damage and are usually associated with release of myoglobin from muscular cells.10 In the current study, 5 participants reported myalgia and nonspecific back pain at 3-month follow-up; however, no participants reported muscle weakness. Differences in the isokinetic measurements of participants with myalgia at baseline and at 3-month follow-up were not statistically significant.
Muscles mainly consist of type I (slow oxidative), type IIA (fast oxidative), and type IIB (fast glycolytic) muscle fibers. Type I fibers produce low force and high endurance, type IIB fibers produce high force and low endurance, and type IIA fibers fall in between the two. At low AVs (eg, 60° per second), only type II fibers contract. As the AV increases (eg, 180° per second), only type II fibers contract. Consequently, the observation of a decrease in the isokinetic test parameters at low or high AVs indicate the decrease in type I or type II contracting muscle fibers.11,12 In our study, the isokinetic values did not significantly change. As such, we concluded that isotretinoin treatment did not result in the reduction of muscle fibers in our patient population.
The H:Q ratio is the indicator of muscle balance and dynamic stabilization of the knee. It is calculated by dividing the PT of the hamstrings by the PT of the quadriceps in concentric motion.13 Additionally, muscle fatigue demonstrates the endurance of the contraction of type IIB fibers (anaerobic).14 In our study, isotretinoin treatment did not impact the H:Q ratio or muscle fatigue.
This study included a few important limitations. The sample size was small, particularly concerning the number of participants who reported myalgia. The lack of laboratory evaluations (eg, creatinine kinase) also was a limitation. Finally, the short study period limited the conclusions that could be drawn from the data.
Conclusion
Results from the current study revealed that systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance. Further studies taking into account histologic evaluations with larger sample sizes and long-term follow-up are needed.
1. Yıldızgören MT, Karatas Togral A, Baki AE, et al. Effects of isotretinoin treatment on cartilage and tendon thicknesses: an ultrasonographic study [published online ahead of print July 2, 2014]. Clin Rheumatol. doi:10.1007/s10067-014-2733-9.
2. Karatas Togral A, Yıldızgören MT, Mustu Koryürek Ö, et al. Can isotretinoin induce SAPHO syndrome? West Indian Med J. In press.
3. Yıldızgören MT, Ekiz T, Karatas Togral A. Bilateral sacroiliitis induced by systemic isotretinoin treatment. West Indian Med J. In press.
4. Chapman MS. Vitamin A: history, current uses, and controversies. Semin Cutan Med Surg. 2012;31:11-16.
5. Blasiak RC, Stamey CR, Burkhart CN, et al. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol. 2013;149:1392.
6. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83:191-201.
7. DiGiovanna JJ. Isotretinoin effects on bone. J Am Acad Dermatol. 2001;45:S176-S182.
8. Heudes AM, Laroche L. Muscular damage during isotretinoin treatment. Ann Dermatol Venereol. 1998;125:94-97.
9. Goulden V, Layton AM, Cunliffe WJ. Long term safety of isotretinoin as a treatment for acne vulgaris. Br J Dermatol. 1994;131:360-363.
10. Fiallo P, Tagliapietra AG. Severe acute myopathy induced by isotretinoin. Arch Dermatol. 1996;132:1521-1522.
11. Impellizzeri FM, Bizzini M, Rampinini E, et al. Reliability of isokinetic strength imbalance ratios measured using the Cybex NORM dynamometer.
Clin Physiol Funct Imaging. 2008;28:113-119.
12. Brown LE. Isokinetics in Human Performance. Champaign, IL: Human Kinetics; 2000.
13. Alangari AS, Al-Hazzaa HM. Normal isometric and isokinetic peak torques of hamstring and quadriceps muscles in young adult Saudi males. Neurosciences (Riyadh). 2004;9:165-170.
14. Pincivero DM, Gear WS, Sterner RL, et al. Gender differences in the relationship between quadriceps work and fatigue during high intensity exercise. J Strength Cond Res. 2000;14:202-206.
1. Yıldızgören MT, Karatas Togral A, Baki AE, et al. Effects of isotretinoin treatment on cartilage and tendon thicknesses: an ultrasonographic study [published online ahead of print July 2, 2014]. Clin Rheumatol. doi:10.1007/s10067-014-2733-9.
2. Karatas Togral A, Yıldızgören MT, Mustu Koryürek Ö, et al. Can isotretinoin induce SAPHO syndrome? West Indian Med J. In press.
3. Yıldızgören MT, Ekiz T, Karatas Togral A. Bilateral sacroiliitis induced by systemic isotretinoin treatment. West Indian Med J. In press.
4. Chapman MS. Vitamin A: history, current uses, and controversies. Semin Cutan Med Surg. 2012;31:11-16.
5. Blasiak RC, Stamey CR, Burkhart CN, et al. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol. 2013;149:1392.
6. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83:191-201.
7. DiGiovanna JJ. Isotretinoin effects on bone. J Am Acad Dermatol. 2001;45:S176-S182.
8. Heudes AM, Laroche L. Muscular damage during isotretinoin treatment. Ann Dermatol Venereol. 1998;125:94-97.
9. Goulden V, Layton AM, Cunliffe WJ. Long term safety of isotretinoin as a treatment for acne vulgaris. Br J Dermatol. 1994;131:360-363.
10. Fiallo P, Tagliapietra AG. Severe acute myopathy induced by isotretinoin. Arch Dermatol. 1996;132:1521-1522.
11. Impellizzeri FM, Bizzini M, Rampinini E, et al. Reliability of isokinetic strength imbalance ratios measured using the Cybex NORM dynamometer.
Clin Physiol Funct Imaging. 2008;28:113-119.
12. Brown LE. Isokinetics in Human Performance. Champaign, IL: Human Kinetics; 2000.
13. Alangari AS, Al-Hazzaa HM. Normal isometric and isokinetic peak torques of hamstring and quadriceps muscles in young adult Saudi males. Neurosciences (Riyadh). 2004;9:165-170.
14. Pincivero DM, Gear WS, Sterner RL, et al. Gender differences in the relationship between quadriceps work and fatigue during high intensity exercise. J Strength Cond Res. 2000;14:202-206.
- Musculoskeletal adverse effects have been reported due to isotretinoin treatment.
- This study investigated the effects of isotretinoin on muscle strength, fatigue, and endurance in patients with acne vulgaris using an isokinetic dynamometer.
- Systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance.
Product News: 07 2015
Alevicyn SG Antipruritic Spray Gel
IntraDerm Pharmaceuticals, a division of Oculus Innovative Sciences, Inc, receives 510(k) clearance from the US Food and Drug Administration for Alevicyn SG Antipruritic Spray Gel with both prescription and over-the-counter indications. The Alevicyn SG prescription product manages and relieves the burning, itching, and pain experienced with dermatoses such as radiation dermatitis and atopic dermatitis. It also relieves the pain of first- and second-degree burns and helps to relieve dry waxy skin by maintaining a moist wound environment, which is beneficial to the healing process. The over-the-counter product relieves the burning and itching associated with many common types of skin irritation, lacerations, abrasions, and minor burns including sunburn. For more information, visit www.intraderm.com.
Promius Promise
Promius Pharma LLC announces that the Promius Promise program has been expanded to include Cloderm (clocortolone pivalate) Cream 0.1% and Trianex (triamcinolone acetonide) Ointment 0.05%, both for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. The Promius Promise program was created in 2013 to support patients. This program features a dedicated call center staff to educate patients about their insurance coverage and answer any questions they may have about their out-of-pocket cost, co-pay assistance, and prior authorizations. For more information, visit www.promiuspharma.com.
Radiesse
Merz North America, Inc, receives US Food and Drug Administration approval of Radiesse for correction of volume loss in the dorsum of the hands. Radiesse is an opaque dermal filler composed of calcium hydroxylapatite microspheres suspended in a water-based gel carrier. It provides an immediate volumizing effect and helps reduce the prominence of tendons and veins in the hands, delivering natural-looking results that can last up to 1 year. Radiesse also is indicated for subdermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. For more information, visit www.MerzUSA.com.
If you would like your product included in Product News, please e-mail a press release to the Editorial Office at [email protected].
Alevicyn SG Antipruritic Spray Gel
IntraDerm Pharmaceuticals, a division of Oculus Innovative Sciences, Inc, receives 510(k) clearance from the US Food and Drug Administration for Alevicyn SG Antipruritic Spray Gel with both prescription and over-the-counter indications. The Alevicyn SG prescription product manages and relieves the burning, itching, and pain experienced with dermatoses such as radiation dermatitis and atopic dermatitis. It also relieves the pain of first- and second-degree burns and helps to relieve dry waxy skin by maintaining a moist wound environment, which is beneficial to the healing process. The over-the-counter product relieves the burning and itching associated with many common types of skin irritation, lacerations, abrasions, and minor burns including sunburn. For more information, visit www.intraderm.com.
Promius Promise
Promius Pharma LLC announces that the Promius Promise program has been expanded to include Cloderm (clocortolone pivalate) Cream 0.1% and Trianex (triamcinolone acetonide) Ointment 0.05%, both for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. The Promius Promise program was created in 2013 to support patients. This program features a dedicated call center staff to educate patients about their insurance coverage and answer any questions they may have about their out-of-pocket cost, co-pay assistance, and prior authorizations. For more information, visit www.promiuspharma.com.
Radiesse
Merz North America, Inc, receives US Food and Drug Administration approval of Radiesse for correction of volume loss in the dorsum of the hands. Radiesse is an opaque dermal filler composed of calcium hydroxylapatite microspheres suspended in a water-based gel carrier. It provides an immediate volumizing effect and helps reduce the prominence of tendons and veins in the hands, delivering natural-looking results that can last up to 1 year. Radiesse also is indicated for subdermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. For more information, visit www.MerzUSA.com.
If you would like your product included in Product News, please e-mail a press release to the Editorial Office at [email protected].
Alevicyn SG Antipruritic Spray Gel
IntraDerm Pharmaceuticals, a division of Oculus Innovative Sciences, Inc, receives 510(k) clearance from the US Food and Drug Administration for Alevicyn SG Antipruritic Spray Gel with both prescription and over-the-counter indications. The Alevicyn SG prescription product manages and relieves the burning, itching, and pain experienced with dermatoses such as radiation dermatitis and atopic dermatitis. It also relieves the pain of first- and second-degree burns and helps to relieve dry waxy skin by maintaining a moist wound environment, which is beneficial to the healing process. The over-the-counter product relieves the burning and itching associated with many common types of skin irritation, lacerations, abrasions, and minor burns including sunburn. For more information, visit www.intraderm.com.
Promius Promise
Promius Pharma LLC announces that the Promius Promise program has been expanded to include Cloderm (clocortolone pivalate) Cream 0.1% and Trianex (triamcinolone acetonide) Ointment 0.05%, both for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. The Promius Promise program was created in 2013 to support patients. This program features a dedicated call center staff to educate patients about their insurance coverage and answer any questions they may have about their out-of-pocket cost, co-pay assistance, and prior authorizations. For more information, visit www.promiuspharma.com.
Radiesse
Merz North America, Inc, receives US Food and Drug Administration approval of Radiesse for correction of volume loss in the dorsum of the hands. Radiesse is an opaque dermal filler composed of calcium hydroxylapatite microspheres suspended in a water-based gel carrier. It provides an immediate volumizing effect and helps reduce the prominence of tendons and veins in the hands, delivering natural-looking results that can last up to 1 year. Radiesse also is indicated for subdermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. For more information, visit www.MerzUSA.com.
If you would like your product included in Product News, please e-mail a press release to the Editorial Office at [email protected].
A Phase 3 Randomized, Double-blind, Vehicle-Controlled Trial of Azelaic Acid Foam 15% in the Treatment of Papulopustular Rosacea
Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.3 Reports of the gender distribution of the disease vary but often show female predominance.4 Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.1
The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.5 Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.2 These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.6 The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.2
Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.7
Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.8 Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).9 Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.10 Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.11 Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.12
In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.16
Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.17 Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.18 In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.19 The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.
We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.8
Methods
Study Design
This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.
Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.
The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.
Efficacy Evaluations
There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.
The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.
Safety
Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).
Statistical Analysis
Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)
Results
Study Participants
Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.
Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.
Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.
Efficacy
Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.
 |
 |
Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).
Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.
Safety
Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.
The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).
All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).
More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.
Comment
Overall, the results from this phase 3 trial demonstrate that the new foam formulation of AzA was efficacious and safe in a 12-week, twice-daily course of treatment for moderate to severe PPR. The AzA foam formulation was significantly superior to vehicle (P<.001) for both primary efficacy end points. Participants in the AzA foam group achieved therapeutic success at a higher rate than the vehicle group, and the change in nominal ILC at EoT was significantly greater for participants treated with AzA foam than for those treated with vehicle (P<.001). Differences between the 2 treatment groups for the coprimary end point measures arose early in the study, demonstrating that symptoms were rapidly controlled. Between weeks 8 and 12 (EoT), the rate of increase of beneficial effects in the AzA foam group remained high, while the vehicle group showed a notable slowing. There was no indication of any rebound effect in overall disease severity subsequent to EoT. After 4 weeks of follow-up, there was still a beneficial treatment effect present in favor of the AzA foam group, as indicated by the persistence of improvements in both coprimary end point measures throughout the follow-up period.
Analyses of alternative populations and secondary end points (data not shown) supported the efficacy results reported here. There was no indication of irregular study center effects, and the sensitivity analyses demonstrated robustness of the data for the observed treatment effects.
The use of vehicle foam alone appeared to be beneficial in reducing ILC and improving IGA rating, which suggests that the properties of the new foam formulation are favorable for the inflamed lesional skin of rosacea. Of note, other dermatology studies, including trials in rosacea, have reported therapeutic effects of vehicle treatment that may be attributable to the positive effects of skin care with certain formulations.20
Azelaic acid foam was well tolerated in the current study. More than 93% of AEs in either treatment group were of mild or moderate severity. The incidence of drug-related AEs was low in both groups and mainly occurred at the application site. There were no drug-related severe or serious AEs. The low incidence of reported drug-related noncutaneous AEs in the AzA foam group (dysgeusia in 1 patient and headache in 2 patients) supports the known favorable systemic tolerance profile of AzA.
Although most drug-related AEs occurred at the application site, they were generally transient, with the majority of events in the AzA foam group lasting no more than 1 hour. Most cutaneous AEs developed early in the study. In the AzA foam group, the prevalence of drug-related cutaneous AEs dropped at every time interval as the study progressed (eFigure). Very few AEs of any type persisted through the end of the study. These safety results were accompanied by a high compliance rate and a high participation rate throughout the course of the study. Taken together, the available data for this AzA foam formulation support a favorable tolerability profile. The results of this study are consistent with and expand on data from an earlier investigation of similar design.8
Conclusion
The development of an AzA foam formulation with higher lipid content was intended to expand the treatment options available to physicians and patients who are managing rosacea. Most topical dermatologic treatments are currently delivered in classical formulations such as creams or gels, but patients who use topical therapies have rated messiness and ease of application among the most important characteristics affecting quality of life.17,21 Foam formulations may offer improvements in this regard; ease of application may minimize unnecessary manipulation of inflamed skin and contribute to a high level of user satisfaction.22 However, the design of the current study was limited to evaluating only the AzA foam formulation versus a foam vehicle, and direct comparisons of clinical efficacy and tolerability to other AzA topical preparations were not performed. Nonetheless, patients have previously reported that they would be more likely to comply with a recommended course of dermatologic foam therapy than other topical formulations.18 The proposed foam formulation was designed to attend to the specific needs of the dry and sensitive skin in rosacea by combining the demonstrated efficacy properties exhibited by AzA gel 15% with the good tolerability and acceptability of a lipid-containing foam formulation. Development of this formulation was targeted to obtain a product that would be highly spreadable, dry quickly, and be easy to apply. The available data for this AzA foam formulation support the value of this option in the topical treatment of rosacea. The success in reduction of overall disease severity, lack of any rebound after EoT, and the observed tolerability and high adherence rates suggest that this novel formulation is a useful addition to current treatment options for rosacea.
Addendum
After release of the study data for unblinding and statistical evaluation, the following inconsistency regarding patient distribution was noted: 1 participant was incorrectly evaluated as part of the AzA foam analysis group when in fact this patient was randomized to vehicle and was treated throughout the study with vehicle. This participant did not experience any AE and did not show any IGA improvement at the EoT. As this single case did not have an impact on the statistical conclusions or interpretation of the results, the released study data have not been changed. This deviation was described as a database erratum in the study report.
Acknowledgement—Editorial support through inVentiv Medical Communications, New York, New York, was provided by Bayer HealthCare Pharmaceuticals Inc.
APPENDIX
Supplementary Methods
Supplementary Study Design
This study met all local legal and regulatory requirements and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study and implementation, the protocol and all amendments were approved by the appropriate independent ethics committee or institutional review board at each study site. Two protocol amendments were implemented before the first participant visit.
Exclusion criteria included the presence of dermatoses that could interfere with rosacea diagnosis or evaluation, facial laser surgery or topical use of any medication to treat rosacea within 6 weeks before randomization, systemic use of any medications to treat rosacea, and known unresponsiveness to AzA treatment. Further standard exclusion criteria included alcohol or drug use or parallel participation in other clinical studies, which were necessary to exclude undue influence on study evaluations and/or participant safety. The study was conducted by qualified investigators at 48 centers in the United States.
The investigational product was filled in identical containers according to the randomization list generated by a computer program using blocks. Complete blocks of study medication were distributed to the centers. Eligible participants were randomized 1:1 into either AzA foam or vehicle treatment groups by assignment of a randomization number at baseline. A blind investigational product under the same randomization number was dispensed to and returned from participants by study personnel who were not involved in the assessments. Blinding was achieved by using labels on the investigational products that did not allow identification of the true medication.
Compliance was evaluated from participant diaries as well as the number of expected doses and actually applied doses.
Additional Efficacy Evaluations
A number of secondary variables (not reported here) were assessed, including changes in other manifestations of PPR, as well as participant assessments of treatment response, tolerability, cosmetic preferences, and quality of life.
Additional Safety
Investigators reported a yes or no response as to whether there was a reasonable causal relationship between AEs and treatment. Moreover, AEs that began at the start of or during treatment were considered treatment emergent. Cutaneous AEs were further assessed regarding location and duration. An AE was deemed local if it occurred at the application site and transient if it subsided within 60 minutes of onset.
Statistical Analysis
The primary efficacy analyses presented here were based on the full analysis set of participants who were randomized and had medication dispensed. For participants with no EoT value, the last nonmissing value was used including baseline (last-observation-carried-forward methodology). Participants who discontinued treatment prematurely because of lack of efficacy were considered to be treatment failures, regardless of the reported IGA score. Statistical significance was needed for both coprimary efficacy variables at a 1-sided 2.5% significance level to show confirmed superiority of AzA foam versus vehicle.
A number of sensitivity analyses were performed, including an analysis of the coprimary end points using observed data, analysis of the per-protocol population of participants who did not prematurely discontinue treatment and had no major protocol deviations, subgroup analyses, and the use of statistical methods to investigate the effect of missing observations. Analyses of success rate and nominal change in ILC were repeated for each postbaseline visit using χ² and t tests, respectively. All summary and statistical analyses were performed according to the study protocol (unchanged after the start of the study) using SAS version 9.2.
Results from a prior study provided the basis for the sample size, which was calculated to show a significant difference in both primary efficacy end points with a power of 90%.8 To allow for dropouts, 480 participants in each treatment group were to be randomized for a total of 960 participants.
1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46:584-587.
2. Del Rosso JQ. Advances in understanding and managing rosacea: part 1: connecting the dots between pathophysiological mechanisms and common clinical features of rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol. 2012;5:16-25.
3. Huynh TT. Burden of disease: the psychosocial impact of rosacea on a patient’s quality of life. Am Health Drug Benefits. 2013;6:348-354.
4. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 suppl 1):S27-S35.
5. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 suppl 1):S15-S26.
6. Wollina U. Recent advances in the understanding and management of rosacea. F1000Prime Rep. 2014;6:50.
7. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 5: a guide on the management of rosacea. Cutis. 2014;93:134-138.
8. Draelos ZD, Elewski B, Staedtler G, et al. Azelaic acid foam 15% in the treatment of papulopustular rosacea: a randomized, double-blind, vehicle-controlled study. Cutis. 2013;92:306-317.
9. Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13:975-980.
10. Mastrofrancesco A, Ottaviani M, Aspite N, et al. Azelaic acid modulates the inflammatory response in normal human keratinocytes through PPARg activation. Exp Dermatol. 2010;19:813-820.
11. Akamatsu H, Komura J, Asada Y, et al. Inhibitory effect of azelaic acid on neutrophil functions: a possible cause for its efficacy in treating pathogenetically unrelated diseases. Arch Dermatol Res. 1991;283:162-166.
12. Coda AB, Hata T, Miller J, et al. Cathelicidin, kalli-krein 5, and serine protease activity is inhibited during treatment of rosacea with azelaic acid 15% gel. J Am Acad Dermatol. 2013;69:570-577.
13. van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011;165:760-781.
14. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies. J Am Acad Dermatol. 2003;48:836-845.
15. Thiboutot DM, Fleischer AB Jr, Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008;7:541-546.
16. Finacea [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015.
17. Zhao Y, Jones SA, Brown MB. Dynamic foams in topical drug delivery. J Pharm Pharmacol. 2010;62:678-684.
18. Gottlieb AB, Ford RO, Spellman MC. The efficacy and tolerability of clobetasol propionate foam 0.05% in the treatment of mild to moderate plaque-type psoriasis of nonscalp regions. J Cutan Med Surg. 2003;7:185-192.
19. Loden M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol. 2003;4:771-788.
20. Jackson JM, Pelle M. Topical rosacea therapy: the importance of vehicles for efficacy, tolerability and compliance. J Drugs Dermatol. 2011;10:627-633.
21. Housman TS, Mellen BG, Rapp SR, et al. Patients with psoriasis prefer solution and foam vehicles: a quantitative assessment of vehicle preference. Cutis. 2002;70:327-332.
22. Kircik LH, Bikowski JB. Vehicles matter: topical foam formulations. Practical Dermatology. January 2012(suppl):3-18.
Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.3 Reports of the gender distribution of the disease vary but often show female predominance.4 Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.1
The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.5 Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.2 These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.6 The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.2
Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.7
Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.8 Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).9 Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.10 Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.11 Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.12
In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.16
Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.17 Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.18 In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.19 The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.
We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.8
Methods
Study Design
This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.
Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.
The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.
Efficacy Evaluations
There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.
The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.
Safety
Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).
Statistical Analysis
Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)
Results
Study Participants
Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.
Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.
Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.
Efficacy
Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.
|
|
Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).
Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.
Safety
Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.
The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).
All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).
More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.
Comment
Overall, the results from this phase 3 trial demonstrate that the new foam formulation of AzA was efficacious and safe in a 12-week, twice-daily course of treatment for moderate to severe PPR. The AzA foam formulation was significantly superior to vehicle (P<.001) for both primary efficacy end points. Participants in the AzA foam group achieved therapeutic success at a higher rate than the vehicle group, and the change in nominal ILC at EoT was significantly greater for participants treated with AzA foam than for those treated with vehicle (P<.001). Differences between the 2 treatment groups for the coprimary end point measures arose early in the study, demonstrating that symptoms were rapidly controlled. Between weeks 8 and 12 (EoT), the rate of increase of beneficial effects in the AzA foam group remained high, while the vehicle group showed a notable slowing. There was no indication of any rebound effect in overall disease severity subsequent to EoT. After 4 weeks of follow-up, there was still a beneficial treatment effect present in favor of the AzA foam group, as indicated by the persistence of improvements in both coprimary end point measures throughout the follow-up period.
Analyses of alternative populations and secondary end points (data not shown) supported the efficacy results reported here. There was no indication of irregular study center effects, and the sensitivity analyses demonstrated robustness of the data for the observed treatment effects.
The use of vehicle foam alone appeared to be beneficial in reducing ILC and improving IGA rating, which suggests that the properties of the new foam formulation are favorable for the inflamed lesional skin of rosacea. Of note, other dermatology studies, including trials in rosacea, have reported therapeutic effects of vehicle treatment that may be attributable to the positive effects of skin care with certain formulations.20
Azelaic acid foam was well tolerated in the current study. More than 93% of AEs in either treatment group were of mild or moderate severity. The incidence of drug-related AEs was low in both groups and mainly occurred at the application site. There were no drug-related severe or serious AEs. The low incidence of reported drug-related noncutaneous AEs in the AzA foam group (dysgeusia in 1 patient and headache in 2 patients) supports the known favorable systemic tolerance profile of AzA.
Although most drug-related AEs occurred at the application site, they were generally transient, with the majority of events in the AzA foam group lasting no more than 1 hour. Most cutaneous AEs developed early in the study. In the AzA foam group, the prevalence of drug-related cutaneous AEs dropped at every time interval as the study progressed (eFigure). Very few AEs of any type persisted through the end of the study. These safety results were accompanied by a high compliance rate and a high participation rate throughout the course of the study. Taken together, the available data for this AzA foam formulation support a favorable tolerability profile. The results of this study are consistent with and expand on data from an earlier investigation of similar design.8
Conclusion
The development of an AzA foam formulation with higher lipid content was intended to expand the treatment options available to physicians and patients who are managing rosacea. Most topical dermatologic treatments are currently delivered in classical formulations such as creams or gels, but patients who use topical therapies have rated messiness and ease of application among the most important characteristics affecting quality of life.17,21 Foam formulations may offer improvements in this regard; ease of application may minimize unnecessary manipulation of inflamed skin and contribute to a high level of user satisfaction.22 However, the design of the current study was limited to evaluating only the AzA foam formulation versus a foam vehicle, and direct comparisons of clinical efficacy and tolerability to other AzA topical preparations were not performed. Nonetheless, patients have previously reported that they would be more likely to comply with a recommended course of dermatologic foam therapy than other topical formulations.18 The proposed foam formulation was designed to attend to the specific needs of the dry and sensitive skin in rosacea by combining the demonstrated efficacy properties exhibited by AzA gel 15% with the good tolerability and acceptability of a lipid-containing foam formulation. Development of this formulation was targeted to obtain a product that would be highly spreadable, dry quickly, and be easy to apply. The available data for this AzA foam formulation support the value of this option in the topical treatment of rosacea. The success in reduction of overall disease severity, lack of any rebound after EoT, and the observed tolerability and high adherence rates suggest that this novel formulation is a useful addition to current treatment options for rosacea.
Addendum
After release of the study data for unblinding and statistical evaluation, the following inconsistency regarding patient distribution was noted: 1 participant was incorrectly evaluated as part of the AzA foam analysis group when in fact this patient was randomized to vehicle and was treated throughout the study with vehicle. This participant did not experience any AE and did not show any IGA improvement at the EoT. As this single case did not have an impact on the statistical conclusions or interpretation of the results, the released study data have not been changed. This deviation was described as a database erratum in the study report.
Acknowledgement—Editorial support through inVentiv Medical Communications, New York, New York, was provided by Bayer HealthCare Pharmaceuticals Inc.
APPENDIX
Supplementary Methods
Supplementary Study Design
This study met all local legal and regulatory requirements and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study and implementation, the protocol and all amendments were approved by the appropriate independent ethics committee or institutional review board at each study site. Two protocol amendments were implemented before the first participant visit.
Exclusion criteria included the presence of dermatoses that could interfere with rosacea diagnosis or evaluation, facial laser surgery or topical use of any medication to treat rosacea within 6 weeks before randomization, systemic use of any medications to treat rosacea, and known unresponsiveness to AzA treatment. Further standard exclusion criteria included alcohol or drug use or parallel participation in other clinical studies, which were necessary to exclude undue influence on study evaluations and/or participant safety. The study was conducted by qualified investigators at 48 centers in the United States.
The investigational product was filled in identical containers according to the randomization list generated by a computer program using blocks. Complete blocks of study medication were distributed to the centers. Eligible participants were randomized 1:1 into either AzA foam or vehicle treatment groups by assignment of a randomization number at baseline. A blind investigational product under the same randomization number was dispensed to and returned from participants by study personnel who were not involved in the assessments. Blinding was achieved by using labels on the investigational products that did not allow identification of the true medication.
Compliance was evaluated from participant diaries as well as the number of expected doses and actually applied doses.
Additional Efficacy Evaluations
A number of secondary variables (not reported here) were assessed, including changes in other manifestations of PPR, as well as participant assessments of treatment response, tolerability, cosmetic preferences, and quality of life.
Additional Safety
Investigators reported a yes or no response as to whether there was a reasonable causal relationship between AEs and treatment. Moreover, AEs that began at the start of or during treatment were considered treatment emergent. Cutaneous AEs were further assessed regarding location and duration. An AE was deemed local if it occurred at the application site and transient if it subsided within 60 minutes of onset.
Statistical Analysis
The primary efficacy analyses presented here were based on the full analysis set of participants who were randomized and had medication dispensed. For participants with no EoT value, the last nonmissing value was used including baseline (last-observation-carried-forward methodology). Participants who discontinued treatment prematurely because of lack of efficacy were considered to be treatment failures, regardless of the reported IGA score. Statistical significance was needed for both coprimary efficacy variables at a 1-sided 2.5% significance level to show confirmed superiority of AzA foam versus vehicle.
A number of sensitivity analyses were performed, including an analysis of the coprimary end points using observed data, analysis of the per-protocol population of participants who did not prematurely discontinue treatment and had no major protocol deviations, subgroup analyses, and the use of statistical methods to investigate the effect of missing observations. Analyses of success rate and nominal change in ILC were repeated for each postbaseline visit using χ² and t tests, respectively. All summary and statistical analyses were performed according to the study protocol (unchanged after the start of the study) using SAS version 9.2.
Results from a prior study provided the basis for the sample size, which was calculated to show a significant difference in both primary efficacy end points with a power of 90%.8 To allow for dropouts, 480 participants in each treatment group were to be randomized for a total of 960 participants.
Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.3 Reports of the gender distribution of the disease vary but often show female predominance.4 Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.1
The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.5 Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.2 These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.6 The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.2
Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.7
Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.8 Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).9 Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.10 Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.11 Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.12
In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.16
Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.17 Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.18 In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.19 The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.
We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.8
Methods
Study Design
This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.
Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.
The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.
Efficacy Evaluations
There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.
The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.
Safety
Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).
Statistical Analysis
Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)
Results
Study Participants
Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.
Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.
Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.
Efficacy
Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.
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Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).
Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.
Safety
Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.
The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).
All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).
More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.
Comment
Overall, the results from this phase 3 trial demonstrate that the new foam formulation of AzA was efficacious and safe in a 12-week, twice-daily course of treatment for moderate to severe PPR. The AzA foam formulation was significantly superior to vehicle (P<.001) for both primary efficacy end points. Participants in the AzA foam group achieved therapeutic success at a higher rate than the vehicle group, and the change in nominal ILC at EoT was significantly greater for participants treated with AzA foam than for those treated with vehicle (P<.001). Differences between the 2 treatment groups for the coprimary end point measures arose early in the study, demonstrating that symptoms were rapidly controlled. Between weeks 8 and 12 (EoT), the rate of increase of beneficial effects in the AzA foam group remained high, while the vehicle group showed a notable slowing. There was no indication of any rebound effect in overall disease severity subsequent to EoT. After 4 weeks of follow-up, there was still a beneficial treatment effect present in favor of the AzA foam group, as indicated by the persistence of improvements in both coprimary end point measures throughout the follow-up period.
Analyses of alternative populations and secondary end points (data not shown) supported the efficacy results reported here. There was no indication of irregular study center effects, and the sensitivity analyses demonstrated robustness of the data for the observed treatment effects.
The use of vehicle foam alone appeared to be beneficial in reducing ILC and improving IGA rating, which suggests that the properties of the new foam formulation are favorable for the inflamed lesional skin of rosacea. Of note, other dermatology studies, including trials in rosacea, have reported therapeutic effects of vehicle treatment that may be attributable to the positive effects of skin care with certain formulations.20
Azelaic acid foam was well tolerated in the current study. More than 93% of AEs in either treatment group were of mild or moderate severity. The incidence of drug-related AEs was low in both groups and mainly occurred at the application site. There were no drug-related severe or serious AEs. The low incidence of reported drug-related noncutaneous AEs in the AzA foam group (dysgeusia in 1 patient and headache in 2 patients) supports the known favorable systemic tolerance profile of AzA.
Although most drug-related AEs occurred at the application site, they were generally transient, with the majority of events in the AzA foam group lasting no more than 1 hour. Most cutaneous AEs developed early in the study. In the AzA foam group, the prevalence of drug-related cutaneous AEs dropped at every time interval as the study progressed (eFigure). Very few AEs of any type persisted through the end of the study. These safety results were accompanied by a high compliance rate and a high participation rate throughout the course of the study. Taken together, the available data for this AzA foam formulation support a favorable tolerability profile. The results of this study are consistent with and expand on data from an earlier investigation of similar design.8
Conclusion
The development of an AzA foam formulation with higher lipid content was intended to expand the treatment options available to physicians and patients who are managing rosacea. Most topical dermatologic treatments are currently delivered in classical formulations such as creams or gels, but patients who use topical therapies have rated messiness and ease of application among the most important characteristics affecting quality of life.17,21 Foam formulations may offer improvements in this regard; ease of application may minimize unnecessary manipulation of inflamed skin and contribute to a high level of user satisfaction.22 However, the design of the current study was limited to evaluating only the AzA foam formulation versus a foam vehicle, and direct comparisons of clinical efficacy and tolerability to other AzA topical preparations were not performed. Nonetheless, patients have previously reported that they would be more likely to comply with a recommended course of dermatologic foam therapy than other topical formulations.18 The proposed foam formulation was designed to attend to the specific needs of the dry and sensitive skin in rosacea by combining the demonstrated efficacy properties exhibited by AzA gel 15% with the good tolerability and acceptability of a lipid-containing foam formulation. Development of this formulation was targeted to obtain a product that would be highly spreadable, dry quickly, and be easy to apply. The available data for this AzA foam formulation support the value of this option in the topical treatment of rosacea. The success in reduction of overall disease severity, lack of any rebound after EoT, and the observed tolerability and high adherence rates suggest that this novel formulation is a useful addition to current treatment options for rosacea.
Addendum
After release of the study data for unblinding and statistical evaluation, the following inconsistency regarding patient distribution was noted: 1 participant was incorrectly evaluated as part of the AzA foam analysis group when in fact this patient was randomized to vehicle and was treated throughout the study with vehicle. This participant did not experience any AE and did not show any IGA improvement at the EoT. As this single case did not have an impact on the statistical conclusions or interpretation of the results, the released study data have not been changed. This deviation was described as a database erratum in the study report.
Acknowledgement—Editorial support through inVentiv Medical Communications, New York, New York, was provided by Bayer HealthCare Pharmaceuticals Inc.
APPENDIX
Supplementary Methods
Supplementary Study Design
This study met all local legal and regulatory requirements and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study and implementation, the protocol and all amendments were approved by the appropriate independent ethics committee or institutional review board at each study site. Two protocol amendments were implemented before the first participant visit.
Exclusion criteria included the presence of dermatoses that could interfere with rosacea diagnosis or evaluation, facial laser surgery or topical use of any medication to treat rosacea within 6 weeks before randomization, systemic use of any medications to treat rosacea, and known unresponsiveness to AzA treatment. Further standard exclusion criteria included alcohol or drug use or parallel participation in other clinical studies, which were necessary to exclude undue influence on study evaluations and/or participant safety. The study was conducted by qualified investigators at 48 centers in the United States.
The investigational product was filled in identical containers according to the randomization list generated by a computer program using blocks. Complete blocks of study medication were distributed to the centers. Eligible participants were randomized 1:1 into either AzA foam or vehicle treatment groups by assignment of a randomization number at baseline. A blind investigational product under the same randomization number was dispensed to and returned from participants by study personnel who were not involved in the assessments. Blinding was achieved by using labels on the investigational products that did not allow identification of the true medication.
Compliance was evaluated from participant diaries as well as the number of expected doses and actually applied doses.
Additional Efficacy Evaluations
A number of secondary variables (not reported here) were assessed, including changes in other manifestations of PPR, as well as participant assessments of treatment response, tolerability, cosmetic preferences, and quality of life.
Additional Safety
Investigators reported a yes or no response as to whether there was a reasonable causal relationship between AEs and treatment. Moreover, AEs that began at the start of or during treatment were considered treatment emergent. Cutaneous AEs were further assessed regarding location and duration. An AE was deemed local if it occurred at the application site and transient if it subsided within 60 minutes of onset.
Statistical Analysis
The primary efficacy analyses presented here were based on the full analysis set of participants who were randomized and had medication dispensed. For participants with no EoT value, the last nonmissing value was used including baseline (last-observation-carried-forward methodology). Participants who discontinued treatment prematurely because of lack of efficacy were considered to be treatment failures, regardless of the reported IGA score. Statistical significance was needed for both coprimary efficacy variables at a 1-sided 2.5% significance level to show confirmed superiority of AzA foam versus vehicle.
A number of sensitivity analyses were performed, including an analysis of the coprimary end points using observed data, analysis of the per-protocol population of participants who did not prematurely discontinue treatment and had no major protocol deviations, subgroup analyses, and the use of statistical methods to investigate the effect of missing observations. Analyses of success rate and nominal change in ILC were repeated for each postbaseline visit using χ² and t tests, respectively. All summary and statistical analyses were performed according to the study protocol (unchanged after the start of the study) using SAS version 9.2.
Results from a prior study provided the basis for the sample size, which was calculated to show a significant difference in both primary efficacy end points with a power of 90%.8 To allow for dropouts, 480 participants in each treatment group were to be randomized for a total of 960 participants.
1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46:584-587.
2. Del Rosso JQ. Advances in understanding and managing rosacea: part 1: connecting the dots between pathophysiological mechanisms and common clinical features of rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol. 2012;5:16-25.
3. Huynh TT. Burden of disease: the psychosocial impact of rosacea on a patient’s quality of life. Am Health Drug Benefits. 2013;6:348-354.
4. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 suppl 1):S27-S35.
5. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 suppl 1):S15-S26.
6. Wollina U. Recent advances in the understanding and management of rosacea. F1000Prime Rep. 2014;6:50.
7. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 5: a guide on the management of rosacea. Cutis. 2014;93:134-138.
8. Draelos ZD, Elewski B, Staedtler G, et al. Azelaic acid foam 15% in the treatment of papulopustular rosacea: a randomized, double-blind, vehicle-controlled study. Cutis. 2013;92:306-317.
9. Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13:975-980.
10. Mastrofrancesco A, Ottaviani M, Aspite N, et al. Azelaic acid modulates the inflammatory response in normal human keratinocytes through PPARg activation. Exp Dermatol. 2010;19:813-820.
11. Akamatsu H, Komura J, Asada Y, et al. Inhibitory effect of azelaic acid on neutrophil functions: a possible cause for its efficacy in treating pathogenetically unrelated diseases. Arch Dermatol Res. 1991;283:162-166.
12. Coda AB, Hata T, Miller J, et al. Cathelicidin, kalli-krein 5, and serine protease activity is inhibited during treatment of rosacea with azelaic acid 15% gel. J Am Acad Dermatol. 2013;69:570-577.
13. van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011;165:760-781.
14. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies. J Am Acad Dermatol. 2003;48:836-845.
15. Thiboutot DM, Fleischer AB Jr, Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008;7:541-546.
16. Finacea [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015.
17. Zhao Y, Jones SA, Brown MB. Dynamic foams in topical drug delivery. J Pharm Pharmacol. 2010;62:678-684.
18. Gottlieb AB, Ford RO, Spellman MC. The efficacy and tolerability of clobetasol propionate foam 0.05% in the treatment of mild to moderate plaque-type psoriasis of nonscalp regions. J Cutan Med Surg. 2003;7:185-192.
19. Loden M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol. 2003;4:771-788.
20. Jackson JM, Pelle M. Topical rosacea therapy: the importance of vehicles for efficacy, tolerability and compliance. J Drugs Dermatol. 2011;10:627-633.
21. Housman TS, Mellen BG, Rapp SR, et al. Patients with psoriasis prefer solution and foam vehicles: a quantitative assessment of vehicle preference. Cutis. 2002;70:327-332.
22. Kircik LH, Bikowski JB. Vehicles matter: topical foam formulations. Practical Dermatology. January 2012(suppl):3-18.
1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46:584-587.
2. Del Rosso JQ. Advances in understanding and managing rosacea: part 1: connecting the dots between pathophysiological mechanisms and common clinical features of rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol. 2012;5:16-25.
3. Huynh TT. Burden of disease: the psychosocial impact of rosacea on a patient’s quality of life. Am Health Drug Benefits. 2013;6:348-354.
4. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 suppl 1):S27-S35.
5. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 suppl 1):S15-S26.
6. Wollina U. Recent advances in the understanding and management of rosacea. F1000Prime Rep. 2014;6:50.
7. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 5: a guide on the management of rosacea. Cutis. 2014;93:134-138.
8. Draelos ZD, Elewski B, Staedtler G, et al. Azelaic acid foam 15% in the treatment of papulopustular rosacea: a randomized, double-blind, vehicle-controlled study. Cutis. 2013;92:306-317.
9. Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13:975-980.
10. Mastrofrancesco A, Ottaviani M, Aspite N, et al. Azelaic acid modulates the inflammatory response in normal human keratinocytes through PPARg activation. Exp Dermatol. 2010;19:813-820.
11. Akamatsu H, Komura J, Asada Y, et al. Inhibitory effect of azelaic acid on neutrophil functions: a possible cause for its efficacy in treating pathogenetically unrelated diseases. Arch Dermatol Res. 1991;283:162-166.
12. Coda AB, Hata T, Miller J, et al. Cathelicidin, kalli-krein 5, and serine protease activity is inhibited during treatment of rosacea with azelaic acid 15% gel. J Am Acad Dermatol. 2013;69:570-577.
13. van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011;165:760-781.
14. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies. J Am Acad Dermatol. 2003;48:836-845.
15. Thiboutot DM, Fleischer AB Jr, Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008;7:541-546.
16. Finacea [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015.
17. Zhao Y, Jones SA, Brown MB. Dynamic foams in topical drug delivery. J Pharm Pharmacol. 2010;62:678-684.
18. Gottlieb AB, Ford RO, Spellman MC. The efficacy and tolerability of clobetasol propionate foam 0.05% in the treatment of mild to moderate plaque-type psoriasis of nonscalp regions. J Cutan Med Surg. 2003;7:185-192.
19. Loden M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol. 2003;4:771-788.
20. Jackson JM, Pelle M. Topical rosacea therapy: the importance of vehicles for efficacy, tolerability and compliance. J Drugs Dermatol. 2011;10:627-633.
21. Housman TS, Mellen BG, Rapp SR, et al. Patients with psoriasis prefer solution and foam vehicles: a quantitative assessment of vehicle preference. Cutis. 2002;70:327-332.
22. Kircik LH, Bikowski JB. Vehicles matter: topical foam formulations. Practical Dermatology. January 2012(suppl):3-18.
Piercing Regret: Correcting Earlobe Defects From Gauges
The use of gauges to expand or alter the shape of the earlobe is a relatively popular trend in this day and age. However, as with tattoos, patients sometimes request removal of this physical alteration out of regret or a change in lifestyle. Managing these patients poses a challenge for dermatologists due to the variable degree of tissue ptosis left behind.
Collins et al published a retrospective review in JAMA Facial Plastic Surgery (2015;17:144-148) of their last 20 patients treated for earlobe reconstruction that had at least 1 year of follow-up. The earlobe deformities were classified as small, medium, or large. Small defects were those that were small enough to be treated with an elliptical excision and primary closure. Medium defects were those that had a disruption of the natural curve of the inferior earlobe and a more distinct soft tissue loss of the lobule. A primary closure of this type of defect may cause an unnaturally long lobule. The authors suggested excising the opening and then using a posterior-based advancement flap to restore the natural earlobe contour while improving some of the soft tissue loss. Large defects were those with a lot of volume loss and tissue redundancy. These defects required a wedge excision of the elongated piercing site and a posterior-superior–based advancement flap with 2 arms to it.
Results showed that all 20 patients did well after at least 1 year without the need for further reconstruction or excisional scar revision. Two patients did undergo dermabrasion at 1 year to help blend the final scar.
What’s the issue?
Trends such as the placement of earlobe gauges may wane at some point, resulting in a number of patients seeking our help to repair their earlobes. The approach presented in this study tailors the method of repair to the size of the defect. By doing so, one can hope to restore the natural shape and volume to achieve a natural-appearing earlobe. Have you seen an increase in the number of patients seeking this type of repair?
The use of gauges to expand or alter the shape of the earlobe is a relatively popular trend in this day and age. However, as with tattoos, patients sometimes request removal of this physical alteration out of regret or a change in lifestyle. Managing these patients poses a challenge for dermatologists due to the variable degree of tissue ptosis left behind.
Collins et al published a retrospective review in JAMA Facial Plastic Surgery (2015;17:144-148) of their last 20 patients treated for earlobe reconstruction that had at least 1 year of follow-up. The earlobe deformities were classified as small, medium, or large. Small defects were those that were small enough to be treated with an elliptical excision and primary closure. Medium defects were those that had a disruption of the natural curve of the inferior earlobe and a more distinct soft tissue loss of the lobule. A primary closure of this type of defect may cause an unnaturally long lobule. The authors suggested excising the opening and then using a posterior-based advancement flap to restore the natural earlobe contour while improving some of the soft tissue loss. Large defects were those with a lot of volume loss and tissue redundancy. These defects required a wedge excision of the elongated piercing site and a posterior-superior–based advancement flap with 2 arms to it.
Results showed that all 20 patients did well after at least 1 year without the need for further reconstruction or excisional scar revision. Two patients did undergo dermabrasion at 1 year to help blend the final scar.
What’s the issue?
Trends such as the placement of earlobe gauges may wane at some point, resulting in a number of patients seeking our help to repair their earlobes. The approach presented in this study tailors the method of repair to the size of the defect. By doing so, one can hope to restore the natural shape and volume to achieve a natural-appearing earlobe. Have you seen an increase in the number of patients seeking this type of repair?
The use of gauges to expand or alter the shape of the earlobe is a relatively popular trend in this day and age. However, as with tattoos, patients sometimes request removal of this physical alteration out of regret or a change in lifestyle. Managing these patients poses a challenge for dermatologists due to the variable degree of tissue ptosis left behind.
Collins et al published a retrospective review in JAMA Facial Plastic Surgery (2015;17:144-148) of their last 20 patients treated for earlobe reconstruction that had at least 1 year of follow-up. The earlobe deformities were classified as small, medium, or large. Small defects were those that were small enough to be treated with an elliptical excision and primary closure. Medium defects were those that had a disruption of the natural curve of the inferior earlobe and a more distinct soft tissue loss of the lobule. A primary closure of this type of defect may cause an unnaturally long lobule. The authors suggested excising the opening and then using a posterior-based advancement flap to restore the natural earlobe contour while improving some of the soft tissue loss. Large defects were those with a lot of volume loss and tissue redundancy. These defects required a wedge excision of the elongated piercing site and a posterior-superior–based advancement flap with 2 arms to it.
Results showed that all 20 patients did well after at least 1 year without the need for further reconstruction or excisional scar revision. Two patients did undergo dermabrasion at 1 year to help blend the final scar.
What’s the issue?
Trends such as the placement of earlobe gauges may wane at some point, resulting in a number of patients seeking our help to repair their earlobes. The approach presented in this study tailors the method of repair to the size of the defect. By doing so, one can hope to restore the natural shape and volume to achieve a natural-appearing earlobe. Have you seen an increase in the number of patients seeking this type of repair?
Player-to-player contact, not ‘heading,’ is main source of soccer concussions
Head contact with other players, not with the ball, is the main source of concussions among high-school soccer players of both sexes, according to a report published online July 13 in JAMA Pediatrics.
Several studies have shown that “heading” the ball during soccer practices and games is responsible for many soccer-related concussions, and some have called for banning such heading, especially among children and adolescents, to make the sport safer. But until now, no large study has examined the exact mechanism of head injuries among school-aged soccer players, so such prevention efforts cannot be considered evidence based, said R. Dawn Comstock, Ph.D., an epidemiologist at the University of Colorado Denver, Aurora, and her associates.
The investigators performed a retrospective analysis of data from a large, Internet-based sports injury surveillance study, focusing on concussions sustained during soccer practices or games which required medical attention and restricted the athlete’s participation for 1 or more days. They assessed nationally representative samples of 100 high schools every year for a 9-year period. There were 627 concussions during 1,393,753 athletic exposures among girls (4.50 per 10,000 exposures) and 442 concussions during 1,592,238 athletic exposures among boys (2.78 per 10,000 exposures).
The most common mechanism of concussion was player-to-player contact among both boys (68.8% of concussions) and girls (51.3% of concussions). In contrast, contact with the ball accounted for 17% of concussions among boys and 29% among girls.
The number and types of concussion symptoms were the same, regardless of whether the concussion was caused by player-to-player contact or player-to-ball contact. However, symptom resolution time was slightly but significantly longer for both boys and girls when the concussion was caused by collision with a ball or goal post (JAMA Pediatr. 2015 July 13 [doi:10.1001/jamapediatrics.2015.1062]).
“We postulate that banning heading from soccer will have limited effectiveness as a primary prevention mechanism (i.e., in preventing concussion injuries) unless such a ban is combined with concurrent efforts to reduce athlete-athlete contact throughout the game,” Dr. Comstock and her associates said.
Moreover, “it may be culturally more tolerable to the soccer community to attempt to reduce athlete-athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” rather than simply banning heading, they added.
Head contact with other players, not with the ball, is the main source of concussions among high-school soccer players of both sexes, according to a report published online July 13 in JAMA Pediatrics.
Several studies have shown that “heading” the ball during soccer practices and games is responsible for many soccer-related concussions, and some have called for banning such heading, especially among children and adolescents, to make the sport safer. But until now, no large study has examined the exact mechanism of head injuries among school-aged soccer players, so such prevention efforts cannot be considered evidence based, said R. Dawn Comstock, Ph.D., an epidemiologist at the University of Colorado Denver, Aurora, and her associates.
The investigators performed a retrospective analysis of data from a large, Internet-based sports injury surveillance study, focusing on concussions sustained during soccer practices or games which required medical attention and restricted the athlete’s participation for 1 or more days. They assessed nationally representative samples of 100 high schools every year for a 9-year period. There were 627 concussions during 1,393,753 athletic exposures among girls (4.50 per 10,000 exposures) and 442 concussions during 1,592,238 athletic exposures among boys (2.78 per 10,000 exposures).
The most common mechanism of concussion was player-to-player contact among both boys (68.8% of concussions) and girls (51.3% of concussions). In contrast, contact with the ball accounted for 17% of concussions among boys and 29% among girls.
The number and types of concussion symptoms were the same, regardless of whether the concussion was caused by player-to-player contact or player-to-ball contact. However, symptom resolution time was slightly but significantly longer for both boys and girls when the concussion was caused by collision with a ball or goal post (JAMA Pediatr. 2015 July 13 [doi:10.1001/jamapediatrics.2015.1062]).
“We postulate that banning heading from soccer will have limited effectiveness as a primary prevention mechanism (i.e., in preventing concussion injuries) unless such a ban is combined with concurrent efforts to reduce athlete-athlete contact throughout the game,” Dr. Comstock and her associates said.
Moreover, “it may be culturally more tolerable to the soccer community to attempt to reduce athlete-athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” rather than simply banning heading, they added.
Head contact with other players, not with the ball, is the main source of concussions among high-school soccer players of both sexes, according to a report published online July 13 in JAMA Pediatrics.
Several studies have shown that “heading” the ball during soccer practices and games is responsible for many soccer-related concussions, and some have called for banning such heading, especially among children and adolescents, to make the sport safer. But until now, no large study has examined the exact mechanism of head injuries among school-aged soccer players, so such prevention efforts cannot be considered evidence based, said R. Dawn Comstock, Ph.D., an epidemiologist at the University of Colorado Denver, Aurora, and her associates.
The investigators performed a retrospective analysis of data from a large, Internet-based sports injury surveillance study, focusing on concussions sustained during soccer practices or games which required medical attention and restricted the athlete’s participation for 1 or more days. They assessed nationally representative samples of 100 high schools every year for a 9-year period. There were 627 concussions during 1,393,753 athletic exposures among girls (4.50 per 10,000 exposures) and 442 concussions during 1,592,238 athletic exposures among boys (2.78 per 10,000 exposures).
The most common mechanism of concussion was player-to-player contact among both boys (68.8% of concussions) and girls (51.3% of concussions). In contrast, contact with the ball accounted for 17% of concussions among boys and 29% among girls.
The number and types of concussion symptoms were the same, regardless of whether the concussion was caused by player-to-player contact or player-to-ball contact. However, symptom resolution time was slightly but significantly longer for both boys and girls when the concussion was caused by collision with a ball or goal post (JAMA Pediatr. 2015 July 13 [doi:10.1001/jamapediatrics.2015.1062]).
“We postulate that banning heading from soccer will have limited effectiveness as a primary prevention mechanism (i.e., in preventing concussion injuries) unless such a ban is combined with concurrent efforts to reduce athlete-athlete contact throughout the game,” Dr. Comstock and her associates said.
Moreover, “it may be culturally more tolerable to the soccer community to attempt to reduce athlete-athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” rather than simply banning heading, they added.
FROM JAMA PEDIATRICS
Key clinical point: Head contact with other players, not with the ball, is the main source of concussions in high-school soccer.
Major finding: The most common mechanism of concussion was player-to-player contact among both boys (68.8% of concussions) and girls (51.3% of concussions), while contact with the ball accounted for 17% of concussions among boys and 29% among girls.
Data source: A retrospective analysis of 9 years of surveillance data regarding soccer-related concussions in a nationally representative sample of high-school boys (442 concussions in nearly 1.6 million athletic exposures) and girls (627 concussions in nearly 1.4 million athletic exposures).
Disclosures: The Centers for Disease Control and Prevention, the National Federation of State High School Associations, the National Operating Committee on Standards for Athletic Equipment, DonJoy Orthotics, and EyeBlack funded the study. Dr. Comstock and her associates reported having no relevant financial disclosures.
Therapies to Improve the Cosmetic Symptoms of Rosacea
Rosacea is a commonly encountered chronic inflammatory skin disease that affects an estimated 16 million Americans and exhibits a particular predilection for the convexities of the central face (eg, forehead, cheeks, nose, chin).1,2 The pathophysiology of rosacea remains poorly understood despite the relatively high prevalence of the disease and substantial ongoing research.3 The current paradigm suggests a complex multifactorial interplay involving aberrations of the innate and adaptive immune system, neurovascular dysregulation, blood and lymphatic vessel changes, genetic predispositions, and overgrowth of commensal organisms such as Demodex.3 Additionally, a variety of external factors may exacerbate clinical symptoms (eg, UV radiation, heat exposure, spicy food, alcohol, stress).
The diagnosis of rosacea is made clinically and rarely requires histologic confirmation. Although rosacea can present with a wide range of clinical features that often wax and wane over time, a near universal finding is diffuse centrofacial erythema.4 This centrofacial redness may symptomatically worsen during a flare period, causing flushing, but it often persists nontransiently between flares as background erythema. Other variable findings of rosacea include the presence of telangiectases, edema, plaques, phymatous changes, dry skin, ocular manifestations, and inflammatory lesions in the form of papules and pustules.5 Patients also may report a stinging or burning sensation in affected areas. It is important to note that most patients will only exhibit some of these clinical features and that symptoms often vary in the timing of their emergence or regression.5 A classification system has been developed for rosacea that categorizes the disease into 4 subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) and one variant (granulomatous).6 These categories are determined by the grouping of clinical features present, but it is not uncommon for patients to exhibit clinical manifestations of more than 1 subtype.7
The detrimental cosmetic effects of rosacea are obvious given its chronic nature and tendency to affect highly visible areas such as the face. As such, rosacea can have a devastating impact on patients’ quality of life.8 Patients with rosacea have been reported to have higher incidence rates of low self-esteem, embarrassment, social anxiety, and depression as compared to the rest of the population. Effective treatment, however, can improve cosmetic appearance and mitigate the negative psychosocial impacts of the disease.8
Treatment of rosacea focuses on relieving cosmetic symptoms, as no curative therapy currently exists. Treatment comes in a wide variety of forms, including topical medications, systemic pharmacologic therapies, light-based modalities, and procedural interventions. Choice of therapy should be determined on a case-by-case basis as guided by the clinical features present, and combination or sequential therapies often are required to achieve optimal cosmetic results. In this article, we review both existing and emerging treatments of rosacea and assess their ability to improve the cosmetic symptoms of rosacea (Table).
Skin Care
Proper skin care is an important aspect of treatment for all patients with rosacea and thus includes the use of over-the-counter cleansers, moisturizers, and sunscreens.9 The choice of skin care products is an important consideration given the often hypersensitive skin of rosacea patients. Moisturizers and cleansers should have an acidic to neutral pH, similar to normal skin. They should not contain emulsifiers that strip moisture from the skin or protective lipids and proteins from the stratum corneum.10 Moisturizers without irritants, abrasives, or allergens should be used following skin cleansing. Protection from UV radiation with sunscreen, ideally with a sun protection factor greater than 30, is particularly important, as it can prevent UV-induced rosacea flares as well as photodamage that can cause additional erythema and telangiectasia.4 Rosacea patients also may find green-tinted makeup to be useful in concealing areas of erythema.8
Topical Therapy
Currently, there are only 5 US Food and Drug Administration (FDA)–approved topical medications for the treatment of rosacea: metronidazole (MTZ) gel 0.75% and 1%, azelaic acid (AzA) gel 15%, sodium sulfacetamide (SS) 10%–sulfur 5% lotion and cream, brimonidine tartrate (BT) gel 0.5%, and the most recently approved ivermectin (IVM) cream 1%.7 Metronidazole, AzA, and SS primarily are used to treat the inflammatory papules and pustules of rosacea, while BT is used to treat persistent background erythema. The exact mechanisms of action by which MTZ, AzA, and SS treat rosacea are unclear, but they are thought to reduce inflammation and/or immune response. Metronidazole and AzA both have demonstrated favorable safety profiles and significant (P<.05) efficacy over vehicle in reducing inflammatory lesions in numerous well-controlled randomized clinical studies.4,11,12 There is some evidence that AzA may be more effective than MTZ; one 15-week multicenter, double-blind, randomized, parallel-group study demonstrated that twice-daily AzA gel 15% showed significant superiority (P=.02) over twice-daily MTZ gel 0.75% in improving the inflammatory lesions and erythema of rosacea.13 Sodium sulfacetamide also has shown good efficacy in the treatment of inflammatory lesions and performed significantly better (P=.04) than MTZ according to one multicenter, investigator-blinded, randomized, parallel-group study,14 but the overall evidence is not as strong as MTZ and AzA.4,11,15 The most common adverse effect for MTZ, AzA, and SS is application-site irritation, but overall most patients report good tolerance to these topical medications.4 Azelaic acid is unique in that patients may report stinging, tingling, or burning after application, but these effects are not associated with visible skin changes and usually are transient, generally remitting after 1 to 2 weeks.4
Brimonidine tartrate is a highly selective α2-adrenergic receptor agonist whose mechanism of action in the treatment of rosacea is thought to involve vasoconstriction of superficial skin vasculature and to a lesser extent anti-inflammatory effects.16 In a double-blind, randomized, vehicle-controlled phase 3 trial, application of BT gel 0.5% once daily for 4 weeks demonstrated significant efficacy over vehicle (P<.001) in treating persistent nontransient facial erythema in 553 adult patients with 2 or fewer papulopustular lesions as evaluated over 12 hours on days 1, 15, and 29.17 Notably, a substantial difference in cosmetic appearance was observed in another study as early as 30 minutes after the first gel application on day 1.18 The results of this phase 3 trial17 mirrored those of the phase 2 dose-optimization and safety studies of similar design.18 In addition to another long-term, 1-year, open-label study,19 both phase 2 and 3 studies have shown favorable safety profiles with no reports of tachyphylaxis, rebound erythema, or aggravation of other disease features such as telangiectases or inflammatory lesions.17,18 Recently, however, there have been some reports of considerable rebound erythema with BT use and thus patients should be made aware of this possibility.20,21 Case reports of successful treatment of background erythema and flushing with other topically applied adrenergic receptor modifiers such as oxymetazoline and xylometazoline have been published in the literature,22,23 but additional research will be necessary to validate these claims.
Ivermectin, a decades-old antiparasitic, has recently shown promising results as a treatment of rosacea patients with moderate to severe papulopustular lesions. Its therapeutic effect is believed to be mediated by its activity against Demodex, a natural skin mite that has been found at increased concentrations in a subset of patients with rosacea, as well as by its natural anti-inflammatory properties.24 In 2 identically designed, randomized, double-blind, controlled trials of IVM cream 1% applied once daily for 12 weeks, a significantly larger proportion of patients in the IVM groups achieved an investigator global assessment of clear or almost clear as compared to vehicle (IVM: 38.4% and 40.1%, respectively; vehicle: 11.6% and 18.8%, respectively; P<.001). Both trials also demonstrated that IVM was significantly superior to vehicle in the reduction of inflammatory lesion counts measured at week 12 as compared to baseline (IVM: 76.0% and 75.0%, respectively; vehicle: 50.0% and 50.0%, respectively; P<.001).24 An extension of these original trials demonstrated long-term safety with up to 52 weeks of topical IVM use and reported a low incidence rate of adverse effects, most commonly transient skin burning, pruritus, and dryness. Notably, the incidence rate of these adverse effects was lower than a comparison group receiving AzA gel 15% once daily.25 Once-daily application of IVM cream 1% also has recently demonstrated superiority over twice-daily MTZ cream 0.75% for 16 weeks in a phase 3 investigator-blinded, randomized, parallel-group study. The IVM group was significantly superior to MTZ in the reduction of inflammatory lesions as compared to baseline (83.0% vs 73.7%) and in the number of participants who achieved an investigator global assessment score of clear or almost clear (84.9% vs 75.4%)(both P<.001).26 There also is limited evidence for the use of other antiparasitic topical medications such as crotamiton 10% and permethrin 5%, but such agents frequently cause irritation and may not be well tolerated in rosacea patients.27-29
There are a variety of other non–FDA-approved topical medications that have been used with varying success in the literature, including cyclosporine, macrolides, benzoyl peroxide, retinoids, and calcineurin inhibitors such as tacrolimus and pimecrolimus. Evidence for the use of these medications generally is limited to a few studies with small numbers of patients and will not be discussed further in this article.4,11,30 These agents, however, may be useful in select cases when first-line regimens have failed and also may be good targets for future research.
Systemic Therapy
The mainstay of systemic treatment of rosacea centers around the tetracyclines, a group of antibiotics that have been used off label for rosacea since the 1950s.31 The therapeutic effects of tetracyclines in the treatment of rosacea are thought to revolve around their anti-inflammatory effects rather than their antibacterial properties.32 Currently, the only FDA-approved oral agent for treatment of the inflammatory lesions of rosacea is doxycycline 40-mg modified-release capsules taken once daily. These modified capsules allow for instant release of 30 mg and delayed release of 10 mg of doxycycline. This dosing is considered to be anti-inflammatory rather than antimicrobial, as it does not produce antibiotic selection pressure even with prolonged use.33 Efficacy of 40-mg subantimicrobial-dose doxycycline (SDD) has been demonstrated in 2 phase 3 multicenter, parallel-group, randomized, double-blind, placebo-controlled studies in which SDD demonstrated a significantly greater reduction in the number of total inflammatory lesions at week 16 compared to placebo (P<.001).34 Subantimicrobial-dose doxycycline also has been shown to be equally as efficacious in reducing inflammatory lesions as traditional-dose doxycycline.35 There also is some evidence for the efficacy of SDD in reducing overall erythema, as demonstrated by one open-label, community-based study in which SDD monotherapy resulted in clinician erythema assessment scores of mild or no erythema in 75% of patients with mild to severe rosacea at baseline after 12 weeks of therapy.35 Additionally, SDD is considered to be safe and well-tolerated and does not generally result in the adverse effects that may be seen in antibiotic-level doses of doxycycline (eg, gastrointestinal upset, vaginal candidiasis, photosensitivity).34,36,37 Other antibiotics such as clarithromycin, azithromycin, and MTZ also have been studied as treatments of papulopustular rosacea at antibiotic-level doses with good therapeutic effect.38-40 These therapies, however, generally are not used unless there are contraindications for use of tetracycline antibiotics, such as pregnancy or allergy, as the overall evidence is not as strong and there may be increased risks for serious adverse effects.30
Although it is not FDA approved, isotretinoin is an important therapeutic option for select rosacea patients, as it is the only pharmacologic agent that has shown efficacy for the phymatous changes of rosacea. Its efficacy, however, is limited to early-stage rhinophyma that has not yet progressed to the fibrotic or mucinous stages of disease in which it has been shown to reduce the size and number of cutaneous sebaceous glands.30,41 Isotretinoin at 0.3 mg/kg daily also has shown noninferiority in treatment of the inflammatory papules and pustules of rosacea as compared to antibiotic dosing of doxycycline in one large-scale, placebo-controlled, randomized, 12-week multicenter study.42 Unfortunately, recurrence is highly likely after isotretinoin therapy is discontinued.30,41 However, continuous “microdose” isotretinoin at 0.03 to 0.17 mg/kg daily has shown evidence for efficacy in treatment of recalcitrant papulopustular disease.43 Such dosing may have the added benefit of reduced risk for radiographic changes associated with long-term isotretinoin use.43
Light-Based Therapy
Light-based modalities are an important tool set in the management of rosacea symptoms, as they can treat telangiectases for which medical therapy is not generally effective.9 To a lesser extent, light-based modalities also can help alleviate background erythema. The most commonly used light-based modalities include the pulsed dye laser (PDL)(Figure), potassium titanyl phosphate (KTP) laser, Nd:YAG laser, intense pulsed light, photodynamic therapy, CO2 laser, and erbium-doped YAG (Er:YAG) laser. These treatments produce clinical results by targeting specific chromophores such as oxyhemoglobin, deoxyhemoglobin, methemoglobin, and clotted blood with light of specific wavelengths to induce thermolysis of vasculature while sparing collateral tissue.44 Generally, larger telangiectatic vessels are more amenable to therapy than smaller vessels, which usually require higher energy to be delivered in a shorter period of time, thus predisposing the patient to the development of purpura that may last for 1 to 2 weeks.44
  |
Historically, PDL used a light wavelength of 577 nm and was classically associated with posttherapy purpura; however, modern PDLs use wavelengths of 585 or 595 nm and are associated with a reduced risk for purpura through the use of longer pulse durations (ie, 10–40 millisecond), multiple minipulses, multiple passes, and advanced epidermal cooling methods.9,44 In a small, prospective, randomized, controlled, nonblinded study, PDL therapy with fluence sufficiently high enough to induce purpura achieved an approximate 50% improvement in telangiectasia grading scores in most patients after a single treatment.45 Notably, PDL therapy at purpura-inducing settings was reported to be much more efficacious than settings that did not induce purpura (purpura free), especially in the treatment of thicker telangiectases.45
Potassium titanyl phosphate lasers make use of shorter wavelengths (532 nm) than PDL and thus are better able to target superficial vasculature, which translates into a reduced risk for purpura and faster healing times. However, KTP laser therapy typically is only reserved for patients with lighter skin types, as this wavelength of light is more likely to result in higher melanin absorption and possible postinflammatory hyperpigmentation.44 A split-face study comparing the KTP laser with PDL determined that the KTP laser was able to achieve 62% clearing after the first treatment and 85% clearance after the third treatment versus 49% and 75% for PDL treatment, respectively; however, the KTP laser had higher rates of posttherapy erythema lasting at least 1 day (58% vs 8%).46
Conversely, the Nd:YAG laser uses longer wavelengths (1064 nm) and can achieve deeper skin penetration, which may be effective for larger, recalcitrant, or deeper blue-tinted vessels. A split-face, double-blind, randomized, controlled trial found Nd:YAG laser therapy to be an effective treatment of facial erythema, though it was observed to be less effective than purpura-free PDL therapy in reducing redness after 4 treatments (34% vs 52% improvement, respectively); however, treatment with the Nd:YAG laser was found to be significantly (P=.0028) less painful.47
Intense pulsed light is unique from the previously discussed light-based therapies in that it uses noncoherent light with wavelengths between 500 and 1200 nm. Cutoff filters may be used to allow for more selective tissue damage depending on the depth of penetration desired. Intense pulsed light has been shown to be equally as efficacious as purpura-free PDL therapy in the treatment of erythema and telangiectasia in a randomized, controlled, single-blind, split-face trial.48 Additionally, a study of 200 patients with facial vascular lesions, of whom 74 patients had rosacea, showed that intense pulsed light therapy resulted in a 75% to 100% improvement of lesions in 174 of 188 (92.5%) patients who returned for follow-up. Treatment often required at least 2 sessions, but overall adverse effects were reported to be minimal.49
Photodynamic therapy is a well-studied and often utilized treatment of a variety of skin conditions, but there have only been a few studies regarding its use in rosacea. Photodynamic therapy involves the use of topically applied photosensitizing agents such as 5-aminolevulinic acid or methyl aminolevulinate before exposure to red or blue light. This process generates reactive oxygen species, though the exact mechanism of action through which patients achieve cosmetic improvement in rosacea is unclear. In one study of 17 patients with varying rosacea subtypes treated with methyl aminolevulinate and red light, drastic relief of symptoms was seen in 10 (58.8%) patients, marked improvement in 4 (23.5%) patients, and no response in 3 (17.6%) patients. Most patients report a transient irritant skin reaction at the site of therapy.50
Ablative lasers such as the CO2 (10,600 nm) and Er:YAG (2940 nm) lasers also have been shown to be useful in the treatment of rosacea, specifically for the management of rhinophymatous features. Excellent results have been achieved with these lasers given their ability to provide near-bloodless surgical fields. In a 13-year review of 124 patients with rhinophyma receiving a single CO2 laser treatment, good to excellent results were achieved in 118 (95.2%) of patients when evaluated at 3 months posttreatment.51 Patient satisfaction also is reported to be high with few adverse effects reported. The evidence for the Er:YAG laser is not as strong, but the current reports indicate efficacy and safety similar to that of the CO2 laser.52
Procedural Therapies
Procedural therapies in rosacea generally are reserved for management of rhinophyma and include electrocautery, cryotherapy, radiotherapy, dermabrasion, scalpel excisions, flap reconstruction, and skin grafts.30,53 The details and evidence for these methods is beyond the scope of this paper, but it is important to be aware of such modalities. As with most surgical procedures, operator skill and experience may affect treatment outcomes, and there also are definite risks for postprocedural scarring, swelling, erythema, and pigmentation changes. Recently, anecdotal evidence has shown that botulinum toxin injections may be effective for patients with refractory flushing and erythema, but larger studies will be necessary to better assess these claims.54,55
Conclusion
Although recent advances in pharmacology and laser technology have provided physicians with new and effective treatment modalities for rosacea, it remains a poorly understood disease without a definitive cure. The negative impact of rosacea on patients’ quality of life can be substantial, but effective management of cosmetic symptoms can minimize such deleterious effects. Therapy should be individualized and directed at treating the symptoms that are most bothersome to the patient. Additionally, effective treatment often will require a combination of modalities or sequential therapies to achieve optimal cosmetic outcomes.
1. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 suppl 1):S27-S35.
2. Rosacea prevalence map. National Rosacea Society Web site. http://rosacea.org/press/prevalencemap. Accessed June 16, 2015.
3. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 suppl 1):S15-S26.
4. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 1: a status report on the disease state, general measures, and adjunctive skin care. Cutis. 2013;92:234-240.
5. Wilkin J, Dahl M, Detmar M, et al. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2004;50:907-912.
6. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society expert committee on the classification and staging of rosacea. J Am Acad Dermatol. 2002;46:584-587.
7. Feldman SR, Huang WW, Huynh TT. Current drug therapies for rosacea: a chronic vascular and inflammatory skin disease. J Manag Care Spec Pharm. 2014;20:623-629.
8. Moustafa F, Lewallen RS, Feldman SR. The psychological impact of rosacea and the influence of current management options. J Am Acad Dermatol. 2014;71:973-980.
9. Mansouri Y, Goldenberg G. Devices and topical agents for rosacea management. Cutis. 2014;94:21-25.
10. Levin J, Miller R. A guide to the ingredients and potential benefits of over-the-counter cleansers and moisturizers for rosacea patients. J Clin Aesthet Dermatol. 2011;4:31-49.
11. van Zuuren EJ, Kramer S, Carter B, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2011;3:CD003262.
12. Liu RH, Smith MK, Basta SA, et al. Azelaic acid in the treatment of papulopustular rosacea: a systematic review of randomized controlled trials. Arch Dermatol. 2006;142:1047-1052.
13. Elewski B, Fleischer AB Jr, Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003;139:1444-1450.
14. Torok HM, Webster G, Dunlap FE, et al. Combination sodium sulfacetamide 10% and sulfur 5% cream with sunscreens versus metronidazole 0.75% cream for rosacea. Cutis. 2005;75:357-363.
15. Trumbore MW, Goldstein JA, Gurge RM. Treatment of papulopustular rosacea with sodium sulfacetamide 10%/sulfur 5% emollient foam. J Drugs Dermatol. 2009;8:299-304.
16. Piwnica D, Rosignoli C, de Menonville ST, et al. Vasoconstriction and anti-inflammatory properties of the selective alpha-adrenergic receptor agonist brimonidine. J Dermatol Sci. 2014;75:49-54.
17. Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12:650-656.
18. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate gel 0.5% is a novel treatment of moderate to severe facial erythema of rosacea: results of two multicenter, randomized and vehicle-controlled studies. Br J Dermatol. 2012;166:633-641.
19. Moore A, Kempers S, Murakawa G, et al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol. 2014;13:56-61.
20. Routt ET, Levitt JO. Rebound erythema and burning sensation from a new topical brimonidine tartrate gel 0.33%. J Am Acad Dermatol. 2014;70:e37-e38.
21. Ilkovitch D, Pomerantz RG. Brimonidine effective but may lead to significant rebound erythema. J Am Acad Dermatol. 2014;70:e109-e110.
22. Kim JH, Oh YS, Ji JH, et al. Rosacea (erythematotelangiectatic type) effectively improved by topical xylometazoline. J Dermatol. 2011;38:510-513.
23. Shanler SD, Ondo AL. Successful treatment of erythema and flushing of rosacea using a topically applied selective alpha1-adrenergic receptor antagonist, oxymetazoline. Arch Dermatol. 2007;143:1369-1371.
24. Stein-Gold L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13:316-323.
25. Stein-Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled, investigator-blinded trials. J Drugs Dermatol. 2014;13:1380-1386.
26. Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015;172:1103-1110.
27. Koçak M, Ya˘gli S, Vahapo˘glu G, et al. Permethrin 5% cream versus metronidazole 0.75% gel for the treatment of papulopustular rosacea. a randomized double-blind placebo-controlled study. Dermatology (Basel). 2002;205:265-270.
28. Bikowski JB, Del Rosso JQ. Demodex dermatitis: a retrospective analysis of clinical diagnosis and successful treatment with topical crotamiton. J Clin Aesthet Dermatol. 2009;2:20-25.
29. Layton A, Thiboutot D. Emerging therapies in rosacea. J Am Acad Dermatol. 2013;69(6 suppl 1):S57-S65.
30. Pelle MT, Crawford GH, James WD. Rosacea: II. therapy. J Am Acad Dermatol. 2004;51:499-512, quiz 513-514.
31. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54:258-265.
32. Korting HC, Schöllmann C. Tetracycline actions relevant to rosacea treatment. Skin Pharmacol Physiol. 2009;22:287-294.
33. Thomas J, Walker C, Bradshaw M. Long-term use of subantimicrobial dose doxycycline does not lead to changes in antimicrobial susceptibility. J Periodontol. 2000;71:1472-1483.
34. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56:791-802.
35. Webster GF. An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads). Cutis. 2010;86(suppl 5):7-15.
36. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-576.
37. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies. Cutis. 2014;93:18-28.
38. Torresani C. Clarithromycin: a new perspective in rosacea treatment. Int J Dermatol. 1998;37:347-349.
39. Bakar O, Demircay Z, Gürbüz O. Therapeutic potential of azithromycin in rosacea. Int J Dermatol. 2004;43:151-154.
40. Saihan EM, Burton JL. A double-blind trial of metronidazole versus oxytetracycline therapy for rosacea. Br J Dermatol. 1980;102:443-445.
41. Park H, Del Rosso JQ. Use of oral isotretinoin in the management of rosacea. J Clin Aesthet Dermatol. 2011;4:54-61.
42. Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea—doxycycline-and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010;8:505-515.
43. Hofer T. Continuous “microdose” isotretinoin in adult recalcitrant rosacea. Clin Exp Dermatol. 2004;29:204-205.
44. Tanghetti E, Del Rosso JQ, Thiboutot D, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 4: a status report on physical modalities and devices. Cutis. 2014;93:71-76.
45. Alam M, Dover JS, Arndt KA. Treatment of facial telangiectasia with variable-pulse high-fluence pulsed-dye laser: comparison of efficacy with fluences immediately above and below the purpura threshold. Dermatol Surg. 2003;29:681-684.
46. Uebelhoer NS, Bogle MA, Stewart B, et al. A split-face comparison study of pulsed 532-nm KTP laser and 595-nm pulsed dye laser in the treatment of facial telangiectasias and diffuse telangiectatic facial erythema. Dermatol Surg. 2007;33:441-448.
47. Alam M, Voravutinon N, Warycha M, et al. Comparative effectiveness of nonpurpuragenic 595-nm pulsed dye laser and microsecond 1064-nm neodymium:yttrium-aluminum-garnet laser for treatment of diffuse facial erythema: a double-blind randomized controlled trial. J Am Acad Dermatol. 2013;69:438-443.
48. Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg. 2009;35:920-928.
49. Angermeier MC. Treatment of facial vascular lesions with intense pulsed light. J Cutan Laser Ther. 1999;1:95-100.
50. Bryld LE, Jemec GB. Photodynamic therapy in a series of rosacea patients. J Eur Acad Dermatol Venereol. 2007;21:1199-1202.
51. Maden V, Ferguson JE, August PJ. Carbon dioxide laser treatment of rhinophyma: a review of 124 patients. Br J Dermatol. 2009;161:814-818.
52. Fincher EF, Gladstone HB. Use of a dual-mode erbium:YAG laser for the surgical correction of rhinophyma. Arch Facial Plast Surg. 2004;6:267-271.
53. Lloyd KM. Surgical correction of rhinophyma. Arch Dermatol. 1990;126:721-723.
54. Dayan SH, Pritzker RN, Arkins JP. A new treatment regimen for rosacea: onabotulinumtoxinA. J Drugs Dermatol. 2012;11:e76-e79.
55. Park KY, Hyun MY, Jeong SY, et al. Botulinum toxin for the treatment of refractory erythema and flushing of rosacea. Dermatology. 2015;230:299-301.
Rosacea is a commonly encountered chronic inflammatory skin disease that affects an estimated 16 million Americans and exhibits a particular predilection for the convexities of the central face (eg, forehead, cheeks, nose, chin).1,2 The pathophysiology of rosacea remains poorly understood despite the relatively high prevalence of the disease and substantial ongoing research.3 The current paradigm suggests a complex multifactorial interplay involving aberrations of the innate and adaptive immune system, neurovascular dysregulation, blood and lymphatic vessel changes, genetic predispositions, and overgrowth of commensal organisms such as Demodex.3 Additionally, a variety of external factors may exacerbate clinical symptoms (eg, UV radiation, heat exposure, spicy food, alcohol, stress).
The diagnosis of rosacea is made clinically and rarely requires histologic confirmation. Although rosacea can present with a wide range of clinical features that often wax and wane over time, a near universal finding is diffuse centrofacial erythema.4 This centrofacial redness may symptomatically worsen during a flare period, causing flushing, but it often persists nontransiently between flares as background erythema. Other variable findings of rosacea include the presence of telangiectases, edema, plaques, phymatous changes, dry skin, ocular manifestations, and inflammatory lesions in the form of papules and pustules.5 Patients also may report a stinging or burning sensation in affected areas. It is important to note that most patients will only exhibit some of these clinical features and that symptoms often vary in the timing of their emergence or regression.5 A classification system has been developed for rosacea that categorizes the disease into 4 subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) and one variant (granulomatous).6 These categories are determined by the grouping of clinical features present, but it is not uncommon for patients to exhibit clinical manifestations of more than 1 subtype.7
The detrimental cosmetic effects of rosacea are obvious given its chronic nature and tendency to affect highly visible areas such as the face. As such, rosacea can have a devastating impact on patients’ quality of life.8 Patients with rosacea have been reported to have higher incidence rates of low self-esteem, embarrassment, social anxiety, and depression as compared to the rest of the population. Effective treatment, however, can improve cosmetic appearance and mitigate the negative psychosocial impacts of the disease.8
Treatment of rosacea focuses on relieving cosmetic symptoms, as no curative therapy currently exists. Treatment comes in a wide variety of forms, including topical medications, systemic pharmacologic therapies, light-based modalities, and procedural interventions. Choice of therapy should be determined on a case-by-case basis as guided by the clinical features present, and combination or sequential therapies often are required to achieve optimal cosmetic results. In this article, we review both existing and emerging treatments of rosacea and assess their ability to improve the cosmetic symptoms of rosacea (Table).
Skin Care
Proper skin care is an important aspect of treatment for all patients with rosacea and thus includes the use of over-the-counter cleansers, moisturizers, and sunscreens.9 The choice of skin care products is an important consideration given the often hypersensitive skin of rosacea patients. Moisturizers and cleansers should have an acidic to neutral pH, similar to normal skin. They should not contain emulsifiers that strip moisture from the skin or protective lipids and proteins from the stratum corneum.10 Moisturizers without irritants, abrasives, or allergens should be used following skin cleansing. Protection from UV radiation with sunscreen, ideally with a sun protection factor greater than 30, is particularly important, as it can prevent UV-induced rosacea flares as well as photodamage that can cause additional erythema and telangiectasia.4 Rosacea patients also may find green-tinted makeup to be useful in concealing areas of erythema.8
Topical Therapy
Currently, there are only 5 US Food and Drug Administration (FDA)–approved topical medications for the treatment of rosacea: metronidazole (MTZ) gel 0.75% and 1%, azelaic acid (AzA) gel 15%, sodium sulfacetamide (SS) 10%–sulfur 5% lotion and cream, brimonidine tartrate (BT) gel 0.5%, and the most recently approved ivermectin (IVM) cream 1%.7 Metronidazole, AzA, and SS primarily are used to treat the inflammatory papules and pustules of rosacea, while BT is used to treat persistent background erythema. The exact mechanisms of action by which MTZ, AzA, and SS treat rosacea are unclear, but they are thought to reduce inflammation and/or immune response. Metronidazole and AzA both have demonstrated favorable safety profiles and significant (P<.05) efficacy over vehicle in reducing inflammatory lesions in numerous well-controlled randomized clinical studies.4,11,12 There is some evidence that AzA may be more effective than MTZ; one 15-week multicenter, double-blind, randomized, parallel-group study demonstrated that twice-daily AzA gel 15% showed significant superiority (P=.02) over twice-daily MTZ gel 0.75% in improving the inflammatory lesions and erythema of rosacea.13 Sodium sulfacetamide also has shown good efficacy in the treatment of inflammatory lesions and performed significantly better (P=.04) than MTZ according to one multicenter, investigator-blinded, randomized, parallel-group study,14 but the overall evidence is not as strong as MTZ and AzA.4,11,15 The most common adverse effect for MTZ, AzA, and SS is application-site irritation, but overall most patients report good tolerance to these topical medications.4 Azelaic acid is unique in that patients may report stinging, tingling, or burning after application, but these effects are not associated with visible skin changes and usually are transient, generally remitting after 1 to 2 weeks.4
Brimonidine tartrate is a highly selective α2-adrenergic receptor agonist whose mechanism of action in the treatment of rosacea is thought to involve vasoconstriction of superficial skin vasculature and to a lesser extent anti-inflammatory effects.16 In a double-blind, randomized, vehicle-controlled phase 3 trial, application of BT gel 0.5% once daily for 4 weeks demonstrated significant efficacy over vehicle (P<.001) in treating persistent nontransient facial erythema in 553 adult patients with 2 or fewer papulopustular lesions as evaluated over 12 hours on days 1, 15, and 29.17 Notably, a substantial difference in cosmetic appearance was observed in another study as early as 30 minutes after the first gel application on day 1.18 The results of this phase 3 trial17 mirrored those of the phase 2 dose-optimization and safety studies of similar design.18 In addition to another long-term, 1-year, open-label study,19 both phase 2 and 3 studies have shown favorable safety profiles with no reports of tachyphylaxis, rebound erythema, or aggravation of other disease features such as telangiectases or inflammatory lesions.17,18 Recently, however, there have been some reports of considerable rebound erythema with BT use and thus patients should be made aware of this possibility.20,21 Case reports of successful treatment of background erythema and flushing with other topically applied adrenergic receptor modifiers such as oxymetazoline and xylometazoline have been published in the literature,22,23 but additional research will be necessary to validate these claims.
Ivermectin, a decades-old antiparasitic, has recently shown promising results as a treatment of rosacea patients with moderate to severe papulopustular lesions. Its therapeutic effect is believed to be mediated by its activity against Demodex, a natural skin mite that has been found at increased concentrations in a subset of patients with rosacea, as well as by its natural anti-inflammatory properties.24 In 2 identically designed, randomized, double-blind, controlled trials of IVM cream 1% applied once daily for 12 weeks, a significantly larger proportion of patients in the IVM groups achieved an investigator global assessment of clear or almost clear as compared to vehicle (IVM: 38.4% and 40.1%, respectively; vehicle: 11.6% and 18.8%, respectively; P<.001). Both trials also demonstrated that IVM was significantly superior to vehicle in the reduction of inflammatory lesion counts measured at week 12 as compared to baseline (IVM: 76.0% and 75.0%, respectively; vehicle: 50.0% and 50.0%, respectively; P<.001).24 An extension of these original trials demonstrated long-term safety with up to 52 weeks of topical IVM use and reported a low incidence rate of adverse effects, most commonly transient skin burning, pruritus, and dryness. Notably, the incidence rate of these adverse effects was lower than a comparison group receiving AzA gel 15% once daily.25 Once-daily application of IVM cream 1% also has recently demonstrated superiority over twice-daily MTZ cream 0.75% for 16 weeks in a phase 3 investigator-blinded, randomized, parallel-group study. The IVM group was significantly superior to MTZ in the reduction of inflammatory lesions as compared to baseline (83.0% vs 73.7%) and in the number of participants who achieved an investigator global assessment score of clear or almost clear (84.9% vs 75.4%)(both P<.001).26 There also is limited evidence for the use of other antiparasitic topical medications such as crotamiton 10% and permethrin 5%, but such agents frequently cause irritation and may not be well tolerated in rosacea patients.27-29
There are a variety of other non–FDA-approved topical medications that have been used with varying success in the literature, including cyclosporine, macrolides, benzoyl peroxide, retinoids, and calcineurin inhibitors such as tacrolimus and pimecrolimus. Evidence for the use of these medications generally is limited to a few studies with small numbers of patients and will not be discussed further in this article.4,11,30 These agents, however, may be useful in select cases when first-line regimens have failed and also may be good targets for future research.
Systemic Therapy
The mainstay of systemic treatment of rosacea centers around the tetracyclines, a group of antibiotics that have been used off label for rosacea since the 1950s.31 The therapeutic effects of tetracyclines in the treatment of rosacea are thought to revolve around their anti-inflammatory effects rather than their antibacterial properties.32 Currently, the only FDA-approved oral agent for treatment of the inflammatory lesions of rosacea is doxycycline 40-mg modified-release capsules taken once daily. These modified capsules allow for instant release of 30 mg and delayed release of 10 mg of doxycycline. This dosing is considered to be anti-inflammatory rather than antimicrobial, as it does not produce antibiotic selection pressure even with prolonged use.33 Efficacy of 40-mg subantimicrobial-dose doxycycline (SDD) has been demonstrated in 2 phase 3 multicenter, parallel-group, randomized, double-blind, placebo-controlled studies in which SDD demonstrated a significantly greater reduction in the number of total inflammatory lesions at week 16 compared to placebo (P<.001).34 Subantimicrobial-dose doxycycline also has been shown to be equally as efficacious in reducing inflammatory lesions as traditional-dose doxycycline.35 There also is some evidence for the efficacy of SDD in reducing overall erythema, as demonstrated by one open-label, community-based study in which SDD monotherapy resulted in clinician erythema assessment scores of mild or no erythema in 75% of patients with mild to severe rosacea at baseline after 12 weeks of therapy.35 Additionally, SDD is considered to be safe and well-tolerated and does not generally result in the adverse effects that may be seen in antibiotic-level doses of doxycycline (eg, gastrointestinal upset, vaginal candidiasis, photosensitivity).34,36,37 Other antibiotics such as clarithromycin, azithromycin, and MTZ also have been studied as treatments of papulopustular rosacea at antibiotic-level doses with good therapeutic effect.38-40 These therapies, however, generally are not used unless there are contraindications for use of tetracycline antibiotics, such as pregnancy or allergy, as the overall evidence is not as strong and there may be increased risks for serious adverse effects.30
Although it is not FDA approved, isotretinoin is an important therapeutic option for select rosacea patients, as it is the only pharmacologic agent that has shown efficacy for the phymatous changes of rosacea. Its efficacy, however, is limited to early-stage rhinophyma that has not yet progressed to the fibrotic or mucinous stages of disease in which it has been shown to reduce the size and number of cutaneous sebaceous glands.30,41 Isotretinoin at 0.3 mg/kg daily also has shown noninferiority in treatment of the inflammatory papules and pustules of rosacea as compared to antibiotic dosing of doxycycline in one large-scale, placebo-controlled, randomized, 12-week multicenter study.42 Unfortunately, recurrence is highly likely after isotretinoin therapy is discontinued.30,41 However, continuous “microdose” isotretinoin at 0.03 to 0.17 mg/kg daily has shown evidence for efficacy in treatment of recalcitrant papulopustular disease.43 Such dosing may have the added benefit of reduced risk for radiographic changes associated with long-term isotretinoin use.43
Light-Based Therapy
Light-based modalities are an important tool set in the management of rosacea symptoms, as they can treat telangiectases for which medical therapy is not generally effective.9 To a lesser extent, light-based modalities also can help alleviate background erythema. The most commonly used light-based modalities include the pulsed dye laser (PDL)(Figure), potassium titanyl phosphate (KTP) laser, Nd:YAG laser, intense pulsed light, photodynamic therapy, CO2 laser, and erbium-doped YAG (Er:YAG) laser. These treatments produce clinical results by targeting specific chromophores such as oxyhemoglobin, deoxyhemoglobin, methemoglobin, and clotted blood with light of specific wavelengths to induce thermolysis of vasculature while sparing collateral tissue.44 Generally, larger telangiectatic vessels are more amenable to therapy than smaller vessels, which usually require higher energy to be delivered in a shorter period of time, thus predisposing the patient to the development of purpura that may last for 1 to 2 weeks.44
|
Historically, PDL used a light wavelength of 577 nm and was classically associated with posttherapy purpura; however, modern PDLs use wavelengths of 585 or 595 nm and are associated with a reduced risk for purpura through the use of longer pulse durations (ie, 10–40 millisecond), multiple minipulses, multiple passes, and advanced epidermal cooling methods.9,44 In a small, prospective, randomized, controlled, nonblinded study, PDL therapy with fluence sufficiently high enough to induce purpura achieved an approximate 50% improvement in telangiectasia grading scores in most patients after a single treatment.45 Notably, PDL therapy at purpura-inducing settings was reported to be much more efficacious than settings that did not induce purpura (purpura free), especially in the treatment of thicker telangiectases.45
Potassium titanyl phosphate lasers make use of shorter wavelengths (532 nm) than PDL and thus are better able to target superficial vasculature, which translates into a reduced risk for purpura and faster healing times. However, KTP laser therapy typically is only reserved for patients with lighter skin types, as this wavelength of light is more likely to result in higher melanin absorption and possible postinflammatory hyperpigmentation.44 A split-face study comparing the KTP laser with PDL determined that the KTP laser was able to achieve 62% clearing after the first treatment and 85% clearance after the third treatment versus 49% and 75% for PDL treatment, respectively; however, the KTP laser had higher rates of posttherapy erythema lasting at least 1 day (58% vs 8%).46
Conversely, the Nd:YAG laser uses longer wavelengths (1064 nm) and can achieve deeper skin penetration, which may be effective for larger, recalcitrant, or deeper blue-tinted vessels. A split-face, double-blind, randomized, controlled trial found Nd:YAG laser therapy to be an effective treatment of facial erythema, though it was observed to be less effective than purpura-free PDL therapy in reducing redness after 4 treatments (34% vs 52% improvement, respectively); however, treatment with the Nd:YAG laser was found to be significantly (P=.0028) less painful.47
Intense pulsed light is unique from the previously discussed light-based therapies in that it uses noncoherent light with wavelengths between 500 and 1200 nm. Cutoff filters may be used to allow for more selective tissue damage depending on the depth of penetration desired. Intense pulsed light has been shown to be equally as efficacious as purpura-free PDL therapy in the treatment of erythema and telangiectasia in a randomized, controlled, single-blind, split-face trial.48 Additionally, a study of 200 patients with facial vascular lesions, of whom 74 patients had rosacea, showed that intense pulsed light therapy resulted in a 75% to 100% improvement of lesions in 174 of 188 (92.5%) patients who returned for follow-up. Treatment often required at least 2 sessions, but overall adverse effects were reported to be minimal.49
Photodynamic therapy is a well-studied and often utilized treatment of a variety of skin conditions, but there have only been a few studies regarding its use in rosacea. Photodynamic therapy involves the use of topically applied photosensitizing agents such as 5-aminolevulinic acid or methyl aminolevulinate before exposure to red or blue light. This process generates reactive oxygen species, though the exact mechanism of action through which patients achieve cosmetic improvement in rosacea is unclear. In one study of 17 patients with varying rosacea subtypes treated with methyl aminolevulinate and red light, drastic relief of symptoms was seen in 10 (58.8%) patients, marked improvement in 4 (23.5%) patients, and no response in 3 (17.6%) patients. Most patients report a transient irritant skin reaction at the site of therapy.50
Ablative lasers such as the CO2 (10,600 nm) and Er:YAG (2940 nm) lasers also have been shown to be useful in the treatment of rosacea, specifically for the management of rhinophymatous features. Excellent results have been achieved with these lasers given their ability to provide near-bloodless surgical fields. In a 13-year review of 124 patients with rhinophyma receiving a single CO2 laser treatment, good to excellent results were achieved in 118 (95.2%) of patients when evaluated at 3 months posttreatment.51 Patient satisfaction also is reported to be high with few adverse effects reported. The evidence for the Er:YAG laser is not as strong, but the current reports indicate efficacy and safety similar to that of the CO2 laser.52
Procedural Therapies
Procedural therapies in rosacea generally are reserved for management of rhinophyma and include electrocautery, cryotherapy, radiotherapy, dermabrasion, scalpel excisions, flap reconstruction, and skin grafts.30,53 The details and evidence for these methods is beyond the scope of this paper, but it is important to be aware of such modalities. As with most surgical procedures, operator skill and experience may affect treatment outcomes, and there also are definite risks for postprocedural scarring, swelling, erythema, and pigmentation changes. Recently, anecdotal evidence has shown that botulinum toxin injections may be effective for patients with refractory flushing and erythema, but larger studies will be necessary to better assess these claims.54,55
Conclusion
Although recent advances in pharmacology and laser technology have provided physicians with new and effective treatment modalities for rosacea, it remains a poorly understood disease without a definitive cure. The negative impact of rosacea on patients’ quality of life can be substantial, but effective management of cosmetic symptoms can minimize such deleterious effects. Therapy should be individualized and directed at treating the symptoms that are most bothersome to the patient. Additionally, effective treatment often will require a combination of modalities or sequential therapies to achieve optimal cosmetic outcomes.
Rosacea is a commonly encountered chronic inflammatory skin disease that affects an estimated 16 million Americans and exhibits a particular predilection for the convexities of the central face (eg, forehead, cheeks, nose, chin).1,2 The pathophysiology of rosacea remains poorly understood despite the relatively high prevalence of the disease and substantial ongoing research.3 The current paradigm suggests a complex multifactorial interplay involving aberrations of the innate and adaptive immune system, neurovascular dysregulation, blood and lymphatic vessel changes, genetic predispositions, and overgrowth of commensal organisms such as Demodex.3 Additionally, a variety of external factors may exacerbate clinical symptoms (eg, UV radiation, heat exposure, spicy food, alcohol, stress).
The diagnosis of rosacea is made clinically and rarely requires histologic confirmation. Although rosacea can present with a wide range of clinical features that often wax and wane over time, a near universal finding is diffuse centrofacial erythema.4 This centrofacial redness may symptomatically worsen during a flare period, causing flushing, but it often persists nontransiently between flares as background erythema. Other variable findings of rosacea include the presence of telangiectases, edema, plaques, phymatous changes, dry skin, ocular manifestations, and inflammatory lesions in the form of papules and pustules.5 Patients also may report a stinging or burning sensation in affected areas. It is important to note that most patients will only exhibit some of these clinical features and that symptoms often vary in the timing of their emergence or regression.5 A classification system has been developed for rosacea that categorizes the disease into 4 subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) and one variant (granulomatous).6 These categories are determined by the grouping of clinical features present, but it is not uncommon for patients to exhibit clinical manifestations of more than 1 subtype.7
The detrimental cosmetic effects of rosacea are obvious given its chronic nature and tendency to affect highly visible areas such as the face. As such, rosacea can have a devastating impact on patients’ quality of life.8 Patients with rosacea have been reported to have higher incidence rates of low self-esteem, embarrassment, social anxiety, and depression as compared to the rest of the population. Effective treatment, however, can improve cosmetic appearance and mitigate the negative psychosocial impacts of the disease.8
Treatment of rosacea focuses on relieving cosmetic symptoms, as no curative therapy currently exists. Treatment comes in a wide variety of forms, including topical medications, systemic pharmacologic therapies, light-based modalities, and procedural interventions. Choice of therapy should be determined on a case-by-case basis as guided by the clinical features present, and combination or sequential therapies often are required to achieve optimal cosmetic results. In this article, we review both existing and emerging treatments of rosacea and assess their ability to improve the cosmetic symptoms of rosacea (Table).
Skin Care
Proper skin care is an important aspect of treatment for all patients with rosacea and thus includes the use of over-the-counter cleansers, moisturizers, and sunscreens.9 The choice of skin care products is an important consideration given the often hypersensitive skin of rosacea patients. Moisturizers and cleansers should have an acidic to neutral pH, similar to normal skin. They should not contain emulsifiers that strip moisture from the skin or protective lipids and proteins from the stratum corneum.10 Moisturizers without irritants, abrasives, or allergens should be used following skin cleansing. Protection from UV radiation with sunscreen, ideally with a sun protection factor greater than 30, is particularly important, as it can prevent UV-induced rosacea flares as well as photodamage that can cause additional erythema and telangiectasia.4 Rosacea patients also may find green-tinted makeup to be useful in concealing areas of erythema.8
Topical Therapy
Currently, there are only 5 US Food and Drug Administration (FDA)–approved topical medications for the treatment of rosacea: metronidazole (MTZ) gel 0.75% and 1%, azelaic acid (AzA) gel 15%, sodium sulfacetamide (SS) 10%–sulfur 5% lotion and cream, brimonidine tartrate (BT) gel 0.5%, and the most recently approved ivermectin (IVM) cream 1%.7 Metronidazole, AzA, and SS primarily are used to treat the inflammatory papules and pustules of rosacea, while BT is used to treat persistent background erythema. The exact mechanisms of action by which MTZ, AzA, and SS treat rosacea are unclear, but they are thought to reduce inflammation and/or immune response. Metronidazole and AzA both have demonstrated favorable safety profiles and significant (P<.05) efficacy over vehicle in reducing inflammatory lesions in numerous well-controlled randomized clinical studies.4,11,12 There is some evidence that AzA may be more effective than MTZ; one 15-week multicenter, double-blind, randomized, parallel-group study demonstrated that twice-daily AzA gel 15% showed significant superiority (P=.02) over twice-daily MTZ gel 0.75% in improving the inflammatory lesions and erythema of rosacea.13 Sodium sulfacetamide also has shown good efficacy in the treatment of inflammatory lesions and performed significantly better (P=.04) than MTZ according to one multicenter, investigator-blinded, randomized, parallel-group study,14 but the overall evidence is not as strong as MTZ and AzA.4,11,15 The most common adverse effect for MTZ, AzA, and SS is application-site irritation, but overall most patients report good tolerance to these topical medications.4 Azelaic acid is unique in that patients may report stinging, tingling, or burning after application, but these effects are not associated with visible skin changes and usually are transient, generally remitting after 1 to 2 weeks.4
Brimonidine tartrate is a highly selective α2-adrenergic receptor agonist whose mechanism of action in the treatment of rosacea is thought to involve vasoconstriction of superficial skin vasculature and to a lesser extent anti-inflammatory effects.16 In a double-blind, randomized, vehicle-controlled phase 3 trial, application of BT gel 0.5% once daily for 4 weeks demonstrated significant efficacy over vehicle (P<.001) in treating persistent nontransient facial erythema in 553 adult patients with 2 or fewer papulopustular lesions as evaluated over 12 hours on days 1, 15, and 29.17 Notably, a substantial difference in cosmetic appearance was observed in another study as early as 30 minutes after the first gel application on day 1.18 The results of this phase 3 trial17 mirrored those of the phase 2 dose-optimization and safety studies of similar design.18 In addition to another long-term, 1-year, open-label study,19 both phase 2 and 3 studies have shown favorable safety profiles with no reports of tachyphylaxis, rebound erythema, or aggravation of other disease features such as telangiectases or inflammatory lesions.17,18 Recently, however, there have been some reports of considerable rebound erythema with BT use and thus patients should be made aware of this possibility.20,21 Case reports of successful treatment of background erythema and flushing with other topically applied adrenergic receptor modifiers such as oxymetazoline and xylometazoline have been published in the literature,22,23 but additional research will be necessary to validate these claims.
Ivermectin, a decades-old antiparasitic, has recently shown promising results as a treatment of rosacea patients with moderate to severe papulopustular lesions. Its therapeutic effect is believed to be mediated by its activity against Demodex, a natural skin mite that has been found at increased concentrations in a subset of patients with rosacea, as well as by its natural anti-inflammatory properties.24 In 2 identically designed, randomized, double-blind, controlled trials of IVM cream 1% applied once daily for 12 weeks, a significantly larger proportion of patients in the IVM groups achieved an investigator global assessment of clear or almost clear as compared to vehicle (IVM: 38.4% and 40.1%, respectively; vehicle: 11.6% and 18.8%, respectively; P<.001). Both trials also demonstrated that IVM was significantly superior to vehicle in the reduction of inflammatory lesion counts measured at week 12 as compared to baseline (IVM: 76.0% and 75.0%, respectively; vehicle: 50.0% and 50.0%, respectively; P<.001).24 An extension of these original trials demonstrated long-term safety with up to 52 weeks of topical IVM use and reported a low incidence rate of adverse effects, most commonly transient skin burning, pruritus, and dryness. Notably, the incidence rate of these adverse effects was lower than a comparison group receiving AzA gel 15% once daily.25 Once-daily application of IVM cream 1% also has recently demonstrated superiority over twice-daily MTZ cream 0.75% for 16 weeks in a phase 3 investigator-blinded, randomized, parallel-group study. The IVM group was significantly superior to MTZ in the reduction of inflammatory lesions as compared to baseline (83.0% vs 73.7%) and in the number of participants who achieved an investigator global assessment score of clear or almost clear (84.9% vs 75.4%)(both P<.001).26 There also is limited evidence for the use of other antiparasitic topical medications such as crotamiton 10% and permethrin 5%, but such agents frequently cause irritation and may not be well tolerated in rosacea patients.27-29
There are a variety of other non–FDA-approved topical medications that have been used with varying success in the literature, including cyclosporine, macrolides, benzoyl peroxide, retinoids, and calcineurin inhibitors such as tacrolimus and pimecrolimus. Evidence for the use of these medications generally is limited to a few studies with small numbers of patients and will not be discussed further in this article.4,11,30 These agents, however, may be useful in select cases when first-line regimens have failed and also may be good targets for future research.
Systemic Therapy
The mainstay of systemic treatment of rosacea centers around the tetracyclines, a group of antibiotics that have been used off label for rosacea since the 1950s.31 The therapeutic effects of tetracyclines in the treatment of rosacea are thought to revolve around their anti-inflammatory effects rather than their antibacterial properties.32 Currently, the only FDA-approved oral agent for treatment of the inflammatory lesions of rosacea is doxycycline 40-mg modified-release capsules taken once daily. These modified capsules allow for instant release of 30 mg and delayed release of 10 mg of doxycycline. This dosing is considered to be anti-inflammatory rather than antimicrobial, as it does not produce antibiotic selection pressure even with prolonged use.33 Efficacy of 40-mg subantimicrobial-dose doxycycline (SDD) has been demonstrated in 2 phase 3 multicenter, parallel-group, randomized, double-blind, placebo-controlled studies in which SDD demonstrated a significantly greater reduction in the number of total inflammatory lesions at week 16 compared to placebo (P<.001).34 Subantimicrobial-dose doxycycline also has been shown to be equally as efficacious in reducing inflammatory lesions as traditional-dose doxycycline.35 There also is some evidence for the efficacy of SDD in reducing overall erythema, as demonstrated by one open-label, community-based study in which SDD monotherapy resulted in clinician erythema assessment scores of mild or no erythema in 75% of patients with mild to severe rosacea at baseline after 12 weeks of therapy.35 Additionally, SDD is considered to be safe and well-tolerated and does not generally result in the adverse effects that may be seen in antibiotic-level doses of doxycycline (eg, gastrointestinal upset, vaginal candidiasis, photosensitivity).34,36,37 Other antibiotics such as clarithromycin, azithromycin, and MTZ also have been studied as treatments of papulopustular rosacea at antibiotic-level doses with good therapeutic effect.38-40 These therapies, however, generally are not used unless there are contraindications for use of tetracycline antibiotics, such as pregnancy or allergy, as the overall evidence is not as strong and there may be increased risks for serious adverse effects.30
Although it is not FDA approved, isotretinoin is an important therapeutic option for select rosacea patients, as it is the only pharmacologic agent that has shown efficacy for the phymatous changes of rosacea. Its efficacy, however, is limited to early-stage rhinophyma that has not yet progressed to the fibrotic or mucinous stages of disease in which it has been shown to reduce the size and number of cutaneous sebaceous glands.30,41 Isotretinoin at 0.3 mg/kg daily also has shown noninferiority in treatment of the inflammatory papules and pustules of rosacea as compared to antibiotic dosing of doxycycline in one large-scale, placebo-controlled, randomized, 12-week multicenter study.42 Unfortunately, recurrence is highly likely after isotretinoin therapy is discontinued.30,41 However, continuous “microdose” isotretinoin at 0.03 to 0.17 mg/kg daily has shown evidence for efficacy in treatment of recalcitrant papulopustular disease.43 Such dosing may have the added benefit of reduced risk for radiographic changes associated with long-term isotretinoin use.43
Light-Based Therapy
Light-based modalities are an important tool set in the management of rosacea symptoms, as they can treat telangiectases for which medical therapy is not generally effective.9 To a lesser extent, light-based modalities also can help alleviate background erythema. The most commonly used light-based modalities include the pulsed dye laser (PDL)(Figure), potassium titanyl phosphate (KTP) laser, Nd:YAG laser, intense pulsed light, photodynamic therapy, CO2 laser, and erbium-doped YAG (Er:YAG) laser. These treatments produce clinical results by targeting specific chromophores such as oxyhemoglobin, deoxyhemoglobin, methemoglobin, and clotted blood with light of specific wavelengths to induce thermolysis of vasculature while sparing collateral tissue.44 Generally, larger telangiectatic vessels are more amenable to therapy than smaller vessels, which usually require higher energy to be delivered in a shorter period of time, thus predisposing the patient to the development of purpura that may last for 1 to 2 weeks.44
|
Historically, PDL used a light wavelength of 577 nm and was classically associated with posttherapy purpura; however, modern PDLs use wavelengths of 585 or 595 nm and are associated with a reduced risk for purpura through the use of longer pulse durations (ie, 10–40 millisecond), multiple minipulses, multiple passes, and advanced epidermal cooling methods.9,44 In a small, prospective, randomized, controlled, nonblinded study, PDL therapy with fluence sufficiently high enough to induce purpura achieved an approximate 50% improvement in telangiectasia grading scores in most patients after a single treatment.45 Notably, PDL therapy at purpura-inducing settings was reported to be much more efficacious than settings that did not induce purpura (purpura free), especially in the treatment of thicker telangiectases.45
Potassium titanyl phosphate lasers make use of shorter wavelengths (532 nm) than PDL and thus are better able to target superficial vasculature, which translates into a reduced risk for purpura and faster healing times. However, KTP laser therapy typically is only reserved for patients with lighter skin types, as this wavelength of light is more likely to result in higher melanin absorption and possible postinflammatory hyperpigmentation.44 A split-face study comparing the KTP laser with PDL determined that the KTP laser was able to achieve 62% clearing after the first treatment and 85% clearance after the third treatment versus 49% and 75% for PDL treatment, respectively; however, the KTP laser had higher rates of posttherapy erythema lasting at least 1 day (58% vs 8%).46
Conversely, the Nd:YAG laser uses longer wavelengths (1064 nm) and can achieve deeper skin penetration, which may be effective for larger, recalcitrant, or deeper blue-tinted vessels. A split-face, double-blind, randomized, controlled trial found Nd:YAG laser therapy to be an effective treatment of facial erythema, though it was observed to be less effective than purpura-free PDL therapy in reducing redness after 4 treatments (34% vs 52% improvement, respectively); however, treatment with the Nd:YAG laser was found to be significantly (P=.0028) less painful.47
Intense pulsed light is unique from the previously discussed light-based therapies in that it uses noncoherent light with wavelengths between 500 and 1200 nm. Cutoff filters may be used to allow for more selective tissue damage depending on the depth of penetration desired. Intense pulsed light has been shown to be equally as efficacious as purpura-free PDL therapy in the treatment of erythema and telangiectasia in a randomized, controlled, single-blind, split-face trial.48 Additionally, a study of 200 patients with facial vascular lesions, of whom 74 patients had rosacea, showed that intense pulsed light therapy resulted in a 75% to 100% improvement of lesions in 174 of 188 (92.5%) patients who returned for follow-up. Treatment often required at least 2 sessions, but overall adverse effects were reported to be minimal.49
Photodynamic therapy is a well-studied and often utilized treatment of a variety of skin conditions, but there have only been a few studies regarding its use in rosacea. Photodynamic therapy involves the use of topically applied photosensitizing agents such as 5-aminolevulinic acid or methyl aminolevulinate before exposure to red or blue light. This process generates reactive oxygen species, though the exact mechanism of action through which patients achieve cosmetic improvement in rosacea is unclear. In one study of 17 patients with varying rosacea subtypes treated with methyl aminolevulinate and red light, drastic relief of symptoms was seen in 10 (58.8%) patients, marked improvement in 4 (23.5%) patients, and no response in 3 (17.6%) patients. Most patients report a transient irritant skin reaction at the site of therapy.50
Ablative lasers such as the CO2 (10,600 nm) and Er:YAG (2940 nm) lasers also have been shown to be useful in the treatment of rosacea, specifically for the management of rhinophymatous features. Excellent results have been achieved with these lasers given their ability to provide near-bloodless surgical fields. In a 13-year review of 124 patients with rhinophyma receiving a single CO2 laser treatment, good to excellent results were achieved in 118 (95.2%) of patients when evaluated at 3 months posttreatment.51 Patient satisfaction also is reported to be high with few adverse effects reported. The evidence for the Er:YAG laser is not as strong, but the current reports indicate efficacy and safety similar to that of the CO2 laser.52
Procedural Therapies
Procedural therapies in rosacea generally are reserved for management of rhinophyma and include electrocautery, cryotherapy, radiotherapy, dermabrasion, scalpel excisions, flap reconstruction, and skin grafts.30,53 The details and evidence for these methods is beyond the scope of this paper, but it is important to be aware of such modalities. As with most surgical procedures, operator skill and experience may affect treatment outcomes, and there also are definite risks for postprocedural scarring, swelling, erythema, and pigmentation changes. Recently, anecdotal evidence has shown that botulinum toxin injections may be effective for patients with refractory flushing and erythema, but larger studies will be necessary to better assess these claims.54,55
Conclusion
Although recent advances in pharmacology and laser technology have provided physicians with new and effective treatment modalities for rosacea, it remains a poorly understood disease without a definitive cure. The negative impact of rosacea on patients’ quality of life can be substantial, but effective management of cosmetic symptoms can minimize such deleterious effects. Therapy should be individualized and directed at treating the symptoms that are most bothersome to the patient. Additionally, effective treatment often will require a combination of modalities or sequential therapies to achieve optimal cosmetic outcomes.
1. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 suppl 1):S27-S35.
2. Rosacea prevalence map. National Rosacea Society Web site. http://rosacea.org/press/prevalencemap. Accessed June 16, 2015.
3. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 suppl 1):S15-S26.
4. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 1: a status report on the disease state, general measures, and adjunctive skin care. Cutis. 2013;92:234-240.
5. Wilkin J, Dahl M, Detmar M, et al. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2004;50:907-912.
6. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society expert committee on the classification and staging of rosacea. J Am Acad Dermatol. 2002;46:584-587.
7. Feldman SR, Huang WW, Huynh TT. Current drug therapies for rosacea: a chronic vascular and inflammatory skin disease. J Manag Care Spec Pharm. 2014;20:623-629.
8. Moustafa F, Lewallen RS, Feldman SR. The psychological impact of rosacea and the influence of current management options. J Am Acad Dermatol. 2014;71:973-980.
9. Mansouri Y, Goldenberg G. Devices and topical agents for rosacea management. Cutis. 2014;94:21-25.
10. Levin J, Miller R. A guide to the ingredients and potential benefits of over-the-counter cleansers and moisturizers for rosacea patients. J Clin Aesthet Dermatol. 2011;4:31-49.
11. van Zuuren EJ, Kramer S, Carter B, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2011;3:CD003262.
12. Liu RH, Smith MK, Basta SA, et al. Azelaic acid in the treatment of papulopustular rosacea: a systematic review of randomized controlled trials. Arch Dermatol. 2006;142:1047-1052.
13. Elewski B, Fleischer AB Jr, Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003;139:1444-1450.
14. Torok HM, Webster G, Dunlap FE, et al. Combination sodium sulfacetamide 10% and sulfur 5% cream with sunscreens versus metronidazole 0.75% cream for rosacea. Cutis. 2005;75:357-363.
15. Trumbore MW, Goldstein JA, Gurge RM. Treatment of papulopustular rosacea with sodium sulfacetamide 10%/sulfur 5% emollient foam. J Drugs Dermatol. 2009;8:299-304.
16. Piwnica D, Rosignoli C, de Menonville ST, et al. Vasoconstriction and anti-inflammatory properties of the selective alpha-adrenergic receptor agonist brimonidine. J Dermatol Sci. 2014;75:49-54.
17. Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12:650-656.
18. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate gel 0.5% is a novel treatment of moderate to severe facial erythema of rosacea: results of two multicenter, randomized and vehicle-controlled studies. Br J Dermatol. 2012;166:633-641.
19. Moore A, Kempers S, Murakawa G, et al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol. 2014;13:56-61.
20. Routt ET, Levitt JO. Rebound erythema and burning sensation from a new topical brimonidine tartrate gel 0.33%. J Am Acad Dermatol. 2014;70:e37-e38.
21. Ilkovitch D, Pomerantz RG. Brimonidine effective but may lead to significant rebound erythema. J Am Acad Dermatol. 2014;70:e109-e110.
22. Kim JH, Oh YS, Ji JH, et al. Rosacea (erythematotelangiectatic type) effectively improved by topical xylometazoline. J Dermatol. 2011;38:510-513.
23. Shanler SD, Ondo AL. Successful treatment of erythema and flushing of rosacea using a topically applied selective alpha1-adrenergic receptor antagonist, oxymetazoline. Arch Dermatol. 2007;143:1369-1371.
24. Stein-Gold L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13:316-323.
25. Stein-Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled, investigator-blinded trials. J Drugs Dermatol. 2014;13:1380-1386.
26. Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015;172:1103-1110.
27. Koçak M, Ya˘gli S, Vahapo˘glu G, et al. Permethrin 5% cream versus metronidazole 0.75% gel for the treatment of papulopustular rosacea. a randomized double-blind placebo-controlled study. Dermatology (Basel). 2002;205:265-270.
28. Bikowski JB, Del Rosso JQ. Demodex dermatitis: a retrospective analysis of clinical diagnosis and successful treatment with topical crotamiton. J Clin Aesthet Dermatol. 2009;2:20-25.
29. Layton A, Thiboutot D. Emerging therapies in rosacea. J Am Acad Dermatol. 2013;69(6 suppl 1):S57-S65.
30. Pelle MT, Crawford GH, James WD. Rosacea: II. therapy. J Am Acad Dermatol. 2004;51:499-512, quiz 513-514.
31. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54:258-265.
32. Korting HC, Schöllmann C. Tetracycline actions relevant to rosacea treatment. Skin Pharmacol Physiol. 2009;22:287-294.
33. Thomas J, Walker C, Bradshaw M. Long-term use of subantimicrobial dose doxycycline does not lead to changes in antimicrobial susceptibility. J Periodontol. 2000;71:1472-1483.
34. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56:791-802.
35. Webster GF. An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads). Cutis. 2010;86(suppl 5):7-15.
36. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-576.
37. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies. Cutis. 2014;93:18-28.
38. Torresani C. Clarithromycin: a new perspective in rosacea treatment. Int J Dermatol. 1998;37:347-349.
39. Bakar O, Demircay Z, Gürbüz O. Therapeutic potential of azithromycin in rosacea. Int J Dermatol. 2004;43:151-154.
40. Saihan EM, Burton JL. A double-blind trial of metronidazole versus oxytetracycline therapy for rosacea. Br J Dermatol. 1980;102:443-445.
41. Park H, Del Rosso JQ. Use of oral isotretinoin in the management of rosacea. J Clin Aesthet Dermatol. 2011;4:54-61.
42. Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea—doxycycline-and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010;8:505-515.
43. Hofer T. Continuous “microdose” isotretinoin in adult recalcitrant rosacea. Clin Exp Dermatol. 2004;29:204-205.
44. Tanghetti E, Del Rosso JQ, Thiboutot D, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 4: a status report on physical modalities and devices. Cutis. 2014;93:71-76.
45. Alam M, Dover JS, Arndt KA. Treatment of facial telangiectasia with variable-pulse high-fluence pulsed-dye laser: comparison of efficacy with fluences immediately above and below the purpura threshold. Dermatol Surg. 2003;29:681-684.
46. Uebelhoer NS, Bogle MA, Stewart B, et al. A split-face comparison study of pulsed 532-nm KTP laser and 595-nm pulsed dye laser in the treatment of facial telangiectasias and diffuse telangiectatic facial erythema. Dermatol Surg. 2007;33:441-448.
47. Alam M, Voravutinon N, Warycha M, et al. Comparative effectiveness of nonpurpuragenic 595-nm pulsed dye laser and microsecond 1064-nm neodymium:yttrium-aluminum-garnet laser for treatment of diffuse facial erythema: a double-blind randomized controlled trial. J Am Acad Dermatol. 2013;69:438-443.
48. Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg. 2009;35:920-928.
49. Angermeier MC. Treatment of facial vascular lesions with intense pulsed light. J Cutan Laser Ther. 1999;1:95-100.
50. Bryld LE, Jemec GB. Photodynamic therapy in a series of rosacea patients. J Eur Acad Dermatol Venereol. 2007;21:1199-1202.
51. Maden V, Ferguson JE, August PJ. Carbon dioxide laser treatment of rhinophyma: a review of 124 patients. Br J Dermatol. 2009;161:814-818.
52. Fincher EF, Gladstone HB. Use of a dual-mode erbium:YAG laser for the surgical correction of rhinophyma. Arch Facial Plast Surg. 2004;6:267-271.
53. Lloyd KM. Surgical correction of rhinophyma. Arch Dermatol. 1990;126:721-723.
54. Dayan SH, Pritzker RN, Arkins JP. A new treatment regimen for rosacea: onabotulinumtoxinA. J Drugs Dermatol. 2012;11:e76-e79.
55. Park KY, Hyun MY, Jeong SY, et al. Botulinum toxin for the treatment of refractory erythema and flushing of rosacea. Dermatology. 2015;230:299-301.
1. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 suppl 1):S27-S35.
2. Rosacea prevalence map. National Rosacea Society Web site. http://rosacea.org/press/prevalencemap. Accessed June 16, 2015.
3. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 suppl 1):S15-S26.
4. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 1: a status report on the disease state, general measures, and adjunctive skin care. Cutis. 2013;92:234-240.
5. Wilkin J, Dahl M, Detmar M, et al. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2004;50:907-912.
6. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society expert committee on the classification and staging of rosacea. J Am Acad Dermatol. 2002;46:584-587.
7. Feldman SR, Huang WW, Huynh TT. Current drug therapies for rosacea: a chronic vascular and inflammatory skin disease. J Manag Care Spec Pharm. 2014;20:623-629.
8. Moustafa F, Lewallen RS, Feldman SR. The psychological impact of rosacea and the influence of current management options. J Am Acad Dermatol. 2014;71:973-980.
9. Mansouri Y, Goldenberg G. Devices and topical agents for rosacea management. Cutis. 2014;94:21-25.
10. Levin J, Miller R. A guide to the ingredients and potential benefits of over-the-counter cleansers and moisturizers for rosacea patients. J Clin Aesthet Dermatol. 2011;4:31-49.
11. van Zuuren EJ, Kramer S, Carter B, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2011;3:CD003262.
12. Liu RH, Smith MK, Basta SA, et al. Azelaic acid in the treatment of papulopustular rosacea: a systematic review of randomized controlled trials. Arch Dermatol. 2006;142:1047-1052.
13. Elewski B, Fleischer AB Jr, Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003;139:1444-1450.
14. Torok HM, Webster G, Dunlap FE, et al. Combination sodium sulfacetamide 10% and sulfur 5% cream with sunscreens versus metronidazole 0.75% cream for rosacea. Cutis. 2005;75:357-363.
15. Trumbore MW, Goldstein JA, Gurge RM. Treatment of papulopustular rosacea with sodium sulfacetamide 10%/sulfur 5% emollient foam. J Drugs Dermatol. 2009;8:299-304.
16. Piwnica D, Rosignoli C, de Menonville ST, et al. Vasoconstriction and anti-inflammatory properties of the selective alpha-adrenergic receptor agonist brimonidine. J Dermatol Sci. 2014;75:49-54.
17. Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12:650-656.
18. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate gel 0.5% is a novel treatment of moderate to severe facial erythema of rosacea: results of two multicenter, randomized and vehicle-controlled studies. Br J Dermatol. 2012;166:633-641.
19. Moore A, Kempers S, Murakawa G, et al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol. 2014;13:56-61.
20. Routt ET, Levitt JO. Rebound erythema and burning sensation from a new topical brimonidine tartrate gel 0.33%. J Am Acad Dermatol. 2014;70:e37-e38.
21. Ilkovitch D, Pomerantz RG. Brimonidine effective but may lead to significant rebound erythema. J Am Acad Dermatol. 2014;70:e109-e110.
22. Kim JH, Oh YS, Ji JH, et al. Rosacea (erythematotelangiectatic type) effectively improved by topical xylometazoline. J Dermatol. 2011;38:510-513.
23. Shanler SD, Ondo AL. Successful treatment of erythema and flushing of rosacea using a topically applied selective alpha1-adrenergic receptor antagonist, oxymetazoline. Arch Dermatol. 2007;143:1369-1371.
24. Stein-Gold L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13:316-323.
25. Stein-Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled, investigator-blinded trials. J Drugs Dermatol. 2014;13:1380-1386.
26. Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015;172:1103-1110.
27. Koçak M, Ya˘gli S, Vahapo˘glu G, et al. Permethrin 5% cream versus metronidazole 0.75% gel for the treatment of papulopustular rosacea. a randomized double-blind placebo-controlled study. Dermatology (Basel). 2002;205:265-270.
28. Bikowski JB, Del Rosso JQ. Demodex dermatitis: a retrospective analysis of clinical diagnosis and successful treatment with topical crotamiton. J Clin Aesthet Dermatol. 2009;2:20-25.
29. Layton A, Thiboutot D. Emerging therapies in rosacea. J Am Acad Dermatol. 2013;69(6 suppl 1):S57-S65.
30. Pelle MT, Crawford GH, James WD. Rosacea: II. therapy. J Am Acad Dermatol. 2004;51:499-512, quiz 513-514.
31. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54:258-265.
32. Korting HC, Schöllmann C. Tetracycline actions relevant to rosacea treatment. Skin Pharmacol Physiol. 2009;22:287-294.
33. Thomas J, Walker C, Bradshaw M. Long-term use of subantimicrobial dose doxycycline does not lead to changes in antimicrobial susceptibility. J Periodontol. 2000;71:1472-1483.
34. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56:791-802.
35. Webster GF. An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads). Cutis. 2010;86(suppl 5):7-15.
36. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-576.
37. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies. Cutis. 2014;93:18-28.
38. Torresani C. Clarithromycin: a new perspective in rosacea treatment. Int J Dermatol. 1998;37:347-349.
39. Bakar O, Demircay Z, Gürbüz O. Therapeutic potential of azithromycin in rosacea. Int J Dermatol. 2004;43:151-154.
40. Saihan EM, Burton JL. A double-blind trial of metronidazole versus oxytetracycline therapy for rosacea. Br J Dermatol. 1980;102:443-445.
41. Park H, Del Rosso JQ. Use of oral isotretinoin in the management of rosacea. J Clin Aesthet Dermatol. 2011;4:54-61.
42. Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea—doxycycline-and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010;8:505-515.
43. Hofer T. Continuous “microdose” isotretinoin in adult recalcitrant rosacea. Clin Exp Dermatol. 2004;29:204-205.
44. Tanghetti E, Del Rosso JQ, Thiboutot D, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 4: a status report on physical modalities and devices. Cutis. 2014;93:71-76.
45. Alam M, Dover JS, Arndt KA. Treatment of facial telangiectasia with variable-pulse high-fluence pulsed-dye laser: comparison of efficacy with fluences immediately above and below the purpura threshold. Dermatol Surg. 2003;29:681-684.
46. Uebelhoer NS, Bogle MA, Stewart B, et al. A split-face comparison study of pulsed 532-nm KTP laser and 595-nm pulsed dye laser in the treatment of facial telangiectasias and diffuse telangiectatic facial erythema. Dermatol Surg. 2007;33:441-448.
47. Alam M, Voravutinon N, Warycha M, et al. Comparative effectiveness of nonpurpuragenic 595-nm pulsed dye laser and microsecond 1064-nm neodymium:yttrium-aluminum-garnet laser for treatment of diffuse facial erythema: a double-blind randomized controlled trial. J Am Acad Dermatol. 2013;69:438-443.
48. Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg. 2009;35:920-928.
49. Angermeier MC. Treatment of facial vascular lesions with intense pulsed light. J Cutan Laser Ther. 1999;1:95-100.
50. Bryld LE, Jemec GB. Photodynamic therapy in a series of rosacea patients. J Eur Acad Dermatol Venereol. 2007;21:1199-1202.
51. Maden V, Ferguson JE, August PJ. Carbon dioxide laser treatment of rhinophyma: a review of 124 patients. Br J Dermatol. 2009;161:814-818.
52. Fincher EF, Gladstone HB. Use of a dual-mode erbium:YAG laser for the surgical correction of rhinophyma. Arch Facial Plast Surg. 2004;6:267-271.
53. Lloyd KM. Surgical correction of rhinophyma. Arch Dermatol. 1990;126:721-723.
54. Dayan SH, Pritzker RN, Arkins JP. A new treatment regimen for rosacea: onabotulinumtoxinA. J Drugs Dermatol. 2012;11:e76-e79.
55. Park KY, Hyun MY, Jeong SY, et al. Botulinum toxin for the treatment of refractory erythema and flushing of rosacea. Dermatology. 2015;230:299-301.
Practice Points
- As no definitive cure for rosacea exists, effective treatment is aimed at improving the cosmetic symptoms.
- Choice of therapy should be determined on a case-by-case basis as guided by the clinical features most bothersome to the patient.
- A combination of modalities and/or sequential therapy often is required to achieve optimal cosmetic outcomes.
Erythematous Papules and Plaques on the Flank of a Child
The Diagnosis: Asymmetric Periflexural Exanthem of Childhood (Unilateral Laterothoracic Exanthem)
Asymmetric periflexural exanthem of childhood (APEC), also known as unilateral laterothoracic exanthem, is a self-limited eruptive dermatosis that occurs most frequently in infants and young children. The term unilateral laterothoracic exanthem was first coined by Bodemer and de Prost1 in 1992 due to its characteristic distribution. The eruption occurs in children aged 4 months to 10 years, with most cases presenting between 2 and 3 years of age.2 Isolated cases also have been reported in adults.3 It affects girls more often than boys (2:1), and the majority of reported cases have occurred in white individuals. The disease is seen throughout Europe and North America, and seasonal variation has been noted with most cases occurring in late winter and early spring.4,5
|
Clinically, APEC is characterized by its asymmetric localization and unilateral onset. In the majority of patients, the eruption presents as discrete erythematous papules that coalesce to form morbilliform plaques that may have reticular or annular configuration (Figure).4 The exanthem begins unilaterally near a flexural area, most commonly the axilla (75% of cases), and spreads centrifugally to the adjacent trunk and proximal extremity. There is no right or left dominance.4,6 There is eventual involvement of the contralateral side in 70% of cases, but a unilateral predominance is maintained throughout the disease course.4 Rarely, the eruption may involve the face, genitals, and palmoplantar surfaces. As in our case, up to three-quarters of affected children report symptoms of an upper respiratory tract or gastrointestinal prodrome, including mild fever, diarrhea, and rhinitis.4 Accompanying regional lymphadenopathy has been reported in the majority of cases, and mild to moderate pruritus is not uncommon. The syndrome is self-limited, with spontaneous resolution commonly occurring 3 to 6 weeks after onset. Although no treatment is required, systemic antihistamines and topical steroids have been used to alleviate pruritus in symptomatic patients. Our patient was treated with triamcinolone cream 0.1% twice daily as well as oral diphenhydramine 25 mg every 6 hours as needed for associated pruritus. The eruption spontaneously resolved over the following 4 weeks.
Although the cause of APEC remains unknown, an infectious etiology has been presumed. The seasonal pattern, lack of efficacy of broad-spectrum antibiotics, frequently reported prodromal symptoms, and reports of familial cases suggest a viral etiology.1 Additionally, the predilection to affect infants and young children as well as lack of recurrence in the same patient suggests that immunity may develop. Although no etiologic agent has been consistently detected, several reports have suggested a possible relationship to parvovirus B19.7,8 Parainfluenzavirus 2, parainfluenzavirus 3, and adenovirus also have been isolated but may represent incidental viral infection.2 An inoculation dermatosis from an arthropod bite also has been suggested, but this claim has not been substantiated.1
The diagnosis often can be made on clinical features alone, and histopathologic evaluation is not required. Histologic features are nonspecific and include a superficial perivascular infiltrate of lymphocytes, often involving the dermal eccrine ducts without involvement of the secretory coils.4,6 Mild lichenoid changes as well as spongiosis with exocytosis of lymphocytes into the acrosyringium also may be present.4 The clinical differential diagnosis of APEC includes allergic contact dermatitis, a nonspecific drug or viral eruption, atypical pityriasis rosea, miliaria, scabies, tinea corporis, and Gianotti-Crosti syndrome. Asymmetric periflexural exanthem of childhood lacks the peripheral scale present in tinea corporis or pityriasis rosea, but when an annular or reticular configuration predominates, a potassium hydroxide preparation of skin scrapings can exclude the presence of a dermatophyte. Similar to APEC, Gianotti-Crosti syndrome affects young children, is preceded by symptoms of a viral prodrome, and spontaneously resolves over several weeks. This condition is distinguished from APEC by the presence of papulovesicles located symmetrically on the face, buttocks, and extensor surface of the extremities, which largely spare the trunk.
Asymmetric periflexural exanthem of childhood is a unique morbilliform eruption of infants and young children characterized by a stereotypical distribution and self-limited course. The cause of this syndrome remains unclear, but most authors suggest a viral etiology. Recognition of this entity and an ability to distinguish it from other common pediatric dermatoses is required to provide reassurance to parents and avoid unnecessary diagnostic procedures and treatments.
1. Bodemer C, de Prost Y. Unilateral laterothoracic exanthem in children: a new disease? J Am Acad Dermatol. 1992;27(5, pt 1):693-696.
2. Nahm WK, Paiva C, Golomb C, et al. Asymmetric periflexural exanthema of childhood: a case involving a 4-month-old infant. Pediatr Dermatol. 2002;19:461-462.
3. Chan PK, To KF, Zawar V, et al. Asymmetric periflexural exanthema in an adult. Clin Exp Dermatol. 2004;29:320-321.
4. McCuaig CC, Russo P, Powell J, et al. Unilateral laterothoracic exanthem. a clinicopathologic study of forty-eight patients. J Am Acad Dermatol. 1996;34:979-984.
5. Taieb A, Megraud F, Legrain V, et al. Asymmetric periflexural exanthem of childhood. J Am Acad Dermatol. 1993;29:391-393.
6. Coustou D, Léauté-Labrèze C, Bioulac-Sage P, et al. Asymmetric periflexural exanthem of childhood. a clinical, pathologic, and epidemiologic prospective study. Arch Dermatol. 1999;135:799-803.
7. Guimerá-Martín-Neda F, Fagundo E, Rodríguez F, et al. Asymmetric periflexural exanthem of childhood: report of two cases with parvovirus B19. J Eur Acad Dermatol Venereol. 2006;20:461-462.
8. Pauluzzi P, Festini G, Gelmetti C. Asymmetric periflexural exanthem of childhood in an adult patient with parvovirus B19. J Eur Acad Dermatol Venereol. 2001;15:372-374.
The Diagnosis: Asymmetric Periflexural Exanthem of Childhood (Unilateral Laterothoracic Exanthem)
Asymmetric periflexural exanthem of childhood (APEC), also known as unilateral laterothoracic exanthem, is a self-limited eruptive dermatosis that occurs most frequently in infants and young children. The term unilateral laterothoracic exanthem was first coined by Bodemer and de Prost1 in 1992 due to its characteristic distribution. The eruption occurs in children aged 4 months to 10 years, with most cases presenting between 2 and 3 years of age.2 Isolated cases also have been reported in adults.3 It affects girls more often than boys (2:1), and the majority of reported cases have occurred in white individuals. The disease is seen throughout Europe and North America, and seasonal variation has been noted with most cases occurring in late winter and early spring.4,5
|
Clinically, APEC is characterized by its asymmetric localization and unilateral onset. In the majority of patients, the eruption presents as discrete erythematous papules that coalesce to form morbilliform plaques that may have reticular or annular configuration (Figure).4 The exanthem begins unilaterally near a flexural area, most commonly the axilla (75% of cases), and spreads centrifugally to the adjacent trunk and proximal extremity. There is no right or left dominance.4,6 There is eventual involvement of the contralateral side in 70% of cases, but a unilateral predominance is maintained throughout the disease course.4 Rarely, the eruption may involve the face, genitals, and palmoplantar surfaces. As in our case, up to three-quarters of affected children report symptoms of an upper respiratory tract or gastrointestinal prodrome, including mild fever, diarrhea, and rhinitis.4 Accompanying regional lymphadenopathy has been reported in the majority of cases, and mild to moderate pruritus is not uncommon. The syndrome is self-limited, with spontaneous resolution commonly occurring 3 to 6 weeks after onset. Although no treatment is required, systemic antihistamines and topical steroids have been used to alleviate pruritus in symptomatic patients. Our patient was treated with triamcinolone cream 0.1% twice daily as well as oral diphenhydramine 25 mg every 6 hours as needed for associated pruritus. The eruption spontaneously resolved over the following 4 weeks.
Although the cause of APEC remains unknown, an infectious etiology has been presumed. The seasonal pattern, lack of efficacy of broad-spectrum antibiotics, frequently reported prodromal symptoms, and reports of familial cases suggest a viral etiology.1 Additionally, the predilection to affect infants and young children as well as lack of recurrence in the same patient suggests that immunity may develop. Although no etiologic agent has been consistently detected, several reports have suggested a possible relationship to parvovirus B19.7,8 Parainfluenzavirus 2, parainfluenzavirus 3, and adenovirus also have been isolated but may represent incidental viral infection.2 An inoculation dermatosis from an arthropod bite also has been suggested, but this claim has not been substantiated.1
The diagnosis often can be made on clinical features alone, and histopathologic evaluation is not required. Histologic features are nonspecific and include a superficial perivascular infiltrate of lymphocytes, often involving the dermal eccrine ducts without involvement of the secretory coils.4,6 Mild lichenoid changes as well as spongiosis with exocytosis of lymphocytes into the acrosyringium also may be present.4 The clinical differential diagnosis of APEC includes allergic contact dermatitis, a nonspecific drug or viral eruption, atypical pityriasis rosea, miliaria, scabies, tinea corporis, and Gianotti-Crosti syndrome. Asymmetric periflexural exanthem of childhood lacks the peripheral scale present in tinea corporis or pityriasis rosea, but when an annular or reticular configuration predominates, a potassium hydroxide preparation of skin scrapings can exclude the presence of a dermatophyte. Similar to APEC, Gianotti-Crosti syndrome affects young children, is preceded by symptoms of a viral prodrome, and spontaneously resolves over several weeks. This condition is distinguished from APEC by the presence of papulovesicles located symmetrically on the face, buttocks, and extensor surface of the extremities, which largely spare the trunk.
Asymmetric periflexural exanthem of childhood is a unique morbilliform eruption of infants and young children characterized by a stereotypical distribution and self-limited course. The cause of this syndrome remains unclear, but most authors suggest a viral etiology. Recognition of this entity and an ability to distinguish it from other common pediatric dermatoses is required to provide reassurance to parents and avoid unnecessary diagnostic procedures and treatments.
The Diagnosis: Asymmetric Periflexural Exanthem of Childhood (Unilateral Laterothoracic Exanthem)
Asymmetric periflexural exanthem of childhood (APEC), also known as unilateral laterothoracic exanthem, is a self-limited eruptive dermatosis that occurs most frequently in infants and young children. The term unilateral laterothoracic exanthem was first coined by Bodemer and de Prost1 in 1992 due to its characteristic distribution. The eruption occurs in children aged 4 months to 10 years, with most cases presenting between 2 and 3 years of age.2 Isolated cases also have been reported in adults.3 It affects girls more often than boys (2:1), and the majority of reported cases have occurred in white individuals. The disease is seen throughout Europe and North America, and seasonal variation has been noted with most cases occurring in late winter and early spring.4,5
|
Clinically, APEC is characterized by its asymmetric localization and unilateral onset. In the majority of patients, the eruption presents as discrete erythematous papules that coalesce to form morbilliform plaques that may have reticular or annular configuration (Figure).4 The exanthem begins unilaterally near a flexural area, most commonly the axilla (75% of cases), and spreads centrifugally to the adjacent trunk and proximal extremity. There is no right or left dominance.4,6 There is eventual involvement of the contralateral side in 70% of cases, but a unilateral predominance is maintained throughout the disease course.4 Rarely, the eruption may involve the face, genitals, and palmoplantar surfaces. As in our case, up to three-quarters of affected children report symptoms of an upper respiratory tract or gastrointestinal prodrome, including mild fever, diarrhea, and rhinitis.4 Accompanying regional lymphadenopathy has been reported in the majority of cases, and mild to moderate pruritus is not uncommon. The syndrome is self-limited, with spontaneous resolution commonly occurring 3 to 6 weeks after onset. Although no treatment is required, systemic antihistamines and topical steroids have been used to alleviate pruritus in symptomatic patients. Our patient was treated with triamcinolone cream 0.1% twice daily as well as oral diphenhydramine 25 mg every 6 hours as needed for associated pruritus. The eruption spontaneously resolved over the following 4 weeks.
Although the cause of APEC remains unknown, an infectious etiology has been presumed. The seasonal pattern, lack of efficacy of broad-spectrum antibiotics, frequently reported prodromal symptoms, and reports of familial cases suggest a viral etiology.1 Additionally, the predilection to affect infants and young children as well as lack of recurrence in the same patient suggests that immunity may develop. Although no etiologic agent has been consistently detected, several reports have suggested a possible relationship to parvovirus B19.7,8 Parainfluenzavirus 2, parainfluenzavirus 3, and adenovirus also have been isolated but may represent incidental viral infection.2 An inoculation dermatosis from an arthropod bite also has been suggested, but this claim has not been substantiated.1
The diagnosis often can be made on clinical features alone, and histopathologic evaluation is not required. Histologic features are nonspecific and include a superficial perivascular infiltrate of lymphocytes, often involving the dermal eccrine ducts without involvement of the secretory coils.4,6 Mild lichenoid changes as well as spongiosis with exocytosis of lymphocytes into the acrosyringium also may be present.4 The clinical differential diagnosis of APEC includes allergic contact dermatitis, a nonspecific drug or viral eruption, atypical pityriasis rosea, miliaria, scabies, tinea corporis, and Gianotti-Crosti syndrome. Asymmetric periflexural exanthem of childhood lacks the peripheral scale present in tinea corporis or pityriasis rosea, but when an annular or reticular configuration predominates, a potassium hydroxide preparation of skin scrapings can exclude the presence of a dermatophyte. Similar to APEC, Gianotti-Crosti syndrome affects young children, is preceded by symptoms of a viral prodrome, and spontaneously resolves over several weeks. This condition is distinguished from APEC by the presence of papulovesicles located symmetrically on the face, buttocks, and extensor surface of the extremities, which largely spare the trunk.
Asymmetric periflexural exanthem of childhood is a unique morbilliform eruption of infants and young children characterized by a stereotypical distribution and self-limited course. The cause of this syndrome remains unclear, but most authors suggest a viral etiology. Recognition of this entity and an ability to distinguish it from other common pediatric dermatoses is required to provide reassurance to parents and avoid unnecessary diagnostic procedures and treatments.
1. Bodemer C, de Prost Y. Unilateral laterothoracic exanthem in children: a new disease? J Am Acad Dermatol. 1992;27(5, pt 1):693-696.
2. Nahm WK, Paiva C, Golomb C, et al. Asymmetric periflexural exanthema of childhood: a case involving a 4-month-old infant. Pediatr Dermatol. 2002;19:461-462.
3. Chan PK, To KF, Zawar V, et al. Asymmetric periflexural exanthema in an adult. Clin Exp Dermatol. 2004;29:320-321.
4. McCuaig CC, Russo P, Powell J, et al. Unilateral laterothoracic exanthem. a clinicopathologic study of forty-eight patients. J Am Acad Dermatol. 1996;34:979-984.
5. Taieb A, Megraud F, Legrain V, et al. Asymmetric periflexural exanthem of childhood. J Am Acad Dermatol. 1993;29:391-393.
6. Coustou D, Léauté-Labrèze C, Bioulac-Sage P, et al. Asymmetric periflexural exanthem of childhood. a clinical, pathologic, and epidemiologic prospective study. Arch Dermatol. 1999;135:799-803.
7. Guimerá-Martín-Neda F, Fagundo E, Rodríguez F, et al. Asymmetric periflexural exanthem of childhood: report of two cases with parvovirus B19. J Eur Acad Dermatol Venereol. 2006;20:461-462.
8. Pauluzzi P, Festini G, Gelmetti C. Asymmetric periflexural exanthem of childhood in an adult patient with parvovirus B19. J Eur Acad Dermatol Venereol. 2001;15:372-374.
1. Bodemer C, de Prost Y. Unilateral laterothoracic exanthem in children: a new disease? J Am Acad Dermatol. 1992;27(5, pt 1):693-696.
2. Nahm WK, Paiva C, Golomb C, et al. Asymmetric periflexural exanthema of childhood: a case involving a 4-month-old infant. Pediatr Dermatol. 2002;19:461-462.
3. Chan PK, To KF, Zawar V, et al. Asymmetric periflexural exanthema in an adult. Clin Exp Dermatol. 2004;29:320-321.
4. McCuaig CC, Russo P, Powell J, et al. Unilateral laterothoracic exanthem. a clinicopathologic study of forty-eight patients. J Am Acad Dermatol. 1996;34:979-984.
5. Taieb A, Megraud F, Legrain V, et al. Asymmetric periflexural exanthem of childhood. J Am Acad Dermatol. 1993;29:391-393.
6. Coustou D, Léauté-Labrèze C, Bioulac-Sage P, et al. Asymmetric periflexural exanthem of childhood. a clinical, pathologic, and epidemiologic prospective study. Arch Dermatol. 1999;135:799-803.
7. Guimerá-Martín-Neda F, Fagundo E, Rodríguez F, et al. Asymmetric periflexural exanthem of childhood: report of two cases with parvovirus B19. J Eur Acad Dermatol Venereol. 2006;20:461-462.
8. Pauluzzi P, Festini G, Gelmetti C. Asymmetric periflexural exanthem of childhood in an adult patient with parvovirus B19. J Eur Acad Dermatol Venereol. 2001;15:372-374.
A 2-year-old girl presented with a mildly pruritic rash on the right flank and axilla of 3 weeks’ duration. Her pediatrician prescribed triamcinolone cream 0.1% daily, which was applied for the last week without much improvement. Her mother reported a history of upper respiratory tract infection approximately 1 to 2 weeks prior to onset of the rash.
Routine screening sufficient for detecting occult cancer in patients with VTE
TORONTO – The prevalence of occult cancer is low in patients with a first unprovoked venous thromboembolism, according to results from a multicenter, randomized study presented at the International Society on Thrombosis and Haemostasis congress.
In addition, routine screening with the addition of a comprehensive CT scan of the abdomen and pelvis was no better than routine screening alone in detecting occult cancer in this population.
Those are key findings that Dr. Marc Carrier of the University of Ottawa presented from the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial, a multicenter, open-label, randomized controlled trial that compared the efficacy of conventional screening with or without comprehensive CT of the abdomen/pelvis for detecting occult cancers in patients with unprovoked venous thromboembolism (VTE). The results of this study were published the same day as his presentation in the New England Journal of Medicine.
“It has been described that up to 10% of patients with unprovoked VTE are diagnosed with cancer in the year following their VTE diagnosis,” Dr. Carrier said. “Therefore, it’s appealing for clinicians to screen these patients for occult cancer but it has led to a lot of great diversity in practices. Some clinicians prefer to use a limited screening strategy that would include a history, physical examination, routine blood tests, and a chest X-ray. Other clinicians prefer to use the limited screening strategy in combination with additional tests. That could be CT of the abdomen and pelvis, ultrasound, or tumor marker, or [computed axial tomography] scan. It’s hard for a physician to know what to use.”
For the SOME trial, a total of 854 patients with unprovoked VTE were randomized to two groups: 431 to limited occult cancer screening (basic blood work, chest X-ray, and breast/cervical/prostate cancer screening) and 423 to limited screening in combination with a comprehensive CT of the abdomen/pelvis. The comprehensive CT included a virtual colonoscopy and gastroscopy, a biphasic enhanced CT, a parenchymal pancreatogram, and a uniphasic enhanced CT of distended bladder. The primary outcome was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period.
Dr. Carrier reported that 33 patients (3.9%) had a new diagnosis of cancer in the interval between randomization and 1-year follow-up: 14 in the limited-screening group and 19 in the limited-screening-plus-CT group, a difference that was not statistically significant (P = .28). In addition, the number of occult cancers missed by the end of the 1-year follow-up period was similar between the two groups: four in the limited-screening group and five in the limited-screening-plus-CT group.
He and his associates also found no significant differences between the limited-screening group and the limited-screening-plus-CT group in the rate of detection of early cancers (0.23% vs. 0.71%, respectively; P = .37), in overall mortality (1.4% vs. 1.2%; P > 0.99), or in cancer-related mortality (1.4% vs. 0.95%; P = .75).
“Occult cancers are not nearly as common as we thought they were, which is reassuring for clinicians and patients because then we don’t have to do a lot of investigations to try and find them, and often scare patients and expose them to radiation and additional procedures,” Dr. Carrier said in an interview. “Limited screening alone, which is what is recommended in Canada and in the United States for age- and gender-specific screening, is more than reasonable for these patients.”
The SOME trial was funded by the Heart and Stroke Foundation of Canada. Dr. Carrier had no relevant financial conflicts to disclose.
Therese Borden contributed to this article.
TORONTO – The prevalence of occult cancer is low in patients with a first unprovoked venous thromboembolism, according to results from a multicenter, randomized study presented at the International Society on Thrombosis and Haemostasis congress.
In addition, routine screening with the addition of a comprehensive CT scan of the abdomen and pelvis was no better than routine screening alone in detecting occult cancer in this population.
Those are key findings that Dr. Marc Carrier of the University of Ottawa presented from the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial, a multicenter, open-label, randomized controlled trial that compared the efficacy of conventional screening with or without comprehensive CT of the abdomen/pelvis for detecting occult cancers in patients with unprovoked venous thromboembolism (VTE). The results of this study were published the same day as his presentation in the New England Journal of Medicine.
“It has been described that up to 10% of patients with unprovoked VTE are diagnosed with cancer in the year following their VTE diagnosis,” Dr. Carrier said. “Therefore, it’s appealing for clinicians to screen these patients for occult cancer but it has led to a lot of great diversity in practices. Some clinicians prefer to use a limited screening strategy that would include a history, physical examination, routine blood tests, and a chest X-ray. Other clinicians prefer to use the limited screening strategy in combination with additional tests. That could be CT of the abdomen and pelvis, ultrasound, or tumor marker, or [computed axial tomography] scan. It’s hard for a physician to know what to use.”
For the SOME trial, a total of 854 patients with unprovoked VTE were randomized to two groups: 431 to limited occult cancer screening (basic blood work, chest X-ray, and breast/cervical/prostate cancer screening) and 423 to limited screening in combination with a comprehensive CT of the abdomen/pelvis. The comprehensive CT included a virtual colonoscopy and gastroscopy, a biphasic enhanced CT, a parenchymal pancreatogram, and a uniphasic enhanced CT of distended bladder. The primary outcome was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period.
Dr. Carrier reported that 33 patients (3.9%) had a new diagnosis of cancer in the interval between randomization and 1-year follow-up: 14 in the limited-screening group and 19 in the limited-screening-plus-CT group, a difference that was not statistically significant (P = .28). In addition, the number of occult cancers missed by the end of the 1-year follow-up period was similar between the two groups: four in the limited-screening group and five in the limited-screening-plus-CT group.
He and his associates also found no significant differences between the limited-screening group and the limited-screening-plus-CT group in the rate of detection of early cancers (0.23% vs. 0.71%, respectively; P = .37), in overall mortality (1.4% vs. 1.2%; P > 0.99), or in cancer-related mortality (1.4% vs. 0.95%; P = .75).
“Occult cancers are not nearly as common as we thought they were, which is reassuring for clinicians and patients because then we don’t have to do a lot of investigations to try and find them, and often scare patients and expose them to radiation and additional procedures,” Dr. Carrier said in an interview. “Limited screening alone, which is what is recommended in Canada and in the United States for age- and gender-specific screening, is more than reasonable for these patients.”
The SOME trial was funded by the Heart and Stroke Foundation of Canada. Dr. Carrier had no relevant financial conflicts to disclose.
Therese Borden contributed to this article.
TORONTO – The prevalence of occult cancer is low in patients with a first unprovoked venous thromboembolism, according to results from a multicenter, randomized study presented at the International Society on Thrombosis and Haemostasis congress.
In addition, routine screening with the addition of a comprehensive CT scan of the abdomen and pelvis was no better than routine screening alone in detecting occult cancer in this population.
Those are key findings that Dr. Marc Carrier of the University of Ottawa presented from the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial, a multicenter, open-label, randomized controlled trial that compared the efficacy of conventional screening with or without comprehensive CT of the abdomen/pelvis for detecting occult cancers in patients with unprovoked venous thromboembolism (VTE). The results of this study were published the same day as his presentation in the New England Journal of Medicine.
“It has been described that up to 10% of patients with unprovoked VTE are diagnosed with cancer in the year following their VTE diagnosis,” Dr. Carrier said. “Therefore, it’s appealing for clinicians to screen these patients for occult cancer but it has led to a lot of great diversity in practices. Some clinicians prefer to use a limited screening strategy that would include a history, physical examination, routine blood tests, and a chest X-ray. Other clinicians prefer to use the limited screening strategy in combination with additional tests. That could be CT of the abdomen and pelvis, ultrasound, or tumor marker, or [computed axial tomography] scan. It’s hard for a physician to know what to use.”
For the SOME trial, a total of 854 patients with unprovoked VTE were randomized to two groups: 431 to limited occult cancer screening (basic blood work, chest X-ray, and breast/cervical/prostate cancer screening) and 423 to limited screening in combination with a comprehensive CT of the abdomen/pelvis. The comprehensive CT included a virtual colonoscopy and gastroscopy, a biphasic enhanced CT, a parenchymal pancreatogram, and a uniphasic enhanced CT of distended bladder. The primary outcome was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period.
Dr. Carrier reported that 33 patients (3.9%) had a new diagnosis of cancer in the interval between randomization and 1-year follow-up: 14 in the limited-screening group and 19 in the limited-screening-plus-CT group, a difference that was not statistically significant (P = .28). In addition, the number of occult cancers missed by the end of the 1-year follow-up period was similar between the two groups: four in the limited-screening group and five in the limited-screening-plus-CT group.
He and his associates also found no significant differences between the limited-screening group and the limited-screening-plus-CT group in the rate of detection of early cancers (0.23% vs. 0.71%, respectively; P = .37), in overall mortality (1.4% vs. 1.2%; P > 0.99), or in cancer-related mortality (1.4% vs. 0.95%; P = .75).
“Occult cancers are not nearly as common as we thought they were, which is reassuring for clinicians and patients because then we don’t have to do a lot of investigations to try and find them, and often scare patients and expose them to radiation and additional procedures,” Dr. Carrier said in an interview. “Limited screening alone, which is what is recommended in Canada and in the United States for age- and gender-specific screening, is more than reasonable for these patients.”
The SOME trial was funded by the Heart and Stroke Foundation of Canada. Dr. Carrier had no relevant financial conflicts to disclose.
Therese Borden contributed to this article.
AT THE 2015 ISTH CONGRESS
Key clinical point: Occult cancers in patients with a first unprovoked VTE are not nearly as common as previously thought, and limited screening for such cancers is appropriate.
Major finding: There were no significant differences between the limited-screening group and the limited-screening-plus-CT group in the rate of detection of early cancers (0.23% vs. 0.71%); in overall mortality (1.4% vs. 1.2%), or in cancer-related mortality (1.4% vs. 0.95%).
Data source: A multicenter, open-label, randomized controlled trial of 854 patients with unprovoked VTE.
Disclosures: The trial was funded by the Heart and Stroke Foundation of Canada. Dr. Carrier reported having no financial disclosures.
Drug worth pursuing as T-ALL therapy, researchers say
Photo courtesy of
Children’s Cancer Institute
A drug that previously fell short of expectations holds promise for treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The drug, PR-104, was originally designed to target hypoxic cells in solid tumors, but it showed less activity than expected in clinical trials, and its development was suspended.
Now, preclinical research has shown that PR-104 can be activated by AKR1C3, an enzyme that is overexpressed in T-ALL.
The researchers described this work in Blood.
“We were so encouraged by our first results with PR-104 that we undertook additional studies which showed the drug to be preferentially active against T-ALL . . . ,” said study author Richard B. Lock, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia.
“We believe that PR-104 might be an effective drug for patients who have initially benefited from conventional treatment for T-ALL but who have subsequently relapsed.”
Developing PR-104: A rocky road
PR-104 is a phosphate ester of the nitrogen mustard prodrug PR-104A. It was invented by William R. Wilson, PhD, of the University of Auckland (UoA) in New Zealand, and licensed to a UoA start-up company called Proacta Inc.
In a phase 1 study of patients with solid tumor malignancies, PR-104 failed to produce responses. The drug did elicit responses in a phase 1/2 trial of patients with advanced ALL or acute myeloid leukemia, but results fell short of expectations, and Proacta suspended development of PR-104.
Another drug Proacta was developing, PR-610, also failed to meet expectations. Because of these setbacks, the company closed its doors.
“As a fragile start-up, [Proacta] could not survive two serial ‘failures’ in phase 1/2,” Dr Wilson said. “Arguably . . . , the failure was more to do with the attempt to develop these compounds without biomarker support . . . than lack of potential of the compounds. Interestingly, PR-610 has subsequently been licensed by UoA to Threshold Pharmaceuticals, who are continuing its development (with biomarker support) as TH-4000.”
“We have a more challenging problem with PR-104 because the original patents have lapsed thanks to the decision of the UoA to not maintain the national phase filings after Proacta pulled the plug. [However,] as a result of [Dr Lock’s] work, it is now clear that PR-104 has exciting potential in leukemias with high activity of
AKR1C3.”
Results in T-ALL
Dr Lock and his colleagues tested PR-104 in a panel of 7 patient-derived pediatric ALL xenografts. Two weekly doses of PR-104 at 200 mg/kg significantly delayed progression in both T-ALL (n=4) and B-cell-precursor (BCP) ALL (n=3) xenografts.
The delay ranged from 10.3 days to 59.2 days and was significantly longer for the T-ALL xenografts (P=0.03).
PR-104 produced objective responses in all 4 T-ALL xenografts, including 2 complete responses. The drug also produced complete responses in 2 of the 3 BCP-ALL xenografts, but the third exhibited progressive disease.
Additional experiments showed that AKR1C3 expression was significantly higher in T-ALL than BCP-ALL, and AKR1C3 was “a major determinant” of sensitivity to PR-104, both in vitro and in vivo.
The researchers confirmed this by overexpressing AKR1C3 in a resistant BCP-ALL xenograft. Once AKR1C3 was overexpressed, the team observed “dramatic sensitization” to PR-104.
The path ahead
Now, Dr Lock and his colleagues are trying to determine why T-ALL cells express high levels of AKR1C3.
“If we can work out what activates this enzyme in T cells, we might find a way of activating it in B cells, making the B-cell disease sensitive to the drug as well,” Dr Lock said. “Obviously, it would be ideal if we could extend this drug’s reach to include all acute lymphoblastic leukemia patients.”
“In the meantime, we can envisage using PR-104 to target highly aggressive T-ALLs that express high levels of AKR1C3. We are in the process of working with our clinician colleagues in Australia and the US to organize a clinical trial of PR-104 in T-ALL.”
Dr Wilson noted that finding a path forward for PR-104 will be challenging due to the lack of patent support.
“[But] there are two reasons that make me think it is worth trying to do so,” he said. “One is the proximate concern that there are kids with high-AKR1C3 leukemias (adults too) who could benefit from this opportunity. The other is that this problem links to a looming paradigm shift in drug development. As we dissect cancer based on molecular analysis . . . , the commercial model will have to change.”
“There will still be ‘blockbuster’ drugs from time to time that address very high numbers of cancers . . . , but my expectation is that most cancer control in the future will depend on understanding the peculiarities of individual tumors and matching these with drugs that exploit these features. PR-104 is currently stuck in the past but could be a poster child for that future.” 
Photo courtesy of
Children’s Cancer Institute
A drug that previously fell short of expectations holds promise for treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The drug, PR-104, was originally designed to target hypoxic cells in solid tumors, but it showed less activity than expected in clinical trials, and its development was suspended.
Now, preclinical research has shown that PR-104 can be activated by AKR1C3, an enzyme that is overexpressed in T-ALL.
The researchers described this work in Blood.
“We were so encouraged by our first results with PR-104 that we undertook additional studies which showed the drug to be preferentially active against T-ALL . . . ,” said study author Richard B. Lock, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia.
“We believe that PR-104 might be an effective drug for patients who have initially benefited from conventional treatment for T-ALL but who have subsequently relapsed.”
Developing PR-104: A rocky road
PR-104 is a phosphate ester of the nitrogen mustard prodrug PR-104A. It was invented by William R. Wilson, PhD, of the University of Auckland (UoA) in New Zealand, and licensed to a UoA start-up company called Proacta Inc.
In a phase 1 study of patients with solid tumor malignancies, PR-104 failed to produce responses. The drug did elicit responses in a phase 1/2 trial of patients with advanced ALL or acute myeloid leukemia, but results fell short of expectations, and Proacta suspended development of PR-104.
Another drug Proacta was developing, PR-610, also failed to meet expectations. Because of these setbacks, the company closed its doors.
“As a fragile start-up, [Proacta] could not survive two serial ‘failures’ in phase 1/2,” Dr Wilson said. “Arguably . . . , the failure was more to do with the attempt to develop these compounds without biomarker support . . . than lack of potential of the compounds. Interestingly, PR-610 has subsequently been licensed by UoA to Threshold Pharmaceuticals, who are continuing its development (with biomarker support) as TH-4000.”
“We have a more challenging problem with PR-104 because the original patents have lapsed thanks to the decision of the UoA to not maintain the national phase filings after Proacta pulled the plug. [However,] as a result of [Dr Lock’s] work, it is now clear that PR-104 has exciting potential in leukemias with high activity of
AKR1C3.”
Results in T-ALL
Dr Lock and his colleagues tested PR-104 in a panel of 7 patient-derived pediatric ALL xenografts. Two weekly doses of PR-104 at 200 mg/kg significantly delayed progression in both T-ALL (n=4) and B-cell-precursor (BCP) ALL (n=3) xenografts.
The delay ranged from 10.3 days to 59.2 days and was significantly longer for the T-ALL xenografts (P=0.03).
PR-104 produced objective responses in all 4 T-ALL xenografts, including 2 complete responses. The drug also produced complete responses in 2 of the 3 BCP-ALL xenografts, but the third exhibited progressive disease.
Additional experiments showed that AKR1C3 expression was significantly higher in T-ALL than BCP-ALL, and AKR1C3 was “a major determinant” of sensitivity to PR-104, both in vitro and in vivo.
The researchers confirmed this by overexpressing AKR1C3 in a resistant BCP-ALL xenograft. Once AKR1C3 was overexpressed, the team observed “dramatic sensitization” to PR-104.
The path ahead
Now, Dr Lock and his colleagues are trying to determine why T-ALL cells express high levels of AKR1C3.
“If we can work out what activates this enzyme in T cells, we might find a way of activating it in B cells, making the B-cell disease sensitive to the drug as well,” Dr Lock said. “Obviously, it would be ideal if we could extend this drug’s reach to include all acute lymphoblastic leukemia patients.”
“In the meantime, we can envisage using PR-104 to target highly aggressive T-ALLs that express high levels of AKR1C3. We are in the process of working with our clinician colleagues in Australia and the US to organize a clinical trial of PR-104 in T-ALL.”
Dr Wilson noted that finding a path forward for PR-104 will be challenging due to the lack of patent support.
“[But] there are two reasons that make me think it is worth trying to do so,” he said. “One is the proximate concern that there are kids with high-AKR1C3 leukemias (adults too) who could benefit from this opportunity. The other is that this problem links to a looming paradigm shift in drug development. As we dissect cancer based on molecular analysis . . . , the commercial model will have to change.”
“There will still be ‘blockbuster’ drugs from time to time that address very high numbers of cancers . . . , but my expectation is that most cancer control in the future will depend on understanding the peculiarities of individual tumors and matching these with drugs that exploit these features. PR-104 is currently stuck in the past but could be a poster child for that future.”
Photo courtesy of
Children’s Cancer Institute
A drug that previously fell short of expectations holds promise for treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The drug, PR-104, was originally designed to target hypoxic cells in solid tumors, but it showed less activity than expected in clinical trials, and its development was suspended.
Now, preclinical research has shown that PR-104 can be activated by AKR1C3, an enzyme that is overexpressed in T-ALL.
The researchers described this work in Blood.
“We were so encouraged by our first results with PR-104 that we undertook additional studies which showed the drug to be preferentially active against T-ALL . . . ,” said study author Richard B. Lock, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia.
“We believe that PR-104 might be an effective drug for patients who have initially benefited from conventional treatment for T-ALL but who have subsequently relapsed.”
Developing PR-104: A rocky road
PR-104 is a phosphate ester of the nitrogen mustard prodrug PR-104A. It was invented by William R. Wilson, PhD, of the University of Auckland (UoA) in New Zealand, and licensed to a UoA start-up company called Proacta Inc.
In a phase 1 study of patients with solid tumor malignancies, PR-104 failed to produce responses. The drug did elicit responses in a phase 1/2 trial of patients with advanced ALL or acute myeloid leukemia, but results fell short of expectations, and Proacta suspended development of PR-104.
Another drug Proacta was developing, PR-610, also failed to meet expectations. Because of these setbacks, the company closed its doors.
“As a fragile start-up, [Proacta] could not survive two serial ‘failures’ in phase 1/2,” Dr Wilson said. “Arguably . . . , the failure was more to do with the attempt to develop these compounds without biomarker support . . . than lack of potential of the compounds. Interestingly, PR-610 has subsequently been licensed by UoA to Threshold Pharmaceuticals, who are continuing its development (with biomarker support) as TH-4000.”
“We have a more challenging problem with PR-104 because the original patents have lapsed thanks to the decision of the UoA to not maintain the national phase filings after Proacta pulled the plug. [However,] as a result of [Dr Lock’s] work, it is now clear that PR-104 has exciting potential in leukemias with high activity of
AKR1C3.”
Results in T-ALL
Dr Lock and his colleagues tested PR-104 in a panel of 7 patient-derived pediatric ALL xenografts. Two weekly doses of PR-104 at 200 mg/kg significantly delayed progression in both T-ALL (n=4) and B-cell-precursor (BCP) ALL (n=3) xenografts.
The delay ranged from 10.3 days to 59.2 days and was significantly longer for the T-ALL xenografts (P=0.03).
PR-104 produced objective responses in all 4 T-ALL xenografts, including 2 complete responses. The drug also produced complete responses in 2 of the 3 BCP-ALL xenografts, but the third exhibited progressive disease.
Additional experiments showed that AKR1C3 expression was significantly higher in T-ALL than BCP-ALL, and AKR1C3 was “a major determinant” of sensitivity to PR-104, both in vitro and in vivo.
The researchers confirmed this by overexpressing AKR1C3 in a resistant BCP-ALL xenograft. Once AKR1C3 was overexpressed, the team observed “dramatic sensitization” to PR-104.
The path ahead
Now, Dr Lock and his colleagues are trying to determine why T-ALL cells express high levels of AKR1C3.
“If we can work out what activates this enzyme in T cells, we might find a way of activating it in B cells, making the B-cell disease sensitive to the drug as well,” Dr Lock said. “Obviously, it would be ideal if we could extend this drug’s reach to include all acute lymphoblastic leukemia patients.”
“In the meantime, we can envisage using PR-104 to target highly aggressive T-ALLs that express high levels of AKR1C3. We are in the process of working with our clinician colleagues in Australia and the US to organize a clinical trial of PR-104 in T-ALL.”
Dr Wilson noted that finding a path forward for PR-104 will be challenging due to the lack of patent support.
“[But] there are two reasons that make me think it is worth trying to do so,” he said. “One is the proximate concern that there are kids with high-AKR1C3 leukemias (adults too) who could benefit from this opportunity. The other is that this problem links to a looming paradigm shift in drug development. As we dissect cancer based on molecular analysis . . . , the commercial model will have to change.”
“There will still be ‘blockbuster’ drugs from time to time that address very high numbers of cancers . . . , but my expectation is that most cancer control in the future will depend on understanding the peculiarities of individual tumors and matching these with drugs that exploit these features. PR-104 is currently stuck in the past but could be a poster child for that future.”