The first randomized controlled trial of forceps-assisted cannulation during endoscopic retrograde cholangiopancreatography (ERCP) has shown that this technique can significantly improve the success rate of the procedure.

The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.

Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.

First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).

The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.

SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.

The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).

Patients who crossed over to forceps assistance all had successful cannulations.

The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”

While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”

Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”

The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”

Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”

He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”

DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.

Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”

This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.

A version of this article first appeared on Medscape.com.

The first randomized controlled trial of forceps-assisted cannulation during endoscopic retrograde cholangiopancreatography (ERCP) has shown that this technique can significantly improve the success rate of the procedure.

The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.

Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.

First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).

The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.

SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.

The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).

Patients who crossed over to forceps assistance all had successful cannulations.

The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”

While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”

Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”

The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”

Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”

He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”

DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.

Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”

This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.

A version of this article first appeared on Medscape.com.

The first randomized controlled trial of forceps-assisted cannulation during endoscopic retrograde cholangiopancreatography (ERCP) has shown that this technique can significantly improve the success rate of the procedure.

The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.

Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.

First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).

The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.

SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.

The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).

Patients who crossed over to forceps assistance all had successful cannulations.

The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”

While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”

Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”

The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”

Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”

He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”

DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.

Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”

This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.

A version of this article first appeared on Medscape.com.

Hypereosinophilic syndrome (HES) is defined by marked, persistent absolute eosinophil count (AEC) > 1500 cells/μL on ≥ 2 peripheral smears separated by ≥ 1 month with evidence of accompanied end-organ damage, in the absence of other causes of eosinophilia such as malignancy, atopy, or parasitic infections.^1-5 Hypereosinophilic infiltration can impact almost every organ system; however, the most profound complications in patients with HES are related to leukemias and cardiac manifestations of the disease.^3,4 Although rare, the associated morbidity and mortality of HES are considerable, making prompt recognition and treatment essential. Management involves targeted therapy based on pathologic classification of HES and on decreasing associated inflammation, fibrosis, and end-organ damage.^3,5-7

The patient in this case report met the diagnostic criteria for HES. However, this patient had several clinical and laboratory features that made it difficult to characterize a specific HES variant. Moreover, she had additional immunomodulating factors in the setting of pregnancy. This is the first documented case of HES of undetermined etiology diagnosed postpartum and managed in the setting of a new pregnancy.^2,8

CASE PRESENTATION

A 32-year-old female active-duty military service member with allergic rhinitis and a history of childhood eczema was referred to allergy/immunology for evaluation of a new, progressive pruritic rash. Symptoms started 3 months after the birth of her first child, with a new diffuse erythematous skin rash sparing her palms, soles, and mucosal surfaces. Given her history of atopy, the rash was initially treated as severe atopic dermatitis with appropriate topical medications. The rash gradually worsened, with the development of intermittent facial swelling, night sweats, dyspnea, recurrent epigastric abdominal pain, and nausea with vomiting, resulting in decreased oral intake and weight loss.

The patient was hospitalized and received an expedited multidisciplinary evaluation by dermatology, hematology/oncology, and gastroenterology. Her AEC of 4787 cells/μL peaked on admission and was markedly elevated from the 1070 cells/μL reported in the third trimester of her pregnancy. She was found to have mature eosinophilia on skin biopsy (Figure 1), endoscopic duodenal biopsy (Figure 2), peripheral blood smear (Figure 3), and bone marrow biopsy (Figure 4). 

Radiographic imaging of the chest, abdomen, and pelvis revealed hepatomegaly without detectable neoplasm. There was no clinical evidence of cardiac involvement, and evaluation with electrocardiography and echocardiography did not indicate myocarditis. Extensive laboratory testing revealed no genetic mutations indicative of familial, myeloproliferative, or lymphocytic variants of HES. 

The patient received topical emollients, omeprazole 40 mg daily, and ondansetron 8 mg 3 times daily as needed for symptom management, and was started on oral prednisone 40 mg daily with improvement in dyspnea, night sweats, and gastrointestinal complaints. During the patient's 6-day hospitalization and treatment, her AECs gradually decreased to 2110 cells/μL, and decreased to 1600 cells/μL over the course of a month, remaining in the hypereosinophilic range. The patient was discovered to be pregnant while symptoms were improving, resulting in stepwise discontinuation of oral steroids, but she reported continued improvement in symptoms.

DISCUSSION

Peripheral eosinophilia has a broad differential diagnoses, including HES, parasitic infections, atopic hypersensitivity diseases, eosinophilic lung diseases, eosinophilic gastrointestinal diseases, vasculitides such as eosinophilic granulomatosis with polyangiitis, genetic syndromes predisposing to eosinophilia, episodic angioedema with eosinophilia, and chronic metabolic disease with adrenal insufficiency.^1-5 HES, although rare, is a disease process with potentially devastating associated morbidity and mortality if not promptly recognized and treated. HES is further delineated by hypereosinophilia with associated eosinophil-mediated organ damage or dysfunction.^3-5

Clinical manifestations of HES can differ greatly depending on the HES variant and degree of organ involvement at the time of diagnosis and throughout the disease course. Patients with HES, as well as those with asymptomatic eosinophilia or hypereosinophilia, should be closely monitored for disease progression. In addition to trending peripheral AECs, clinicians should screen for symptoms of organ involvement and perform targeted evaluation of the suspected organs to promptly identify early signs of organ involvement and initiate treatment.^1-4 Recommendations regarding screening intervals vary widely from monthly to annually, depending on a patient’s specific clinical picture. 

HES has been subdivided into clinically relevant variants, including myeloproliferative (M-HES), T lymphocytic (L-HES), organ-restricted (or overlap) HES, familial HES, idiopathic HES, and specific syndromes with associated hypereosinophilia.^3-5,9 Patients with M-HES have elevated circulating leukocyte precursors and clinical manifestations, including but not limited to hepatosplenomegaly, anemia, and thrombocytopenia. The most commonly associated genetic mutations include the FIP1L1-PDGFR-α fusion, BCR-ABL1, PDGFRA/B, JAK2, KIT, and FGFR1.^3-6 L-HES usually has predominant skin and soft tissue involvement secondary to immunoglobulin E-mediated actions with clonal expansion of T cells (most commonly CD3-4+ or CD3+CD4-CD8-).^3,5,6 Familial HES, a rare variant, follows an autosomal dominant inheritance pattern and is usually present at birth. It involves chromosome 5, which contains genes coding for cytokines that drive eosinophilic proliferation, including interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor.^5,9 Hypereosinophilia in the setting of end-organ damage restricted to a single organ is considered organ-restricted HES. There can be significant hepatic and gastrointestinal dysfunction, with or without malabsorption. 

HES can also manifest with hematologic malignancy, restrictive obliterative cardiomyopathies, renal injury manifested by hematuria and electrolyte derangements, and neurologic complications including hemiparesis, dysarthria, and even coma.⁶ Endothelial damage due to eosinophil-driven inflammation can result in thrombus formation and increased risk of thromboembolic events in various organs.³ Idiopathic HES, otherwise known as HES of unknown etiology or significance, is a diagnosis of exclusion and constitutes a cohort of patients who do not fit into the other delineated categories.^3-5 These patients often have multisystem involvement, making classification and treatment a challenge.⁵

The patient described in this case met the diagnostic criteria for HES, but her complicated clinical and laboratory features were challenging to characterize into a specific variant of HES. Organ-restricted HES was ruled out due to skin, marrow, and duodenal infiltration. She also had the potential for lung involvement based on her clinical symptoms, however no biopsy was obtained. Laboratory testing revealed no deletions or mutations indicative of familial, myeloproliferative, or lymphocytic variants. Her multisystem involvement without an underlying associated syndrome suggests idiopathic HES or HES of undetermined significance.^1-5

Most patients with HES are diagnosed between the ages of 20 and 50 years.¹⁰ While HES has its peak incidence in the fourth decade of life, acute onset of new symptoms 3 months postpartum makes this an unusual presentation. In this unique case, it is important to highlight the role of the physiologic changes of pregnancy in inflammatory mediation. The physiologic changes that occur in pregnancy to ensure fetal tolerance can have profound implications for leukocyte count, AEC, and subsequent inflammatory responses. The phenomenon of inflammatory amelioration during pregnancy is well-documented, but there has only been 1 known published case report discussing decreasing HES symptoms during pregnancy with prepregnancy and postpartum hypereosinophilia.⁸ It is suggested that this amelioration is secondary to cortisol and progesterone shifts that occur in pregnancy. Physiologic increases in adrenocorticotropic hormone in pregnancy leads to subsequent secretion of endogenous steroids by the adrenal cortex. In turn, pregnancy can lead to leukocytosis and eosinopenia.⁸ Overall, pregnancy can have beneficial immunomodulating properties in the spectrum of hypereosinophilic syndromes. Even so, this patient with HES diagnosed postpartum remains at risk for the sequelae of hypereosinophilia, regardless of potential for AEC reduction during pregnancy. Therefore, treatment considerations need to be made with the safety of the maternal-fetal dyad as a priority.

Treatment

The treatment of symptomatic HES without acute life-threatening features or associated malignancy is generally determined by clinical variant.^2-4 There is insufficient data to support initiation of treatment solely based on persistently elevated AEC. Patients with peripheral eosinophilia and hypereosinophilia should be monitored periodically with appropriate subspecialist evaluation for occult end-organ involvement, and targeted therapies should be deferred until an HES diagnosis.^1-4 First-line therapy in most HES variants is systemic glucocorticoids.^2,3,7 Since the disease course for this patient did not precisely match an HES variant, it was challenging to ascertain the optimal personalized treatment regimen. The approach to therapy was further complicated by newly identified pregnancy necessitating cessation of systemic glucocorticoids. In addition to glucocorticoids, hydroxyurea and interferon-α are among treatments historically used for HES, with tyrosine kinase inhibitors and monoclonal antibodies targeting IL-5 becoming more common.^1-4 Although this patient may ultimately benefit from an IL-5 targeting biologic medication such as mepolizumab, safety in pregnancy is not well-studied and may require close clinical monitoring with treatment deferred until after delivery if possible.^3,7,8,11

Military service members with frequent geographic relocation have additional barriers to timely diagnosis with often-limited access to subspecialty care depending on the duty station. While the patient was able to receive care at a large military medical center with many subspecialists, prompt recognition and timely referral to specialists would be even more critical at a smaller treatment facility. Depending on the severity and variant of HES, patients may warrant evaluation and treatment by hematology/oncology, cardiology, pulmonology, and immunology. Although HES can present in young children and older adults, this condition is most often diagnosed during the third and fourth decades of life, putting clinicians on the front line of hypereosinophilia identification and evaluation.¹⁰ Military physicians have the additional duty to not only think ahead in their diverse clinical settings to ensure proper care for patients, but also maintain a broad differential inclusive of more rare disease processes such as HES.

CONCLUSIONS

This case emphasizes how uncontrolled or untreated HES can lead to significant end-organ damage involving multiple systems and high morbidity. Prompt recognition of hypereosinophilia with potential HES can help expedite coordination of multidisciplinary care across multiple specialties to minimize delays in diagnosis and treatment. Doing so may minimize associated morbidity and mortality, especially in individuals located at more remote duty stations or deployed to austere environments.

Hypereosinophilic syndrome (HES) is defined by marked, persistent absolute eosinophil count (AEC) > 1500 cells/μL on ≥ 2 peripheral smears separated by ≥ 1 month with evidence of accompanied end-organ damage, in the absence of other causes of eosinophilia such as malignancy, atopy, or parasitic infections.^1-5 Hypereosinophilic infiltration can impact almost every organ system; however, the most profound complications in patients with HES are related to leukemias and cardiac manifestations of the disease.^3,4 Although rare, the associated morbidity and mortality of HES are considerable, making prompt recognition and treatment essential. Management involves targeted therapy based on pathologic classification of HES and on decreasing associated inflammation, fibrosis, and end-organ damage.^3,5-7

The patient in this case report met the diagnostic criteria for HES. However, this patient had several clinical and laboratory features that made it difficult to characterize a specific HES variant. Moreover, she had additional immunomodulating factors in the setting of pregnancy. This is the first documented case of HES of undetermined etiology diagnosed postpartum and managed in the setting of a new pregnancy.^2,8

CASE PRESENTATION

A 32-year-old female active-duty military service member with allergic rhinitis and a history of childhood eczema was referred to allergy/immunology for evaluation of a new, progressive pruritic rash. Symptoms started 3 months after the birth of her first child, with a new diffuse erythematous skin rash sparing her palms, soles, and mucosal surfaces. Given her history of atopy, the rash was initially treated as severe atopic dermatitis with appropriate topical medications. The rash gradually worsened, with the development of intermittent facial swelling, night sweats, dyspnea, recurrent epigastric abdominal pain, and nausea with vomiting, resulting in decreased oral intake and weight loss.

The patient was hospitalized and received an expedited multidisciplinary evaluation by dermatology, hematology/oncology, and gastroenterology. Her AEC of 4787 cells/μL peaked on admission and was markedly elevated from the 1070 cells/μL reported in the third trimester of her pregnancy. She was found to have mature eosinophilia on skin biopsy (Figure 1), endoscopic duodenal biopsy (Figure 2), peripheral blood smear (Figure 3), and bone marrow biopsy (Figure 4). 

Radiographic imaging of the chest, abdomen, and pelvis revealed hepatomegaly without detectable neoplasm. There was no clinical evidence of cardiac involvement, and evaluation with electrocardiography and echocardiography did not indicate myocarditis. Extensive laboratory testing revealed no genetic mutations indicative of familial, myeloproliferative, or lymphocytic variants of HES. 

The patient received topical emollients, omeprazole 40 mg daily, and ondansetron 8 mg 3 times daily as needed for symptom management, and was started on oral prednisone 40 mg daily with improvement in dyspnea, night sweats, and gastrointestinal complaints. During the patient's 6-day hospitalization and treatment, her AECs gradually decreased to 2110 cells/μL, and decreased to 1600 cells/μL over the course of a month, remaining in the hypereosinophilic range. The patient was discovered to be pregnant while symptoms were improving, resulting in stepwise discontinuation of oral steroids, but she reported continued improvement in symptoms.

DISCUSSION

Peripheral eosinophilia has a broad differential diagnoses, including HES, parasitic infections, atopic hypersensitivity diseases, eosinophilic lung diseases, eosinophilic gastrointestinal diseases, vasculitides such as eosinophilic granulomatosis with polyangiitis, genetic syndromes predisposing to eosinophilia, episodic angioedema with eosinophilia, and chronic metabolic disease with adrenal insufficiency.^1-5 HES, although rare, is a disease process with potentially devastating associated morbidity and mortality if not promptly recognized and treated. HES is further delineated by hypereosinophilia with associated eosinophil-mediated organ damage or dysfunction.^3-5

Clinical manifestations of HES can differ greatly depending on the HES variant and degree of organ involvement at the time of diagnosis and throughout the disease course. Patients with HES, as well as those with asymptomatic eosinophilia or hypereosinophilia, should be closely monitored for disease progression. In addition to trending peripheral AECs, clinicians should screen for symptoms of organ involvement and perform targeted evaluation of the suspected organs to promptly identify early signs of organ involvement and initiate treatment.^1-4 Recommendations regarding screening intervals vary widely from monthly to annually, depending on a patient’s specific clinical picture. 

HES has been subdivided into clinically relevant variants, including myeloproliferative (M-HES), T lymphocytic (L-HES), organ-restricted (or overlap) HES, familial HES, idiopathic HES, and specific syndromes with associated hypereosinophilia.^3-5,9 Patients with M-HES have elevated circulating leukocyte precursors and clinical manifestations, including but not limited to hepatosplenomegaly, anemia, and thrombocytopenia. The most commonly associated genetic mutations include the FIP1L1-PDGFR-α fusion, BCR-ABL1, PDGFRA/B, JAK2, KIT, and FGFR1.^3-6 L-HES usually has predominant skin and soft tissue involvement secondary to immunoglobulin E-mediated actions with clonal expansion of T cells (most commonly CD3-4+ or CD3+CD4-CD8-).^3,5,6 Familial HES, a rare variant, follows an autosomal dominant inheritance pattern and is usually present at birth. It involves chromosome 5, which contains genes coding for cytokines that drive eosinophilic proliferation, including interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor.^5,9 Hypereosinophilia in the setting of end-organ damage restricted to a single organ is considered organ-restricted HES. There can be significant hepatic and gastrointestinal dysfunction, with or without malabsorption. 

HES can also manifest with hematologic malignancy, restrictive obliterative cardiomyopathies, renal injury manifested by hematuria and electrolyte derangements, and neurologic complications including hemiparesis, dysarthria, and even coma.⁶ Endothelial damage due to eosinophil-driven inflammation can result in thrombus formation and increased risk of thromboembolic events in various organs.³ Idiopathic HES, otherwise known as HES of unknown etiology or significance, is a diagnosis of exclusion and constitutes a cohort of patients who do not fit into the other delineated categories.^3-5 These patients often have multisystem involvement, making classification and treatment a challenge.⁵

The patient described in this case met the diagnostic criteria for HES, but her complicated clinical and laboratory features were challenging to characterize into a specific variant of HES. Organ-restricted HES was ruled out due to skin, marrow, and duodenal infiltration. She also had the potential for lung involvement based on her clinical symptoms, however no biopsy was obtained. Laboratory testing revealed no deletions or mutations indicative of familial, myeloproliferative, or lymphocytic variants. Her multisystem involvement without an underlying associated syndrome suggests idiopathic HES or HES of undetermined significance.^1-5

Most patients with HES are diagnosed between the ages of 20 and 50 years.¹⁰ While HES has its peak incidence in the fourth decade of life, acute onset of new symptoms 3 months postpartum makes this an unusual presentation. In this unique case, it is important to highlight the role of the physiologic changes of pregnancy in inflammatory mediation. The physiologic changes that occur in pregnancy to ensure fetal tolerance can have profound implications for leukocyte count, AEC, and subsequent inflammatory responses. The phenomenon of inflammatory amelioration during pregnancy is well-documented, but there has only been 1 known published case report discussing decreasing HES symptoms during pregnancy with prepregnancy and postpartum hypereosinophilia.⁸ It is suggested that this amelioration is secondary to cortisol and progesterone shifts that occur in pregnancy. Physiologic increases in adrenocorticotropic hormone in pregnancy leads to subsequent secretion of endogenous steroids by the adrenal cortex. In turn, pregnancy can lead to leukocytosis and eosinopenia.⁸ Overall, pregnancy can have beneficial immunomodulating properties in the spectrum of hypereosinophilic syndromes. Even so, this patient with HES diagnosed postpartum remains at risk for the sequelae of hypereosinophilia, regardless of potential for AEC reduction during pregnancy. Therefore, treatment considerations need to be made with the safety of the maternal-fetal dyad as a priority.

Treatment

The treatment of symptomatic HES without acute life-threatening features or associated malignancy is generally determined by clinical variant.^2-4 There is insufficient data to support initiation of treatment solely based on persistently elevated AEC. Patients with peripheral eosinophilia and hypereosinophilia should be monitored periodically with appropriate subspecialist evaluation for occult end-organ involvement, and targeted therapies should be deferred until an HES diagnosis.^1-4 First-line therapy in most HES variants is systemic glucocorticoids.^2,3,7 Since the disease course for this patient did not precisely match an HES variant, it was challenging to ascertain the optimal personalized treatment regimen. The approach to therapy was further complicated by newly identified pregnancy necessitating cessation of systemic glucocorticoids. In addition to glucocorticoids, hydroxyurea and interferon-α are among treatments historically used for HES, with tyrosine kinase inhibitors and monoclonal antibodies targeting IL-5 becoming more common.^1-4 Although this patient may ultimately benefit from an IL-5 targeting biologic medication such as mepolizumab, safety in pregnancy is not well-studied and may require close clinical monitoring with treatment deferred until after delivery if possible.^3,7,8,11

Military service members with frequent geographic relocation have additional barriers to timely diagnosis with often-limited access to subspecialty care depending on the duty station. While the patient was able to receive care at a large military medical center with many subspecialists, prompt recognition and timely referral to specialists would be even more critical at a smaller treatment facility. Depending on the severity and variant of HES, patients may warrant evaluation and treatment by hematology/oncology, cardiology, pulmonology, and immunology. Although HES can present in young children and older adults, this condition is most often diagnosed during the third and fourth decades of life, putting clinicians on the front line of hypereosinophilia identification and evaluation.¹⁰ Military physicians have the additional duty to not only think ahead in their diverse clinical settings to ensure proper care for patients, but also maintain a broad differential inclusive of more rare disease processes such as HES.

CONCLUSIONS

This case emphasizes how uncontrolled or untreated HES can lead to significant end-organ damage involving multiple systems and high morbidity. Prompt recognition of hypereosinophilia with potential HES can help expedite coordination of multidisciplinary care across multiple specialties to minimize delays in diagnosis and treatment. Doing so may minimize associated morbidity and mortality, especially in individuals located at more remote duty stations or deployed to austere environments.

Hypereosinophilic syndrome (HES) is defined by marked, persistent absolute eosinophil count (AEC) > 1500 cells/μL on ≥ 2 peripheral smears separated by ≥ 1 month with evidence of accompanied end-organ damage, in the absence of other causes of eosinophilia such as malignancy, atopy, or parasitic infections.^1-5 Hypereosinophilic infiltration can impact almost every organ system; however, the most profound complications in patients with HES are related to leukemias and cardiac manifestations of the disease.^3,4 Although rare, the associated morbidity and mortality of HES are considerable, making prompt recognition and treatment essential. Management involves targeted therapy based on pathologic classification of HES and on decreasing associated inflammation, fibrosis, and end-organ damage.^3,5-7

The patient in this case report met the diagnostic criteria for HES. However, this patient had several clinical and laboratory features that made it difficult to characterize a specific HES variant. Moreover, she had additional immunomodulating factors in the setting of pregnancy. This is the first documented case of HES of undetermined etiology diagnosed postpartum and managed in the setting of a new pregnancy.^2,8

CASE PRESENTATION

A 32-year-old female active-duty military service member with allergic rhinitis and a history of childhood eczema was referred to allergy/immunology for evaluation of a new, progressive pruritic rash. Symptoms started 3 months after the birth of her first child, with a new diffuse erythematous skin rash sparing her palms, soles, and mucosal surfaces. Given her history of atopy, the rash was initially treated as severe atopic dermatitis with appropriate topical medications. The rash gradually worsened, with the development of intermittent facial swelling, night sweats, dyspnea, recurrent epigastric abdominal pain, and nausea with vomiting, resulting in decreased oral intake and weight loss.

The patient was hospitalized and received an expedited multidisciplinary evaluation by dermatology, hematology/oncology, and gastroenterology. Her AEC of 4787 cells/μL peaked on admission and was markedly elevated from the 1070 cells/μL reported in the third trimester of her pregnancy. She was found to have mature eosinophilia on skin biopsy (Figure 1), endoscopic duodenal biopsy (Figure 2), peripheral blood smear (Figure 3), and bone marrow biopsy (Figure 4). 

Radiographic imaging of the chest, abdomen, and pelvis revealed hepatomegaly without detectable neoplasm. There was no clinical evidence of cardiac involvement, and evaluation with electrocardiography and echocardiography did not indicate myocarditis. Extensive laboratory testing revealed no genetic mutations indicative of familial, myeloproliferative, or lymphocytic variants of HES. 

The patient received topical emollients, omeprazole 40 mg daily, and ondansetron 8 mg 3 times daily as needed for symptom management, and was started on oral prednisone 40 mg daily with improvement in dyspnea, night sweats, and gastrointestinal complaints. During the patient's 6-day hospitalization and treatment, her AECs gradually decreased to 2110 cells/μL, and decreased to 1600 cells/μL over the course of a month, remaining in the hypereosinophilic range. The patient was discovered to be pregnant while symptoms were improving, resulting in stepwise discontinuation of oral steroids, but she reported continued improvement in symptoms.

DISCUSSION

Peripheral eosinophilia has a broad differential diagnoses, including HES, parasitic infections, atopic hypersensitivity diseases, eosinophilic lung diseases, eosinophilic gastrointestinal diseases, vasculitides such as eosinophilic granulomatosis with polyangiitis, genetic syndromes predisposing to eosinophilia, episodic angioedema with eosinophilia, and chronic metabolic disease with adrenal insufficiency.^1-5 HES, although rare, is a disease process with potentially devastating associated morbidity and mortality if not promptly recognized and treated. HES is further delineated by hypereosinophilia with associated eosinophil-mediated organ damage or dysfunction.^3-5

Clinical manifestations of HES can differ greatly depending on the HES variant and degree of organ involvement at the time of diagnosis and throughout the disease course. Patients with HES, as well as those with asymptomatic eosinophilia or hypereosinophilia, should be closely monitored for disease progression. In addition to trending peripheral AECs, clinicians should screen for symptoms of organ involvement and perform targeted evaluation of the suspected organs to promptly identify early signs of organ involvement and initiate treatment.^1-4 Recommendations regarding screening intervals vary widely from monthly to annually, depending on a patient’s specific clinical picture. 

HES has been subdivided into clinically relevant variants, including myeloproliferative (M-HES), T lymphocytic (L-HES), organ-restricted (or overlap) HES, familial HES, idiopathic HES, and specific syndromes with associated hypereosinophilia.^3-5,9 Patients with M-HES have elevated circulating leukocyte precursors and clinical manifestations, including but not limited to hepatosplenomegaly, anemia, and thrombocytopenia. The most commonly associated genetic mutations include the FIP1L1-PDGFR-α fusion, BCR-ABL1, PDGFRA/B, JAK2, KIT, and FGFR1.^3-6 L-HES usually has predominant skin and soft tissue involvement secondary to immunoglobulin E-mediated actions with clonal expansion of T cells (most commonly CD3-4+ or CD3+CD4-CD8-).^3,5,6 Familial HES, a rare variant, follows an autosomal dominant inheritance pattern and is usually present at birth. It involves chromosome 5, which contains genes coding for cytokines that drive eosinophilic proliferation, including interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor.^5,9 Hypereosinophilia in the setting of end-organ damage restricted to a single organ is considered organ-restricted HES. There can be significant hepatic and gastrointestinal dysfunction, with or without malabsorption. 

HES can also manifest with hematologic malignancy, restrictive obliterative cardiomyopathies, renal injury manifested by hematuria and electrolyte derangements, and neurologic complications including hemiparesis, dysarthria, and even coma.⁶ Endothelial damage due to eosinophil-driven inflammation can result in thrombus formation and increased risk of thromboembolic events in various organs.³ Idiopathic HES, otherwise known as HES of unknown etiology or significance, is a diagnosis of exclusion and constitutes a cohort of patients who do not fit into the other delineated categories.^3-5 These patients often have multisystem involvement, making classification and treatment a challenge.⁵

The patient described in this case met the diagnostic criteria for HES, but her complicated clinical and laboratory features were challenging to characterize into a specific variant of HES. Organ-restricted HES was ruled out due to skin, marrow, and duodenal infiltration. She also had the potential for lung involvement based on her clinical symptoms, however no biopsy was obtained. Laboratory testing revealed no deletions or mutations indicative of familial, myeloproliferative, or lymphocytic variants. Her multisystem involvement without an underlying associated syndrome suggests idiopathic HES or HES of undetermined significance.^1-5

Most patients with HES are diagnosed between the ages of 20 and 50 years.¹⁰ While HES has its peak incidence in the fourth decade of life, acute onset of new symptoms 3 months postpartum makes this an unusual presentation. In this unique case, it is important to highlight the role of the physiologic changes of pregnancy in inflammatory mediation. The physiologic changes that occur in pregnancy to ensure fetal tolerance can have profound implications for leukocyte count, AEC, and subsequent inflammatory responses. The phenomenon of inflammatory amelioration during pregnancy is well-documented, but there has only been 1 known published case report discussing decreasing HES symptoms during pregnancy with prepregnancy and postpartum hypereosinophilia.⁸ It is suggested that this amelioration is secondary to cortisol and progesterone shifts that occur in pregnancy. Physiologic increases in adrenocorticotropic hormone in pregnancy leads to subsequent secretion of endogenous steroids by the adrenal cortex. In turn, pregnancy can lead to leukocytosis and eosinopenia.⁸ Overall, pregnancy can have beneficial immunomodulating properties in the spectrum of hypereosinophilic syndromes. Even so, this patient with HES diagnosed postpartum remains at risk for the sequelae of hypereosinophilia, regardless of potential for AEC reduction during pregnancy. Therefore, treatment considerations need to be made with the safety of the maternal-fetal dyad as a priority.

Treatment

The treatment of symptomatic HES without acute life-threatening features or associated malignancy is generally determined by clinical variant.^2-4 There is insufficient data to support initiation of treatment solely based on persistently elevated AEC. Patients with peripheral eosinophilia and hypereosinophilia should be monitored periodically with appropriate subspecialist evaluation for occult end-organ involvement, and targeted therapies should be deferred until an HES diagnosis.^1-4 First-line therapy in most HES variants is systemic glucocorticoids.^2,3,7 Since the disease course for this patient did not precisely match an HES variant, it was challenging to ascertain the optimal personalized treatment regimen. The approach to therapy was further complicated by newly identified pregnancy necessitating cessation of systemic glucocorticoids. In addition to glucocorticoids, hydroxyurea and interferon-α are among treatments historically used for HES, with tyrosine kinase inhibitors and monoclonal antibodies targeting IL-5 becoming more common.^1-4 Although this patient may ultimately benefit from an IL-5 targeting biologic medication such as mepolizumab, safety in pregnancy is not well-studied and may require close clinical monitoring with treatment deferred until after delivery if possible.^3,7,8,11

Military service members with frequent geographic relocation have additional barriers to timely diagnosis with often-limited access to subspecialty care depending on the duty station. While the patient was able to receive care at a large military medical center with many subspecialists, prompt recognition and timely referral to specialists would be even more critical at a smaller treatment facility. Depending on the severity and variant of HES, patients may warrant evaluation and treatment by hematology/oncology, cardiology, pulmonology, and immunology. Although HES can present in young children and older adults, this condition is most often diagnosed during the third and fourth decades of life, putting clinicians on the front line of hypereosinophilia identification and evaluation.¹⁰ Military physicians have the additional duty to not only think ahead in their diverse clinical settings to ensure proper care for patients, but also maintain a broad differential inclusive of more rare disease processes such as HES.

CONCLUSIONS

This case emphasizes how uncontrolled or untreated HES can lead to significant end-organ damage involving multiple systems and high morbidity. Prompt recognition of hypereosinophilia with potential HES can help expedite coordination of multidisciplinary care across multiple specialties to minimize delays in diagnosis and treatment. Doing so may minimize associated morbidity and mortality, especially in individuals located at more remote duty stations or deployed to austere environments.

Adults with gastrointestinal (GI) diseases are significantly more likely to experience sleep disturbances than those without GI conditions, a new study involving more than 10,000 individuals has found.

“Emerging evidence suggests a bidirectional relationship between GI diseases and sleep disorders, whereby dysfunction in one domain may exacerbate the other,” wrote Shicheng Ye, PhD, of The Third Clinical Medical College of Guangzhou University of Chinese Medicine, and colleagues. However, previous studies on the association between GI and sleep problems have been small, and the role of depression as a mediator has not been well explored.

In the study, which was published online in BMC Gastroenterology, the researchers reviewed data from the US National Health and Nutrition Examination Survey between 2005 and 2014. The study population included 10,626 adults aged 20 years or older, with a mean age of 45.6 years, 50.8% of whom were women. Of these, 6444 were identified as having GI disease on the basis of a “yes” response to the question of whether they had a stomach or intestinal illness with vomiting or diarrhea within the past 30 days.

Researchers also examined responses to survey questions related to sleep duration, trouble sleeping, and diagnosis of a sleep disorder. Individuals with vs without GI diseases had a significantly higher prevalence of sleep trouble (37.99% vs 24.21%; P < .001) and a greater frequency of diagnosed sleep disorders (14.99% vs 8.08%; P < .001).

An analysis adjusted for demographic, lifestyle, and clinical factors found that individuals with vs without GI diseases were 70% more likely to have sleep trouble. Individuals with vs without GI diseases were also significantly more likely to have a diagnosed sleep disorder and a reduction in sleep duration (adjusted odds ratio, 1.8; adjusted beta, -0.15).

The association between GI diseases and sleep problems remained consistent across individuals of multiple subgroups, including those without hypertension, diabetes, or a history of smoking. It also remained significant among individuals with coronary heart disease and higher scores on the dietary index for gut microbiota. No significant interaction effects related to age, sex, or chronic disease appeared in any subgroup (P > .05).

An additional mediation analysis found that depression partly mediated the associations between GI diseases and sleep issues. Depression accounted for 21.29% of the total effect on sleep problems, 19.23% of the effect on sleep disorders, and 26.68% of the effect on sleep duration.

The mediating role of depression on the association between GI disease and sleep problems may not be exclusive, the researchers wrote. Other potential mechanisms may include systemic inflammation, visceral hypersensitivity, and metabolic dysfunction.

The findings were limited by several factors, including the possibly underpowered sample size for machine-learning models and the reliance on self-reports of GI diseases, sleep outcomes, and coronary heart disease, the researchers noted. Other limitations included the inability to adjust for confounding factors, including obstructive sleep apnea, chronic pain, and hypertension.

However, the results illustrate the need to address both psychological and GI factors in clinical practice to improve sleep health, the researchers wrote. More research is needed to identify causal pathways and develop targeted, multidimensional interventions for this interconnected trio of health problems.

 

Increasing Evidence for Gut-Brain Interaction

Both sleep disorders and disorders of GBI (DGBI) are highly prevalent worldwide, Jatin Roper, MD, gastroenterologist and associate professor of medicine at Duke University, Durham, North Carolina, told GI & Hepatology News.

“A growing body of evidence suggests that DGBI, including irritable bowel syndrome, are caused by imbalances in signaling between the brain and the intestine, which include the vagus nerve, hormonal signals, the gut microbiota, and immune system,” said Roper, who was not involved in the current study.

“Since many sleep disturbances are centrally mediated, it is plausible that sleep and gastrointestinal disorders could be mechanistically linked,” he said. Rigorous analysis of patient databases for a possible association between sleep and GI disorders, as was done in the current study, is an important step.

The current study findings were not unexpected, “particularly the finding that depression may mediate a link between sleep and GI disorders, because depression is well known to be associated to sleep disturbances and DGBI,” Roper said.

However, GI doctors often do not ask patients about problems with sleep, and pulmonary doctors or sleep specialists may not ask patients about GI symptoms, Roper noted. Similarly, patients may not bring up all their symptoms when seeing these specialists.

“The current study underscores the need for comprehensive, multisystem evaluations in specialty clinics for sleep and GI conditions and appropriate referrals to specialists, when necessary,” he said.

The research raised an important question of whether sleep and GI disorders are associated with each other because of other underlying medical conditions, which may be difficult to control for in cross-sectional studies, or whether sleep problems cause GI problems or vice versa, Roper said. Other uncertainties include whether the conditions are biologically linked, possibly through shared changes in the brain-gut axis.

Long-term observational studies would be useful to identify whether sleep disturbances precede DGBI or vice versa, Roper added.

The study received no outside funding. The researchers and Roper had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Adults with gastrointestinal (GI) diseases are significantly more likely to experience sleep disturbances than those without GI conditions, a new study involving more than 10,000 individuals has found.

“Emerging evidence suggests a bidirectional relationship between GI diseases and sleep disorders, whereby dysfunction in one domain may exacerbate the other,” wrote Shicheng Ye, PhD, of The Third Clinical Medical College of Guangzhou University of Chinese Medicine, and colleagues. However, previous studies on the association between GI and sleep problems have been small, and the role of depression as a mediator has not been well explored.

In the study, which was published online in BMC Gastroenterology, the researchers reviewed data from the US National Health and Nutrition Examination Survey between 2005 and 2014. The study population included 10,626 adults aged 20 years or older, with a mean age of 45.6 years, 50.8% of whom were women. Of these, 6444 were identified as having GI disease on the basis of a “yes” response to the question of whether they had a stomach or intestinal illness with vomiting or diarrhea within the past 30 days.

Researchers also examined responses to survey questions related to sleep duration, trouble sleeping, and diagnosis of a sleep disorder. Individuals with vs without GI diseases had a significantly higher prevalence of sleep trouble (37.99% vs 24.21%; P < .001) and a greater frequency of diagnosed sleep disorders (14.99% vs 8.08%; P < .001).

An analysis adjusted for demographic, lifestyle, and clinical factors found that individuals with vs without GI diseases were 70% more likely to have sleep trouble. Individuals with vs without GI diseases were also significantly more likely to have a diagnosed sleep disorder and a reduction in sleep duration (adjusted odds ratio, 1.8; adjusted beta, -0.15).

The association between GI diseases and sleep problems remained consistent across individuals of multiple subgroups, including those without hypertension, diabetes, or a history of smoking. It also remained significant among individuals with coronary heart disease and higher scores on the dietary index for gut microbiota. No significant interaction effects related to age, sex, or chronic disease appeared in any subgroup (P > .05).

An additional mediation analysis found that depression partly mediated the associations between GI diseases and sleep issues. Depression accounted for 21.29% of the total effect on sleep problems, 19.23% of the effect on sleep disorders, and 26.68% of the effect on sleep duration.

The mediating role of depression on the association between GI disease and sleep problems may not be exclusive, the researchers wrote. Other potential mechanisms may include systemic inflammation, visceral hypersensitivity, and metabolic dysfunction.

The findings were limited by several factors, including the possibly underpowered sample size for machine-learning models and the reliance on self-reports of GI diseases, sleep outcomes, and coronary heart disease, the researchers noted. Other limitations included the inability to adjust for confounding factors, including obstructive sleep apnea, chronic pain, and hypertension.

However, the results illustrate the need to address both psychological and GI factors in clinical practice to improve sleep health, the researchers wrote. More research is needed to identify causal pathways and develop targeted, multidimensional interventions for this interconnected trio of health problems.

 

Increasing Evidence for Gut-Brain Interaction

Both sleep disorders and disorders of GBI (DGBI) are highly prevalent worldwide, Jatin Roper, MD, gastroenterologist and associate professor of medicine at Duke University, Durham, North Carolina, told GI & Hepatology News.

“A growing body of evidence suggests that DGBI, including irritable bowel syndrome, are caused by imbalances in signaling between the brain and the intestine, which include the vagus nerve, hormonal signals, the gut microbiota, and immune system,” said Roper, who was not involved in the current study.

“Since many sleep disturbances are centrally mediated, it is plausible that sleep and gastrointestinal disorders could be mechanistically linked,” he said. Rigorous analysis of patient databases for a possible association between sleep and GI disorders, as was done in the current study, is an important step.

The current study findings were not unexpected, “particularly the finding that depression may mediate a link between sleep and GI disorders, because depression is well known to be associated to sleep disturbances and DGBI,” Roper said.

However, GI doctors often do not ask patients about problems with sleep, and pulmonary doctors or sleep specialists may not ask patients about GI symptoms, Roper noted. Similarly, patients may not bring up all their symptoms when seeing these specialists.

“The current study underscores the need for comprehensive, multisystem evaluations in specialty clinics for sleep and GI conditions and appropriate referrals to specialists, when necessary,” he said.

The research raised an important question of whether sleep and GI disorders are associated with each other because of other underlying medical conditions, which may be difficult to control for in cross-sectional studies, or whether sleep problems cause GI problems or vice versa, Roper said. Other uncertainties include whether the conditions are biologically linked, possibly through shared changes in the brain-gut axis.

Long-term observational studies would be useful to identify whether sleep disturbances precede DGBI or vice versa, Roper added.

The study received no outside funding. The researchers and Roper had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Adults with gastrointestinal (GI) diseases are significantly more likely to experience sleep disturbances than those without GI conditions, a new study involving more than 10,000 individuals has found.

“Emerging evidence suggests a bidirectional relationship between GI diseases and sleep disorders, whereby dysfunction in one domain may exacerbate the other,” wrote Shicheng Ye, PhD, of The Third Clinical Medical College of Guangzhou University of Chinese Medicine, and colleagues. However, previous studies on the association between GI and sleep problems have been small, and the role of depression as a mediator has not been well explored.

In the study, which was published online in BMC Gastroenterology, the researchers reviewed data from the US National Health and Nutrition Examination Survey between 2005 and 2014. The study population included 10,626 adults aged 20 years or older, with a mean age of 45.6 years, 50.8% of whom were women. Of these, 6444 were identified as having GI disease on the basis of a “yes” response to the question of whether they had a stomach or intestinal illness with vomiting or diarrhea within the past 30 days.

Researchers also examined responses to survey questions related to sleep duration, trouble sleeping, and diagnosis of a sleep disorder. Individuals with vs without GI diseases had a significantly higher prevalence of sleep trouble (37.99% vs 24.21%; P < .001) and a greater frequency of diagnosed sleep disorders (14.99% vs 8.08%; P < .001).

An analysis adjusted for demographic, lifestyle, and clinical factors found that individuals with vs without GI diseases were 70% more likely to have sleep trouble. Individuals with vs without GI diseases were also significantly more likely to have a diagnosed sleep disorder and a reduction in sleep duration (adjusted odds ratio, 1.8; adjusted beta, -0.15).

The association between GI diseases and sleep problems remained consistent across individuals of multiple subgroups, including those without hypertension, diabetes, or a history of smoking. It also remained significant among individuals with coronary heart disease and higher scores on the dietary index for gut microbiota. No significant interaction effects related to age, sex, or chronic disease appeared in any subgroup (P > .05).

An additional mediation analysis found that depression partly mediated the associations between GI diseases and sleep issues. Depression accounted for 21.29% of the total effect on sleep problems, 19.23% of the effect on sleep disorders, and 26.68% of the effect on sleep duration.

The mediating role of depression on the association between GI disease and sleep problems may not be exclusive, the researchers wrote. Other potential mechanisms may include systemic inflammation, visceral hypersensitivity, and metabolic dysfunction.

The findings were limited by several factors, including the possibly underpowered sample size for machine-learning models and the reliance on self-reports of GI diseases, sleep outcomes, and coronary heart disease, the researchers noted. Other limitations included the inability to adjust for confounding factors, including obstructive sleep apnea, chronic pain, and hypertension.

However, the results illustrate the need to address both psychological and GI factors in clinical practice to improve sleep health, the researchers wrote. More research is needed to identify causal pathways and develop targeted, multidimensional interventions for this interconnected trio of health problems.

 

Increasing Evidence for Gut-Brain Interaction

Both sleep disorders and disorders of GBI (DGBI) are highly prevalent worldwide, Jatin Roper, MD, gastroenterologist and associate professor of medicine at Duke University, Durham, North Carolina, told GI & Hepatology News.

“A growing body of evidence suggests that DGBI, including irritable bowel syndrome, are caused by imbalances in signaling between the brain and the intestine, which include the vagus nerve, hormonal signals, the gut microbiota, and immune system,” said Roper, who was not involved in the current study.

“Since many sleep disturbances are centrally mediated, it is plausible that sleep and gastrointestinal disorders could be mechanistically linked,” he said. Rigorous analysis of patient databases for a possible association between sleep and GI disorders, as was done in the current study, is an important step.

The current study findings were not unexpected, “particularly the finding that depression may mediate a link between sleep and GI disorders, because depression is well known to be associated to sleep disturbances and DGBI,” Roper said.

However, GI doctors often do not ask patients about problems with sleep, and pulmonary doctors or sleep specialists may not ask patients about GI symptoms, Roper noted. Similarly, patients may not bring up all their symptoms when seeing these specialists.

“The current study underscores the need for comprehensive, multisystem evaluations in specialty clinics for sleep and GI conditions and appropriate referrals to specialists, when necessary,” he said.

The research raised an important question of whether sleep and GI disorders are associated with each other because of other underlying medical conditions, which may be difficult to control for in cross-sectional studies, or whether sleep problems cause GI problems or vice versa, Roper said. Other uncertainties include whether the conditions are biologically linked, possibly through shared changes in the brain-gut axis.

Long-term observational studies would be useful to identify whether sleep disturbances precede DGBI or vice versa, Roper added.

The study received no outside funding. The researchers and Roper had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Giant cell arteritis (GCA), the most commonly diagnosed systemic vasculitis, is a large- and medium-vessel vasculitis that can lead to significant morbidity due to aneurysm formation or vascular occlusion if not diagnosed in a timely manner.^1,2 Diagnosis is typically based on clinical history and inflammatory markers. Laboratory inflammatory markers may be normal in the early stages of GCA but can be abnormal due to other unrelated reasons leading to a false positive diagnosis.³ Delayed treatment may lead to visual loss, jaw or limb claudication, or ischemic stroke.² Initial treatment typically includes high-dose steroids that can lead to significant adverse reactions such as hypothalamic-pituitary-adrenal axis dysfunction, metabolic syndrome, premature atherosclerosis, and increased risk of infection.^4-6

The 1990 American College of Rheumatology (ACR) criteria for GCA are widely recognized (Table 1).⁷ The criteria focuses on clinical manifestations, including new onset headache, temporal artery tenderness, age ≥ 50 years, erythrocyte sedimentation rate (ESR) ≥ 50 mm/hr, and temporal artery biopsy with positive anatomical findings.⁸ When 3 of the 5 1990 ACR criteria are present, the sensitivity and specificity is estimated to be > 90% for GCA vs alternative vasculitides.⁷

Although the 1990 ACR criteria do not include imaging, modalities such as ultrasound, computed tomography angiography (CTA), 18F-FDG positron emission tomography (PET), and magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) may be used in GCA diagnosis.^8-10 These imaging modalities have been added to the proposed ACR classification criteria for GCA.¹¹ For this updated point system standard, age ≥ 50 years is a requirement and includes a positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5 points), an ESR ≥ 50 mm/h or C-reactive protein (CRP) ≥ 10 mg/L (+3 points), or sudden visual loss (+3 points). Scalp tenderness, jaw or tongue claudication, new temporal headache, morning stiffness in shoulders or neck, temporal artery abnormality on vascular examination, bilateral axillary vessel involvement on imaging, and 18F-FDG PET activity throughout the aorta are scored +2 points each. With these new criteria, a cumulative score ≥ 6 is classified as GCA. Diagnostic accuracy is further improved with imaging: ultrasonography (sensitivity 55% and specificity 95%) and 18F-FDG PET (sensitivity 69% and specificity 92%), CTA (sensitivity 71% and specificity 86%), and MRI/MRA (sensitivity 73% and specificity 88%).^12-15

In recent years, clinicians have reported increased glucose uptake in arteries observed on PET imaging that suggests GCA.^9,10,16-20 18F-FDG accumulates in cells with high metabolic activity rates, such as areas of inflammation. In assessing temporal arteries or other involved vasculature (eg, axillary or great vessels) for GCA, this modality indicates increased glucose uptake in the lining of vessel walls. The inflammation of vessel walls can then be visualized with PET. 18F-FDG PET presents a noninvasive imaging technique for evaluating GCA but its use has been limited in the United States due to its high cost.

Methods

Approval for a retrospective chart review of patients evaluated for suspected GCA was obtained from the Walter Reed National Military Medical Center (WRNMMC) Institutional Review Board. The review included patients who underwent diagnostic procedures such as ultrasound, MRI, CT angiogram, and PET studies from 2016 through 2022. International Classification of Diseases codes used for case identification included: M31.6, M31.5, I77.6, I77.8, I77.89, I67.7, and I68.2. The Current Procedural Terminology code used for temporal artery biopsy is 37609.

Results

Seventy-eight charts were reviewed and 42 patients (54%) were diagnosed with GCA (Table 2). This study sample had a much higher proportion of African American subjects (31%) when compared with the civilian population, likely reflecting the higher representation of African Americans in the armed forces. Twenty-eight females (67%) were GCA positive. The most common presenting symptoms included 27 patients (64%) with headache, 17 (40%) with scalp tenderness, and 14 (33%) with jaw pain. The mean 1990 ACR score was 3.8 (range, 2-5). With respect to the score criteria: 41 patients (98%) were aged ≥ 50 years, 31 (74%) had new onset headache, and 31 (74%) had elevated ESR (Table 3). Acute ischemic optic neuropathy was documented in 4 patients (10%) with confirmed GCA. The mean ESR and CRP values at diagnosis were 66.2 mm/h (range, 7-122 mm/h) and 8.711 μg/mL (range, 0.054 – 92.690 μg/mL), respectively. Twenty-seven patients (64%) underwent biopsy: 24 (89%) were unilateral and 3 (11%) were bilateral (Table 4). Four patients with GCA (10%) were missing biopsy data. Nineteen patients with GCA (70%) had biopsies with pathologic findings consistent with GCA.

Twenty-five patients with GCA (60%) received ≥ 1 imaging modality. The most common imaging modality was MRI, which was used for 18 (43%) patients. Fourteen patients (33%) had 18F-FDG PET, 12 patients (29%) had MRA, and 11 patients (26%) had CTA. The small number of patients who underwent point-of-care ultrasound (POCUS), brain MRI, or dark blood MRI were negative for disease. Five patients who underwent 18F-FDG PET had findings consistent with GCA. One patient with GCA had CTA of the head and neck with radiographic findings supportive of GCA.

Discussion

The available evidence supports the use of additional screening tests to increase the temporal artery biopsy yield for GCA. Inflammatory laboratory markers demonstrate some sensitivity but are nonspecific for GCA. In this study, only 60% of patients with GCA underwent diagnostic imaging as part of the workup. There are multiple factors that may contribute to the underutilization of advanced imaging in the diagnosis of GCA, including outdated standardized diagnostic criteria, limited resources (direct access to modalities), and lack of clinician awareness of diagnostic testing options. In this retrospective review, 30 patients (71%) were diagnosed with GCA with a 1990 ACR GCA score ≤ 3. Of these 30 patients, 19 underwent confirmatory biopsy followed by prolonged courses of steroid therapy. In addition, only 25 patients underwent advanced imaging to increase diagnostic accuracy of the suspected syndrome.

A large meta-analysis demonstrated a sensitivity of 77.3% (95% CI, 71.8-81.9%) for temporal artery biopsy.²¹ The overall yield was 40% in the meta-analysis. Advanced noninvasive imaging represents an appropriate method of evaluating GCA.^8-20 In our study, 18F-FDG PET demonstrated the highest sensitivity (36%) for the diagnosis of GCA. Ultrasonography is recommended as an initial screening tool to identify the noncompressible halo sign (a hypoechoic circumferential wall thickening due to edema) as a cost-effective and widely available technology.²² Other research has corroborated the beneficial use of ultrasonography in improving diagnostic accuracy by detecting the noncompressible halo sign in temporal arteries.^22,23 GCA diagnostic performance has been significantly improved with the use of B-mode probes ≥ 15 MHz as well as proposals to incorporate a compression sign or interrogating the axillary vessels, showing a sensitivity of 54% to 77%.^23,24

POCUS may reduce the risk of a false-negative biopsy and improve yield with more frequent utilization. However, ultrasonography may be limited by operator skills and visualization of the great vessels. The accuracy of ultrasonography is dependent on the experience and adeptness of the operator. Additional studies are needed to establish a systematic standard for POCUS training to ensure accurate interpretation and uniform interrogation procedure.²⁴ Artificial intelligence (AI) may aid in interpreting results of POCUS and bridging the operator skill gap among operators.^25,26 AI and machine learning techniques can assist in detecting the noncompressible halo sign and compression sign in temporal arteries and other affected vessels.

In comparing the WRNMMC patient population with other US civilian GCA cohorts, there are some differences and similarities. There was a high representation of African American patients in the study, which may reflect a greater severity of autoimmune disease expression in this population.²⁷ We also observed a higher number of females and an association with polymyalgia rheumatica in the data, consistent with previous reports.^28,29 The females in this study were primarily civilians and therefore more similar to the general population of individuals with GCA. In contrast, male patients were more likely to be active-duty service members or have prior service experience with increased exposure to novel environmental factors linked to increased risk of autoimmune disease. This includes an increased risk of Guillain-Barré syndrome and Graves disease among Vietnam veterans exposed to Agent Orange.^30,31 Other studies have found that veterans with posttraumatic stress disorder are at increased risk for severe autoimmune diseases.^32,33 As more women join the active-duty military, the impact of autoimmune disease in the military service population is expected to grow, requiring further research.

Conclusions

Early diagnosis and treatment of GCA are critical to preventing serious outcomes, such as visual loss, jaw or limb claudication, or ischemic stroke. The incidence of autoimmune disease is expected to rise in the armed forces and veteran populations due to exposure to novel environmental factors and the increasing representation of women in the military. The use of additional screening tools can aid in earlier diagnosis of GCA. The 2022 ACR classification criteria for GCA represent significant updates to the 1990 criteria, incorporating ancillary tests such as the temporal artery halo sign on ultrasound, bilateral axillary vessel screening on imaging, and 18F-FDG PET activity throughout the aorta. The updated criteria require further validation and supports the adoption of a multidisciplinary approach that includes ultrasonography, vascular MRI/CT, and 18F-FDG PET. Furthermore, AI may play a future key role in ultrasound interpretation and study interrogation procedure. Ultimately, ultrasonography is a noninvasive and promising technique for the early diagnosis of GCA. A target goal is to increase the yield of positive temporal artery biopsies to ≥ 70%.

Giant cell arteritis (GCA), the most commonly diagnosed systemic vasculitis, is a large- and medium-vessel vasculitis that can lead to significant morbidity due to aneurysm formation or vascular occlusion if not diagnosed in a timely manner.^1,2 Diagnosis is typically based on clinical history and inflammatory markers. Laboratory inflammatory markers may be normal in the early stages of GCA but can be abnormal due to other unrelated reasons leading to a false positive diagnosis.³ Delayed treatment may lead to visual loss, jaw or limb claudication, or ischemic stroke.² Initial treatment typically includes high-dose steroids that can lead to significant adverse reactions such as hypothalamic-pituitary-adrenal axis dysfunction, metabolic syndrome, premature atherosclerosis, and increased risk of infection.^4-6

The 1990 American College of Rheumatology (ACR) criteria for GCA are widely recognized (Table 1).⁷ The criteria focuses on clinical manifestations, including new onset headache, temporal artery tenderness, age ≥ 50 years, erythrocyte sedimentation rate (ESR) ≥ 50 mm/hr, and temporal artery biopsy with positive anatomical findings.⁸ When 3 of the 5 1990 ACR criteria are present, the sensitivity and specificity is estimated to be > 90% for GCA vs alternative vasculitides.⁷

Although the 1990 ACR criteria do not include imaging, modalities such as ultrasound, computed tomography angiography (CTA), 18F-FDG positron emission tomography (PET), and magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) may be used in GCA diagnosis.^8-10 These imaging modalities have been added to the proposed ACR classification criteria for GCA.¹¹ For this updated point system standard, age ≥ 50 years is a requirement and includes a positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5 points), an ESR ≥ 50 mm/h or C-reactive protein (CRP) ≥ 10 mg/L (+3 points), or sudden visual loss (+3 points). Scalp tenderness, jaw or tongue claudication, new temporal headache, morning stiffness in shoulders or neck, temporal artery abnormality on vascular examination, bilateral axillary vessel involvement on imaging, and 18F-FDG PET activity throughout the aorta are scored +2 points each. With these new criteria, a cumulative score ≥ 6 is classified as GCA. Diagnostic accuracy is further improved with imaging: ultrasonography (sensitivity 55% and specificity 95%) and 18F-FDG PET (sensitivity 69% and specificity 92%), CTA (sensitivity 71% and specificity 86%), and MRI/MRA (sensitivity 73% and specificity 88%).^12-15

In recent years, clinicians have reported increased glucose uptake in arteries observed on PET imaging that suggests GCA.^9,10,16-20 18F-FDG accumulates in cells with high metabolic activity rates, such as areas of inflammation. In assessing temporal arteries or other involved vasculature (eg, axillary or great vessels) for GCA, this modality indicates increased glucose uptake in the lining of vessel walls. The inflammation of vessel walls can then be visualized with PET. 18F-FDG PET presents a noninvasive imaging technique for evaluating GCA but its use has been limited in the United States due to its high cost.

Methods

Approval for a retrospective chart review of patients evaluated for suspected GCA was obtained from the Walter Reed National Military Medical Center (WRNMMC) Institutional Review Board. The review included patients who underwent diagnostic procedures such as ultrasound, MRI, CT angiogram, and PET studies from 2016 through 2022. International Classification of Diseases codes used for case identification included: M31.6, M31.5, I77.6, I77.8, I77.89, I67.7, and I68.2. The Current Procedural Terminology code used for temporal artery biopsy is 37609.

Results

Seventy-eight charts were reviewed and 42 patients (54%) were diagnosed with GCA (Table 2). This study sample had a much higher proportion of African American subjects (31%) when compared with the civilian population, likely reflecting the higher representation of African Americans in the armed forces. Twenty-eight females (67%) were GCA positive. The most common presenting symptoms included 27 patients (64%) with headache, 17 (40%) with scalp tenderness, and 14 (33%) with jaw pain. The mean 1990 ACR score was 3.8 (range, 2-5). With respect to the score criteria: 41 patients (98%) were aged ≥ 50 years, 31 (74%) had new onset headache, and 31 (74%) had elevated ESR (Table 3). Acute ischemic optic neuropathy was documented in 4 patients (10%) with confirmed GCA. The mean ESR and CRP values at diagnosis were 66.2 mm/h (range, 7-122 mm/h) and 8.711 μg/mL (range, 0.054 – 92.690 μg/mL), respectively. Twenty-seven patients (64%) underwent biopsy: 24 (89%) were unilateral and 3 (11%) were bilateral (Table 4). Four patients with GCA (10%) were missing biopsy data. Nineteen patients with GCA (70%) had biopsies with pathologic findings consistent with GCA.

Twenty-five patients with GCA (60%) received ≥ 1 imaging modality. The most common imaging modality was MRI, which was used for 18 (43%) patients. Fourteen patients (33%) had 18F-FDG PET, 12 patients (29%) had MRA, and 11 patients (26%) had CTA. The small number of patients who underwent point-of-care ultrasound (POCUS), brain MRI, or dark blood MRI were negative for disease. Five patients who underwent 18F-FDG PET had findings consistent with GCA. One patient with GCA had CTA of the head and neck with radiographic findings supportive of GCA.

Discussion

The available evidence supports the use of additional screening tests to increase the temporal artery biopsy yield for GCA. Inflammatory laboratory markers demonstrate some sensitivity but are nonspecific for GCA. In this study, only 60% of patients with GCA underwent diagnostic imaging as part of the workup. There are multiple factors that may contribute to the underutilization of advanced imaging in the diagnosis of GCA, including outdated standardized diagnostic criteria, limited resources (direct access to modalities), and lack of clinician awareness of diagnostic testing options. In this retrospective review, 30 patients (71%) were diagnosed with GCA with a 1990 ACR GCA score ≤ 3. Of these 30 patients, 19 underwent confirmatory biopsy followed by prolonged courses of steroid therapy. In addition, only 25 patients underwent advanced imaging to increase diagnostic accuracy of the suspected syndrome.

A large meta-analysis demonstrated a sensitivity of 77.3% (95% CI, 71.8-81.9%) for temporal artery biopsy.²¹ The overall yield was 40% in the meta-analysis. Advanced noninvasive imaging represents an appropriate method of evaluating GCA.^8-20 In our study, 18F-FDG PET demonstrated the highest sensitivity (36%) for the diagnosis of GCA. Ultrasonography is recommended as an initial screening tool to identify the noncompressible halo sign (a hypoechoic circumferential wall thickening due to edema) as a cost-effective and widely available technology.²² Other research has corroborated the beneficial use of ultrasonography in improving diagnostic accuracy by detecting the noncompressible halo sign in temporal arteries.^22,23 GCA diagnostic performance has been significantly improved with the use of B-mode probes ≥ 15 MHz as well as proposals to incorporate a compression sign or interrogating the axillary vessels, showing a sensitivity of 54% to 77%.^23,24

POCUS may reduce the risk of a false-negative biopsy and improve yield with more frequent utilization. However, ultrasonography may be limited by operator skills and visualization of the great vessels. The accuracy of ultrasonography is dependent on the experience and adeptness of the operator. Additional studies are needed to establish a systematic standard for POCUS training to ensure accurate interpretation and uniform interrogation procedure.²⁴ Artificial intelligence (AI) may aid in interpreting results of POCUS and bridging the operator skill gap among operators.^25,26 AI and machine learning techniques can assist in detecting the noncompressible halo sign and compression sign in temporal arteries and other affected vessels.

In comparing the WRNMMC patient population with other US civilian GCA cohorts, there are some differences and similarities. There was a high representation of African American patients in the study, which may reflect a greater severity of autoimmune disease expression in this population.²⁷ We also observed a higher number of females and an association with polymyalgia rheumatica in the data, consistent with previous reports.^28,29 The females in this study were primarily civilians and therefore more similar to the general population of individuals with GCA. In contrast, male patients were more likely to be active-duty service members or have prior service experience with increased exposure to novel environmental factors linked to increased risk of autoimmune disease. This includes an increased risk of Guillain-Barré syndrome and Graves disease among Vietnam veterans exposed to Agent Orange.^30,31 Other studies have found that veterans with posttraumatic stress disorder are at increased risk for severe autoimmune diseases.^32,33 As more women join the active-duty military, the impact of autoimmune disease in the military service population is expected to grow, requiring further research.

Conclusions

Early diagnosis and treatment of GCA are critical to preventing serious outcomes, such as visual loss, jaw or limb claudication, or ischemic stroke. The incidence of autoimmune disease is expected to rise in the armed forces and veteran populations due to exposure to novel environmental factors and the increasing representation of women in the military. The use of additional screening tools can aid in earlier diagnosis of GCA. The 2022 ACR classification criteria for GCA represent significant updates to the 1990 criteria, incorporating ancillary tests such as the temporal artery halo sign on ultrasound, bilateral axillary vessel screening on imaging, and 18F-FDG PET activity throughout the aorta. The updated criteria require further validation and supports the adoption of a multidisciplinary approach that includes ultrasonography, vascular MRI/CT, and 18F-FDG PET. Furthermore, AI may play a future key role in ultrasound interpretation and study interrogation procedure. Ultimately, ultrasonography is a noninvasive and promising technique for the early diagnosis of GCA. A target goal is to increase the yield of positive temporal artery biopsies to ≥ 70%.

Giant cell arteritis (GCA), the most commonly diagnosed systemic vasculitis, is a large- and medium-vessel vasculitis that can lead to significant morbidity due to aneurysm formation or vascular occlusion if not diagnosed in a timely manner.^1,2 Diagnosis is typically based on clinical history and inflammatory markers. Laboratory inflammatory markers may be normal in the early stages of GCA but can be abnormal due to other unrelated reasons leading to a false positive diagnosis.³ Delayed treatment may lead to visual loss, jaw or limb claudication, or ischemic stroke.² Initial treatment typically includes high-dose steroids that can lead to significant adverse reactions such as hypothalamic-pituitary-adrenal axis dysfunction, metabolic syndrome, premature atherosclerosis, and increased risk of infection.^4-6

The 1990 American College of Rheumatology (ACR) criteria for GCA are widely recognized (Table 1).⁷ The criteria focuses on clinical manifestations, including new onset headache, temporal artery tenderness, age ≥ 50 years, erythrocyte sedimentation rate (ESR) ≥ 50 mm/hr, and temporal artery biopsy with positive anatomical findings.⁸ When 3 of the 5 1990 ACR criteria are present, the sensitivity and specificity is estimated to be > 90% for GCA vs alternative vasculitides.⁷

Although the 1990 ACR criteria do not include imaging, modalities such as ultrasound, computed tomography angiography (CTA), 18F-FDG positron emission tomography (PET), and magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) may be used in GCA diagnosis.^8-10 These imaging modalities have been added to the proposed ACR classification criteria for GCA.¹¹ For this updated point system standard, age ≥ 50 years is a requirement and includes a positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5 points), an ESR ≥ 50 mm/h or C-reactive protein (CRP) ≥ 10 mg/L (+3 points), or sudden visual loss (+3 points). Scalp tenderness, jaw or tongue claudication, new temporal headache, morning stiffness in shoulders or neck, temporal artery abnormality on vascular examination, bilateral axillary vessel involvement on imaging, and 18F-FDG PET activity throughout the aorta are scored +2 points each. With these new criteria, a cumulative score ≥ 6 is classified as GCA. Diagnostic accuracy is further improved with imaging: ultrasonography (sensitivity 55% and specificity 95%) and 18F-FDG PET (sensitivity 69% and specificity 92%), CTA (sensitivity 71% and specificity 86%), and MRI/MRA (sensitivity 73% and specificity 88%).^12-15

In recent years, clinicians have reported increased glucose uptake in arteries observed on PET imaging that suggests GCA.^9,10,16-20 18F-FDG accumulates in cells with high metabolic activity rates, such as areas of inflammation. In assessing temporal arteries or other involved vasculature (eg, axillary or great vessels) for GCA, this modality indicates increased glucose uptake in the lining of vessel walls. The inflammation of vessel walls can then be visualized with PET. 18F-FDG PET presents a noninvasive imaging technique for evaluating GCA but its use has been limited in the United States due to its high cost.

Methods

Approval for a retrospective chart review of patients evaluated for suspected GCA was obtained from the Walter Reed National Military Medical Center (WRNMMC) Institutional Review Board. The review included patients who underwent diagnostic procedures such as ultrasound, MRI, CT angiogram, and PET studies from 2016 through 2022. International Classification of Diseases codes used for case identification included: M31.6, M31.5, I77.6, I77.8, I77.89, I67.7, and I68.2. The Current Procedural Terminology code used for temporal artery biopsy is 37609.

Results

Seventy-eight charts were reviewed and 42 patients (54%) were diagnosed with GCA (Table 2). This study sample had a much higher proportion of African American subjects (31%) when compared with the civilian population, likely reflecting the higher representation of African Americans in the armed forces. Twenty-eight females (67%) were GCA positive. The most common presenting symptoms included 27 patients (64%) with headache, 17 (40%) with scalp tenderness, and 14 (33%) with jaw pain. The mean 1990 ACR score was 3.8 (range, 2-5). With respect to the score criteria: 41 patients (98%) were aged ≥ 50 years, 31 (74%) had new onset headache, and 31 (74%) had elevated ESR (Table 3). Acute ischemic optic neuropathy was documented in 4 patients (10%) with confirmed GCA. The mean ESR and CRP values at diagnosis were 66.2 mm/h (range, 7-122 mm/h) and 8.711 μg/mL (range, 0.054 – 92.690 μg/mL), respectively. Twenty-seven patients (64%) underwent biopsy: 24 (89%) were unilateral and 3 (11%) were bilateral (Table 4). Four patients with GCA (10%) were missing biopsy data. Nineteen patients with GCA (70%) had biopsies with pathologic findings consistent with GCA.

Twenty-five patients with GCA (60%) received ≥ 1 imaging modality. The most common imaging modality was MRI, which was used for 18 (43%) patients. Fourteen patients (33%) had 18F-FDG PET, 12 patients (29%) had MRA, and 11 patients (26%) had CTA. The small number of patients who underwent point-of-care ultrasound (POCUS), brain MRI, or dark blood MRI were negative for disease. Five patients who underwent 18F-FDG PET had findings consistent with GCA. One patient with GCA had CTA of the head and neck with radiographic findings supportive of GCA.

Discussion

The available evidence supports the use of additional screening tests to increase the temporal artery biopsy yield for GCA. Inflammatory laboratory markers demonstrate some sensitivity but are nonspecific for GCA. In this study, only 60% of patients with GCA underwent diagnostic imaging as part of the workup. There are multiple factors that may contribute to the underutilization of advanced imaging in the diagnosis of GCA, including outdated standardized diagnostic criteria, limited resources (direct access to modalities), and lack of clinician awareness of diagnostic testing options. In this retrospective review, 30 patients (71%) were diagnosed with GCA with a 1990 ACR GCA score ≤ 3. Of these 30 patients, 19 underwent confirmatory biopsy followed by prolonged courses of steroid therapy. In addition, only 25 patients underwent advanced imaging to increase diagnostic accuracy of the suspected syndrome.

A large meta-analysis demonstrated a sensitivity of 77.3% (95% CI, 71.8-81.9%) for temporal artery biopsy.²¹ The overall yield was 40% in the meta-analysis. Advanced noninvasive imaging represents an appropriate method of evaluating GCA.^8-20 In our study, 18F-FDG PET demonstrated the highest sensitivity (36%) for the diagnosis of GCA. Ultrasonography is recommended as an initial screening tool to identify the noncompressible halo sign (a hypoechoic circumferential wall thickening due to edema) as a cost-effective and widely available technology.²² Other research has corroborated the beneficial use of ultrasonography in improving diagnostic accuracy by detecting the noncompressible halo sign in temporal arteries.^22,23 GCA diagnostic performance has been significantly improved with the use of B-mode probes ≥ 15 MHz as well as proposals to incorporate a compression sign or interrogating the axillary vessels, showing a sensitivity of 54% to 77%.^23,24

POCUS may reduce the risk of a false-negative biopsy and improve yield with more frequent utilization. However, ultrasonography may be limited by operator skills and visualization of the great vessels. The accuracy of ultrasonography is dependent on the experience and adeptness of the operator. Additional studies are needed to establish a systematic standard for POCUS training to ensure accurate interpretation and uniform interrogation procedure.²⁴ Artificial intelligence (AI) may aid in interpreting results of POCUS and bridging the operator skill gap among operators.^25,26 AI and machine learning techniques can assist in detecting the noncompressible halo sign and compression sign in temporal arteries and other affected vessels.

In comparing the WRNMMC patient population with other US civilian GCA cohorts, there are some differences and similarities. There was a high representation of African American patients in the study, which may reflect a greater severity of autoimmune disease expression in this population.²⁷ We also observed a higher number of females and an association with polymyalgia rheumatica in the data, consistent with previous reports.^28,29 The females in this study were primarily civilians and therefore more similar to the general population of individuals with GCA. In contrast, male patients were more likely to be active-duty service members or have prior service experience with increased exposure to novel environmental factors linked to increased risk of autoimmune disease. This includes an increased risk of Guillain-Barré syndrome and Graves disease among Vietnam veterans exposed to Agent Orange.^30,31 Other studies have found that veterans with posttraumatic stress disorder are at increased risk for severe autoimmune diseases.^32,33 As more women join the active-duty military, the impact of autoimmune disease in the military service population is expected to grow, requiring further research.

Conclusions

Early diagnosis and treatment of GCA are critical to preventing serious outcomes, such as visual loss, jaw or limb claudication, or ischemic stroke. The incidence of autoimmune disease is expected to rise in the armed forces and veteran populations due to exposure to novel environmental factors and the increasing representation of women in the military. The use of additional screening tools can aid in earlier diagnosis of GCA. The 2022 ACR classification criteria for GCA represent significant updates to the 1990 criteria, incorporating ancillary tests such as the temporal artery halo sign on ultrasound, bilateral axillary vessel screening on imaging, and 18F-FDG PET activity throughout the aorta. The updated criteria require further validation and supports the adoption of a multidisciplinary approach that includes ultrasonography, vascular MRI/CT, and 18F-FDG PET. Furthermore, AI may play a future key role in ultrasound interpretation and study interrogation procedure. Ultimately, ultrasonography is a noninvasive and promising technique for the early diagnosis of GCA. A target goal is to increase the yield of positive temporal artery biopsies to ≥ 70%.

Background

Programmed death-ligand 1 (PD-L1) checkpoint inhibitors revolutionized the treatment of advanced non-small cell lung cancer (aNSCLC) by improving overall survival compared to chemotherapy. PD-L1 biomarker testing is paramount for informing treatment decisions in aNSCLC. Real-world data describing patterns of PD-L1 testing within the Veteran Health Administration (VHA) are limited. This retrospective study seeks to evaluate demographic and clinical factors associated with PD-L1 testing in VHA.

Methods

Veterans diagnosed with aNSCLC from 2019-2022 were identified using VHA’s Corporate Data Warehouse. Wilcoxon Rank Sum and Chi- Square tests measured association between receipt of PD-L1 testing and patient demographic and clinical characteristics at aNSCLC diagnosis. Logistic regression assessed predictors of PD-L1 testing, and subgroup analyses were performed for significant interactions.

Results

Our study included 4575 patients with aNSCLC; 57.0% received PD-L1 testing. The likelihood of PD-L1 testing increased among patients diagnosed with aNSCLC after 2019 vs during 2019 (OR≥1.118, p≤0.035) and in Black vs White patients (OR=1.227, p=0.011). However, the following had decreased likelihood of PD-L1 testing: patients with stage IIIB vs IV cancer (OR=0.683, p=0.004); non vs current/former smokers (OR=0.733, p=0.039); squamous (OR=0.863, p=0.030) or NOS (OR=0.695,p=0.013) vs. adenocarcinoma histology. Interactions were observed between patient residential region and residential rurality (p=0.003), and region and receipt of oncology community care consults (OCCC) (p=0.030). Patients in rural Midwest (OR=0.445,p=0.004) and rural South (OR=0.566, p=0.032) were less likely to receive PD-L1 testing than Metropolitan patients. Across patients with OCCC, Western US patients were more likely to receive PD-L1 testing (OR=1.554, p=0.001) than patients in other regions. However, within Midwestern patients, those without a OCCC were more likely to receive PD-L1 testing (OR=1.724, p< 0.001) than those with a OCCC. High comorbidity index (CCI≥3) is associated with an increased likelihood of PD-L1 testing in a univariable model (OR=1.286 vs. CCI=0,p=0.009), but not in the multivariable model (p=0.278).

Conclusions

We identified demographic and clinical factors, including regional differences in rurality and OCCC patterns, associated with PD-L1 testing. These factors can focus ongoing efforts to improve PD-L1 testing and efforts to be more in line with recommended care.

Background

Programmed death-ligand 1 (PD-L1) checkpoint inhibitors revolutionized the treatment of advanced non-small cell lung cancer (aNSCLC) by improving overall survival compared to chemotherapy. PD-L1 biomarker testing is paramount for informing treatment decisions in aNSCLC. Real-world data describing patterns of PD-L1 testing within the Veteran Health Administration (VHA) are limited. This retrospective study seeks to evaluate demographic and clinical factors associated with PD-L1 testing in VHA.

Methods

Veterans diagnosed with aNSCLC from 2019-2022 were identified using VHA’s Corporate Data Warehouse. Wilcoxon Rank Sum and Chi- Square tests measured association between receipt of PD-L1 testing and patient demographic and clinical characteristics at aNSCLC diagnosis. Logistic regression assessed predictors of PD-L1 testing, and subgroup analyses were performed for significant interactions.

Results

Our study included 4575 patients with aNSCLC; 57.0% received PD-L1 testing. The likelihood of PD-L1 testing increased among patients diagnosed with aNSCLC after 2019 vs during 2019 (OR≥1.118, p≤0.035) and in Black vs White patients (OR=1.227, p=0.011). However, the following had decreased likelihood of PD-L1 testing: patients with stage IIIB vs IV cancer (OR=0.683, p=0.004); non vs current/former smokers (OR=0.733, p=0.039); squamous (OR=0.863, p=0.030) or NOS (OR=0.695,p=0.013) vs. adenocarcinoma histology. Interactions were observed between patient residential region and residential rurality (p=0.003), and region and receipt of oncology community care consults (OCCC) (p=0.030). Patients in rural Midwest (OR=0.445,p=0.004) and rural South (OR=0.566, p=0.032) were less likely to receive PD-L1 testing than Metropolitan patients. Across patients with OCCC, Western US patients were more likely to receive PD-L1 testing (OR=1.554, p=0.001) than patients in other regions. However, within Midwestern patients, those without a OCCC were more likely to receive PD-L1 testing (OR=1.724, p< 0.001) than those with a OCCC. High comorbidity index (CCI≥3) is associated with an increased likelihood of PD-L1 testing in a univariable model (OR=1.286 vs. CCI=0,p=0.009), but not in the multivariable model (p=0.278).

Conclusions

We identified demographic and clinical factors, including regional differences in rurality and OCCC patterns, associated with PD-L1 testing. These factors can focus ongoing efforts to improve PD-L1 testing and efforts to be more in line with recommended care.

Background

Programmed death-ligand 1 (PD-L1) checkpoint inhibitors revolutionized the treatment of advanced non-small cell lung cancer (aNSCLC) by improving overall survival compared to chemotherapy. PD-L1 biomarker testing is paramount for informing treatment decisions in aNSCLC. Real-world data describing patterns of PD-L1 testing within the Veteran Health Administration (VHA) are limited. This retrospective study seeks to evaluate demographic and clinical factors associated with PD-L1 testing in VHA.

Methods

Veterans diagnosed with aNSCLC from 2019-2022 were identified using VHA’s Corporate Data Warehouse. Wilcoxon Rank Sum and Chi- Square tests measured association between receipt of PD-L1 testing and patient demographic and clinical characteristics at aNSCLC diagnosis. Logistic regression assessed predictors of PD-L1 testing, and subgroup analyses were performed for significant interactions.

Results

Our study included 4575 patients with aNSCLC; 57.0% received PD-L1 testing. The likelihood of PD-L1 testing increased among patients diagnosed with aNSCLC after 2019 vs during 2019 (OR≥1.118, p≤0.035) and in Black vs White patients (OR=1.227, p=0.011). However, the following had decreased likelihood of PD-L1 testing: patients with stage IIIB vs IV cancer (OR=0.683, p=0.004); non vs current/former smokers (OR=0.733, p=0.039); squamous (OR=0.863, p=0.030) or NOS (OR=0.695,p=0.013) vs. adenocarcinoma histology. Interactions were observed between patient residential region and residential rurality (p=0.003), and region and receipt of oncology community care consults (OCCC) (p=0.030). Patients in rural Midwest (OR=0.445,p=0.004) and rural South (OR=0.566, p=0.032) were less likely to receive PD-L1 testing than Metropolitan patients. Across patients with OCCC, Western US patients were more likely to receive PD-L1 testing (OR=1.554, p=0.001) than patients in other regions. However, within Midwestern patients, those without a OCCC were more likely to receive PD-L1 testing (OR=1.724, p< 0.001) than those with a OCCC. High comorbidity index (CCI≥3) is associated with an increased likelihood of PD-L1 testing in a univariable model (OR=1.286 vs. CCI=0,p=0.009), but not in the multivariable model (p=0.278).

Conclusions

We identified demographic and clinical factors, including regional differences in rurality and OCCC patterns, associated with PD-L1 testing. These factors can focus ongoing efforts to improve PD-L1 testing and efforts to be more in line with recommended care.

Background

Offering participation in clinical trials is a standard of care practice in oncology. It is also considered a quality indicator by various professional cancer societies, including the American Societies of Hematology (ASH) and Clinical Oncology (ASCO). In 2023, VA launched Clinical Cancer Research Services (CCRS) to ensure that all Veterans with cancer can participate in a clinical trial should they choose to do so. Research teams struggle to identify and engage potentially eligible patients. This is a complex process involving eligibility screening, outreach, and personalized support, which frequently involves a manual workflow with inefficiencies, delays, and missed opportunities for patients. To support CCRS’s mission, we used VA Enterprise Cloud (VAEC) to rapidly develop a clinical workflow support application for CCRS team members.

Methods

We used an internally developed framework to rapidly define program aims, provider workflows, opportunities to augment with data products, and lean principles applied to health information technology to design a clinical workflow supporting application. Data products leveraged VAEC’s Summit Data Platform (SDP), an open, multi-cloud platform for ingesting, curating, and managing multi-source VHA data into usable products. User interface was developed in a low code/no code power platform environment, which integrates with SDP and is also available in VAEC.

Results

An initial aim was identified as supporting engagement for the ‘Reaching Rural Cancer Survivors Who Smoke Using Text-based Cessation Interventions’ study. Augmented workflow was identified by meeting principal stakeholders and staff. Data product development involved retrieval of cancer diagnoses from the VA cancer registry system and smoking status from CDW HealthFactors. Rural residence was identified using 2023 Rural-Urban Continuum Codes. Application design, testing and refinement followed. Design to implementation was accomplished over the span of two months: from Aug 5, 2024 to Oct 3, 2024. Over the next seven months, the application identified 2,603 potentially eligible Veterans, and a single navigator using the tool was able to review 456 cases, send 189 study letters, and enroll 5 Veterans.

Conclusions

Clinical workflow support tools that leverage cloud infrastructure such as VAEC and Summit Data Platform can improve system efficiencies and increase access to clinical trials.

Background

Offering participation in clinical trials is a standard of care practice in oncology. It is also considered a quality indicator by various professional cancer societies, including the American Societies of Hematology (ASH) and Clinical Oncology (ASCO). In 2023, VA launched Clinical Cancer Research Services (CCRS) to ensure that all Veterans with cancer can participate in a clinical trial should they choose to do so. Research teams struggle to identify and engage potentially eligible patients. This is a complex process involving eligibility screening, outreach, and personalized support, which frequently involves a manual workflow with inefficiencies, delays, and missed opportunities for patients. To support CCRS’s mission, we used VA Enterprise Cloud (VAEC) to rapidly develop a clinical workflow support application for CCRS team members.

Methods

We used an internally developed framework to rapidly define program aims, provider workflows, opportunities to augment with data products, and lean principles applied to health information technology to design a clinical workflow supporting application. Data products leveraged VAEC’s Summit Data Platform (SDP), an open, multi-cloud platform for ingesting, curating, and managing multi-source VHA data into usable products. User interface was developed in a low code/no code power platform environment, which integrates with SDP and is also available in VAEC.

Results

An initial aim was identified as supporting engagement for the ‘Reaching Rural Cancer Survivors Who Smoke Using Text-based Cessation Interventions’ study. Augmented workflow was identified by meeting principal stakeholders and staff. Data product development involved retrieval of cancer diagnoses from the VA cancer registry system and smoking status from CDW HealthFactors. Rural residence was identified using 2023 Rural-Urban Continuum Codes. Application design, testing and refinement followed. Design to implementation was accomplished over the span of two months: from Aug 5, 2024 to Oct 3, 2024. Over the next seven months, the application identified 2,603 potentially eligible Veterans, and a single navigator using the tool was able to review 456 cases, send 189 study letters, and enroll 5 Veterans.

Conclusions

Clinical workflow support tools that leverage cloud infrastructure such as VAEC and Summit Data Platform can improve system efficiencies and increase access to clinical trials.

Background

Offering participation in clinical trials is a standard of care practice in oncology. It is also considered a quality indicator by various professional cancer societies, including the American Societies of Hematology (ASH) and Clinical Oncology (ASCO). In 2023, VA launched Clinical Cancer Research Services (CCRS) to ensure that all Veterans with cancer can participate in a clinical trial should they choose to do so. Research teams struggle to identify and engage potentially eligible patients. This is a complex process involving eligibility screening, outreach, and personalized support, which frequently involves a manual workflow with inefficiencies, delays, and missed opportunities for patients. To support CCRS’s mission, we used VA Enterprise Cloud (VAEC) to rapidly develop a clinical workflow support application for CCRS team members.

Methods

We used an internally developed framework to rapidly define program aims, provider workflows, opportunities to augment with data products, and lean principles applied to health information technology to design a clinical workflow supporting application. Data products leveraged VAEC’s Summit Data Platform (SDP), an open, multi-cloud platform for ingesting, curating, and managing multi-source VHA data into usable products. User interface was developed in a low code/no code power platform environment, which integrates with SDP and is also available in VAEC.

Results

An initial aim was identified as supporting engagement for the ‘Reaching Rural Cancer Survivors Who Smoke Using Text-based Cessation Interventions’ study. Augmented workflow was identified by meeting principal stakeholders and staff. Data product development involved retrieval of cancer diagnoses from the VA cancer registry system and smoking status from CDW HealthFactors. Rural residence was identified using 2023 Rural-Urban Continuum Codes. Application design, testing and refinement followed. Design to implementation was accomplished over the span of two months: from Aug 5, 2024 to Oct 3, 2024. Over the next seven months, the application identified 2,603 potentially eligible Veterans, and a single navigator using the tool was able to review 456 cases, send 189 study letters, and enroll 5 Veterans.

Conclusions

Clinical workflow support tools that leverage cloud infrastructure such as VAEC and Summit Data Platform can improve system efficiencies and increase access to clinical trials.

Did you know you can honor a family member, friend, or colleague whose life has been touched by GI research through a gift to the AGA Research Foundation? Your gift will honor a loved one or yourself and support the AGA Research Awards Program, while giving you a tax benefit.

Named award. An AGA pilot award can be renamed after you or a loved one, and targeted for a specific gastrointestinal research area. A new pilot research award can be established with a pledge of $40,000+ or through an estate gift. Gifts of cash or appreciated securities may be used to establish a named award. 

Your next step. A named award gift is a wonderful way to acknowledge a loved one’s vision for the future. To learn more about ways to recognize your honoree, contact us at [email protected].

A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs. A named award donation to the AGA Research Foundation will help support and fund investigators with a research grant in the field of gastroenterology and hepatology.

Did you know you can honor a family member, friend, or colleague whose life has been touched by GI research through a gift to the AGA Research Foundation? Your gift will honor a loved one or yourself and support the AGA Research Awards Program, while giving you a tax benefit.

Named award. An AGA pilot award can be renamed after you or a loved one, and targeted for a specific gastrointestinal research area. A new pilot research award can be established with a pledge of $40,000+ or through an estate gift. Gifts of cash or appreciated securities may be used to establish a named award. 

Your next step. A named award gift is a wonderful way to acknowledge a loved one’s vision for the future. To learn more about ways to recognize your honoree, contact us at [email protected].

A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs. A named award donation to the AGA Research Foundation will help support and fund investigators with a research grant in the field of gastroenterology and hepatology.

Did you know you can honor a family member, friend, or colleague whose life has been touched by GI research through a gift to the AGA Research Foundation? Your gift will honor a loved one or yourself and support the AGA Research Awards Program, while giving you a tax benefit.

Named award. An AGA pilot award can be renamed after you or a loved one, and targeted for a specific gastrointestinal research area. A new pilot research award can be established with a pledge of $40,000+ or through an estate gift. Gifts of cash or appreciated securities may be used to establish a named award. 

Your next step. A named award gift is a wonderful way to acknowledge a loved one’s vision for the future. To learn more about ways to recognize your honoree, contact us at [email protected].

A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs. A named award donation to the AGA Research Foundation will help support and fund investigators with a research grant in the field of gastroenterology and hepatology.

Patients with intestinal methanogen overgrowth (IMO) have a higher rate and severity of constipation but a lower rate and severity of diarrhea, according to a systematic review and meta-analysis published in Clinical Gastroenterology and Hepatology.

“The distinct phenotype of patients with IMO should be incorporated in patient-reported outcome measures and further correlated with mechanistic microbiome studies,” wrote investigators led by gastroenterologist Ali Rezaie, MD, MSc, medical director of the GI Motility Program at Cedars-Sinai Medical Center and director of biotechnology in the center’s Medically Associated Science and Technology (MAST) Program. Recognizing specific GI symptom profiles can improve diagnosis and treatment strategies, facilitating further clinical trials and targeted microbiome studies to optimize patient care. 

Excessive luminal loads of methanogenic archaea – archaea being bacteria-like prokaryotes and one of the main three domains of the tree of life – have been implicated in the pathophysiology of various diseases, including constipation. 

 

The Study

To elucidate the phenotypical presentation of IMO in patients, Rezaie’s group compared the prevalence and severity of gastrointestinal (GI) symptoms in individuals who had IMO with those who did not have IMO. IMO was based on excess levels of this gaseous GI byproduct in exhaled breath tests.

Searching electronic databases from inception to September 2023, the researchers identified 19 eligible studies from diverse geographical regions with 1293 IMO patients and 3208 controls. Eleven studies were performed in the United States; the other studies were conducted in France (n = 2), India (n = 2), New Zealand (n = 1), South Korea (n = 1), Italy (n = 1), and the United Kingdom (n = 1). Thirteen studies were of high quality, as defined by a Newcastle-Ottawa Assessment Scale score of 6. 

Patients with IMO were found to exhibit a range of GI symptoms, including bloating (78%), constipation (51%), diarrhea (33%), abdominal pain (65%), nausea (30%), and flatulence (56%).

In other findings:

• Patients with IMO had a significantly higher prevalence of constipation vs controls: 47% vs 38% (odds ratio [OR], 2.04, 95% confidence interval [CI], 1.48-2.83, P < .0001).
• They had a lower prevalence of diarrhea: 37% vs 52% (OR .58, 95% CI, .37-.90, P = .01); and nausea: 32% vs 45%; (OR, .75; 95% CI, .60-.94, P = .01).
• Patients with IMO had more severe constipation: standard mean deviation [SMD], .77 (95% CI, .11-1.43, P = .02) and a lower severity of diarrhea: SMD, –.71 (95% CI, –1.39 to –.03, P = .04). Significant heterogeneity of effect, however, was detected.
• Constipation was more prevalent in IMO diagnosed with the lactulose breath test and the glucose breath test and constipation was particularly prevalent in Europe and the United States.

Mechanism of Action

The findings on constipation and diarrhea corroborate methane’s slowing physiologic effects on motility, the authors noted. It has been consistently found to delay gut transit, both small bowel and colonic transit.

Mechanistically, methane reduces small intestinal peristaltic velocity while augmenting non-propagating contraction amplitude, suggesting that reduction of intestinal transit time is mediated through promotion of non-propulsive contractions.

“This study further consolidates methane’s causal role in constipation and paves the way to establish validated disease-specific patient-reported outcomes,” Rezaie and associates wrote, calling for longitudinal and mechanistic studies assessing the archaeome in order to advance understanding of IMO.

This study was funded in part by Nancy Stark and Stanley Lezman in support of the MAST Program’s Innovation Project at Cedars-Sinai.

Rezaie serves as a consultant/speaker for Bausch Health. Cedars-Sinai Medical Center has a licensing agreement with Gemelli Biotech, in which Rezaie and coauthor Pimentel have equity. They also hold equity in Good LIFE. Pimentel consults for and has received grant support from Bausch Health.

Patients with intestinal methanogen overgrowth (IMO) have a higher rate and severity of constipation but a lower rate and severity of diarrhea, according to a systematic review and meta-analysis published in Clinical Gastroenterology and Hepatology.

“The distinct phenotype of patients with IMO should be incorporated in patient-reported outcome measures and further correlated with mechanistic microbiome studies,” wrote investigators led by gastroenterologist Ali Rezaie, MD, MSc, medical director of the GI Motility Program at Cedars-Sinai Medical Center and director of biotechnology in the center’s Medically Associated Science and Technology (MAST) Program. Recognizing specific GI symptom profiles can improve diagnosis and treatment strategies, facilitating further clinical trials and targeted microbiome studies to optimize patient care. 

Excessive luminal loads of methanogenic archaea – archaea being bacteria-like prokaryotes and one of the main three domains of the tree of life – have been implicated in the pathophysiology of various diseases, including constipation. 

 

The Study

To elucidate the phenotypical presentation of IMO in patients, Rezaie’s group compared the prevalence and severity of gastrointestinal (GI) symptoms in individuals who had IMO with those who did not have IMO. IMO was based on excess levels of this gaseous GI byproduct in exhaled breath tests.

Searching electronic databases from inception to September 2023, the researchers identified 19 eligible studies from diverse geographical regions with 1293 IMO patients and 3208 controls. Eleven studies were performed in the United States; the other studies were conducted in France (n = 2), India (n = 2), New Zealand (n = 1), South Korea (n = 1), Italy (n = 1), and the United Kingdom (n = 1). Thirteen studies were of high quality, as defined by a Newcastle-Ottawa Assessment Scale score of 6. 

Patients with IMO were found to exhibit a range of GI symptoms, including bloating (78%), constipation (51%), diarrhea (33%), abdominal pain (65%), nausea (30%), and flatulence (56%).

In other findings:

• Patients with IMO had a significantly higher prevalence of constipation vs controls: 47% vs 38% (odds ratio [OR], 2.04, 95% confidence interval [CI], 1.48-2.83, P < .0001).
• They had a lower prevalence of diarrhea: 37% vs 52% (OR .58, 95% CI, .37-.90, P = .01); and nausea: 32% vs 45%; (OR, .75; 95% CI, .60-.94, P = .01).
• Patients with IMO had more severe constipation: standard mean deviation [SMD], .77 (95% CI, .11-1.43, P = .02) and a lower severity of diarrhea: SMD, –.71 (95% CI, –1.39 to –.03, P = .04). Significant heterogeneity of effect, however, was detected.
• Constipation was more prevalent in IMO diagnosed with the lactulose breath test and the glucose breath test and constipation was particularly prevalent in Europe and the United States.

Mechanism of Action

The findings on constipation and diarrhea corroborate methane’s slowing physiologic effects on motility, the authors noted. It has been consistently found to delay gut transit, both small bowel and colonic transit.

Mechanistically, methane reduces small intestinal peristaltic velocity while augmenting non-propagating contraction amplitude, suggesting that reduction of intestinal transit time is mediated through promotion of non-propulsive contractions.

“This study further consolidates methane’s causal role in constipation and paves the way to establish validated disease-specific patient-reported outcomes,” Rezaie and associates wrote, calling for longitudinal and mechanistic studies assessing the archaeome in order to advance understanding of IMO.

This study was funded in part by Nancy Stark and Stanley Lezman in support of the MAST Program’s Innovation Project at Cedars-Sinai.

Rezaie serves as a consultant/speaker for Bausch Health. Cedars-Sinai Medical Center has a licensing agreement with Gemelli Biotech, in which Rezaie and coauthor Pimentel have equity. They also hold equity in Good LIFE. Pimentel consults for and has received grant support from Bausch Health.

Patients with intestinal methanogen overgrowth (IMO) have a higher rate and severity of constipation but a lower rate and severity of diarrhea, according to a systematic review and meta-analysis published in Clinical Gastroenterology and Hepatology.

“The distinct phenotype of patients with IMO should be incorporated in patient-reported outcome measures and further correlated with mechanistic microbiome studies,” wrote investigators led by gastroenterologist Ali Rezaie, MD, MSc, medical director of the GI Motility Program at Cedars-Sinai Medical Center and director of biotechnology in the center’s Medically Associated Science and Technology (MAST) Program. Recognizing specific GI symptom profiles can improve diagnosis and treatment strategies, facilitating further clinical trials and targeted microbiome studies to optimize patient care. 

Excessive luminal loads of methanogenic archaea – archaea being bacteria-like prokaryotes and one of the main three domains of the tree of life – have been implicated in the pathophysiology of various diseases, including constipation. 

 

The Study

To elucidate the phenotypical presentation of IMO in patients, Rezaie’s group compared the prevalence and severity of gastrointestinal (GI) symptoms in individuals who had IMO with those who did not have IMO. IMO was based on excess levels of this gaseous GI byproduct in exhaled breath tests.

Searching electronic databases from inception to September 2023, the researchers identified 19 eligible studies from diverse geographical regions with 1293 IMO patients and 3208 controls. Eleven studies were performed in the United States; the other studies were conducted in France (n = 2), India (n = 2), New Zealand (n = 1), South Korea (n = 1), Italy (n = 1), and the United Kingdom (n = 1). Thirteen studies were of high quality, as defined by a Newcastle-Ottawa Assessment Scale score of 6. 

Patients with IMO were found to exhibit a range of GI symptoms, including bloating (78%), constipation (51%), diarrhea (33%), abdominal pain (65%), nausea (30%), and flatulence (56%).

In other findings:

• Patients with IMO had a significantly higher prevalence of constipation vs controls: 47% vs 38% (odds ratio [OR], 2.04, 95% confidence interval [CI], 1.48-2.83, P < .0001).
• They had a lower prevalence of diarrhea: 37% vs 52% (OR .58, 95% CI, .37-.90, P = .01); and nausea: 32% vs 45%; (OR, .75; 95% CI, .60-.94, P = .01).
• Patients with IMO had more severe constipation: standard mean deviation [SMD], .77 (95% CI, .11-1.43, P = .02) and a lower severity of diarrhea: SMD, –.71 (95% CI, –1.39 to –.03, P = .04). Significant heterogeneity of effect, however, was detected.
• Constipation was more prevalent in IMO diagnosed with the lactulose breath test and the glucose breath test and constipation was particularly prevalent in Europe and the United States.

Mechanism of Action

The findings on constipation and diarrhea corroborate methane’s slowing physiologic effects on motility, the authors noted. It has been consistently found to delay gut transit, both small bowel and colonic transit.

Mechanistically, methane reduces small intestinal peristaltic velocity while augmenting non-propagating contraction amplitude, suggesting that reduction of intestinal transit time is mediated through promotion of non-propulsive contractions.

“This study further consolidates methane’s causal role in constipation and paves the way to establish validated disease-specific patient-reported outcomes,” Rezaie and associates wrote, calling for longitudinal and mechanistic studies assessing the archaeome in order to advance understanding of IMO.

This study was funded in part by Nancy Stark and Stanley Lezman in support of the MAST Program’s Innovation Project at Cedars-Sinai.

Rezaie serves as a consultant/speaker for Bausch Health. Cedars-Sinai Medical Center has a licensing agreement with Gemelli Biotech, in which Rezaie and coauthor Pimentel have equity. They also hold equity in Good LIFE. Pimentel consults for and has received grant support from Bausch Health.

No evidence of a causal relationship between previously suspected pharmacologic triggers and increased risk of microscopic colitis (MC) emerged from a nationwide longitudinal study of older Swedish individuals in a national database.

“Sensitivity analyses suggest that previously reported associations and persistent association with SSRI [selective serotonin reuptake inhibitor] initiation may be due to surveillance bias,” wrote gastroenterologist Hamed Khalili, MD, MPH, of Massachusetts General Hospital, Boston, and colleagues in Annals of Internal Medicine, advising clinicians to carefully balance the benefits of these medication classes against the very low likelihood of a causal relationship with MC.

While two smaller studies had challenged the belief that these medications can cause MC, Khalili told GI & Hepatology News, “the quality of the data that supported or refuted this hypothesis were low. Nevertheless, most in the field consider MC to be largely related to medications so we thought it was important to systematically answer this question.”

While most medications thought to trigger MC were found not to be causally linked, he added, “we did observe a marginal association with SSRIs but could not rule out the possibility that the association is related to residual bias.”

The authors noted that the incidence of MC in older persons is rising rapidly and is thought to account for more than 30% of chronic diarrhea cases in this group.

Despite weak evidence in the literature, the treatment guidelines of several societies, including the American Gastroenterological Association, recommend discontinuing potential pharmacologic triggers as first-line prevention or as an adjunct therapy, particularly in recurrent or refractory MC. But this approach may be ineffective in patients with established disease and could lead to inappropriate discontinuation of medication such as antihypertensives, the authors argued.

As to proposed mechanisms of action, said Khalili, “for PPIs [proton-pump inhibitors,] people thought it was related to changes in the gut microbiome. For NSAIDs [nonsteroidal anti-inflammatory drugs], people thought it could be related to changes in the gut barrier function. But overall, not a single mechanism would have explained all the prior associations that were observed.”

While medications such as PPIs and SSRIs can cause diarrhea in a small subset of users, Khalili added, “most patients generally catch these side effects very quickly and realize that stopping these medications will improve their diarrhea. This is very different than most patients we as gastroenterologists see with a new diagnosis of MC. Many of them may have been on these medications for a long time. We believe that stopping medications in these patients is unnecessary.” 

 

Study Details

The investigators looked at eligible residents in Sweden age 65 years or older in the years 2006 to 2017 (n = 191,482 to 2,634,777). Participants had no history of inflammatory bowel disease and different cohorts were examined for various common medications from calcium channel blockers to statins.

With a primary outcome of biopsy-verified MC, dates of diagnosis were obtained from Sweden’s national histopathology cohort ESPRESSO (Epidemiology Strengthened by Histopathology Reports in Sweden). Among the findings:

• The 12- and 24-month cumulative incidences of MC were less than 0.05% under all treatment strategies.
• Estimated 12-month risk differences were close to null under angiotensin-converting enzyme vs calcium-channel blocker (CCB) initiation, angiotensin-receptor blocker vs CCB initiation, NSAID initiation vs noninitiation, PPI inhibitor initiation vs noninitiation, and statin initiation vs noninitiation.
• The estimated 12-month risk difference was 0.04% (95% CI, 0.03%-0.05%) for SSRIs vs mirtazapine.
• Results were similar for 24-month risk differences. Several medications such as SSRIs were also associated with increased risk for undergoing colonoscopy with a normal colorectal mucosa biopsy result.

“We think it’s unlikely that stopping these medications will improve symptoms of MC,” Khalili said. 

Commenting on the paper but not involved in it, Jordan E. Axelrad, MD, MPH, codirector of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City, said, “This study strengthens the argument that MC is an immune-mediated disease, not primarily driven by drug exposures. But future studies in diverse cohorts are required to validate these findings.” He said the study nevertheless provides reassurance that previously reported associations may have been overstated or confounded by factors such as reverse causation and increased healthcare utilization preceding the MC diagnosis.

In the meantime, Axelrad added, the findings “may reduce the inclination to promptly discontinue medications historically associated with MC in newly diagnosed cases. Also, these data help shift the clinical focus away from medication cessation alone and toward a needed and broader MC management strategy. US-based validation would likely highlight these changes in our patients.”

Despite concerns about the study’s unmeasured confounding because of differential healthcare utilization or surveillance, the modest association observed between SSRI and MC is supported by literature linking catecholamine and serotonin to gut innate immunity and microbiota, Khalili’s group wrote. “However, this finding may also be confounded by other factors including persisting surveillance and protopathic bias, especially since an association was also seen for risk for receipt of a colonoscopy with normal mucosa.”

Khalili believes the Swedish results are applicable even to the more diverse US population. He noted that lack of primary care data limited measurement of and adjustment for symptoms and medical diagnoses that increase risk. But according to Axelrad, MC is more prevalent in White, older patients, who are well-represented in Swedish cohorts but to a lesser extent in US populations. “Additionally, environmental factors and medication use patterns differ between Sweden and the US, particularly in regard to over-the-counter medication access.”

The findings have implications for future research in pharmacoepidemiologic studies of gastrointestinal-related outcomes. Since many routinely prescribed medications such as SSRIs were associated with an apparent increased risk for colonoscopies with normal colorectal biopsy results, future studies that examine gastrointestinal-specific adverse events should carefully consider potential surveillance bias.

In the meantime, Khalili stressed, it’s important to highlight that while some of these medications cause diarrhea in a small subset of patients, stopping medications in these patients is unnecessary.

This study was supported by the National Institutes of Health (NIH) and the Swedish Research Council. Khalili disclosed grants from the Crohn’s & Coiltis Foundation, the NIH and the Helmsley CharitableTrust, as well as stock ownership in Cylinder Health. One coauthor is employed by Massachusetts General Hospital. Axelrad had no relevant competing interests.







 

No evidence of a causal relationship between previously suspected pharmacologic triggers and increased risk of microscopic colitis (MC) emerged from a nationwide longitudinal study of older Swedish individuals in a national database.

“Sensitivity analyses suggest that previously reported associations and persistent association with SSRI [selective serotonin reuptake inhibitor] initiation may be due to surveillance bias,” wrote gastroenterologist Hamed Khalili, MD, MPH, of Massachusetts General Hospital, Boston, and colleagues in Annals of Internal Medicine, advising clinicians to carefully balance the benefits of these medication classes against the very low likelihood of a causal relationship with MC.

While two smaller studies had challenged the belief that these medications can cause MC, Khalili told GI & Hepatology News, “the quality of the data that supported or refuted this hypothesis were low. Nevertheless, most in the field consider MC to be largely related to medications so we thought it was important to systematically answer this question.”

While most medications thought to trigger MC were found not to be causally linked, he added, “we did observe a marginal association with SSRIs but could not rule out the possibility that the association is related to residual bias.”

The authors noted that the incidence of MC in older persons is rising rapidly and is thought to account for more than 30% of chronic diarrhea cases in this group.

Despite weak evidence in the literature, the treatment guidelines of several societies, including the American Gastroenterological Association, recommend discontinuing potential pharmacologic triggers as first-line prevention or as an adjunct therapy, particularly in recurrent or refractory MC. But this approach may be ineffective in patients with established disease and could lead to inappropriate discontinuation of medication such as antihypertensives, the authors argued.

As to proposed mechanisms of action, said Khalili, “for PPIs [proton-pump inhibitors,] people thought it was related to changes in the gut microbiome. For NSAIDs [nonsteroidal anti-inflammatory drugs], people thought it could be related to changes in the gut barrier function. But overall, not a single mechanism would have explained all the prior associations that were observed.”

While medications such as PPIs and SSRIs can cause diarrhea in a small subset of users, Khalili added, “most patients generally catch these side effects very quickly and realize that stopping these medications will improve their diarrhea. This is very different than most patients we as gastroenterologists see with a new diagnosis of MC. Many of them may have been on these medications for a long time. We believe that stopping medications in these patients is unnecessary.” 

 

Study Details

The investigators looked at eligible residents in Sweden age 65 years or older in the years 2006 to 2017 (n = 191,482 to 2,634,777). Participants had no history of inflammatory bowel disease and different cohorts were examined for various common medications from calcium channel blockers to statins.

With a primary outcome of biopsy-verified MC, dates of diagnosis were obtained from Sweden’s national histopathology cohort ESPRESSO (Epidemiology Strengthened by Histopathology Reports in Sweden). Among the findings:

• The 12- and 24-month cumulative incidences of MC were less than 0.05% under all treatment strategies.
• Estimated 12-month risk differences were close to null under angiotensin-converting enzyme vs calcium-channel blocker (CCB) initiation, angiotensin-receptor blocker vs CCB initiation, NSAID initiation vs noninitiation, PPI inhibitor initiation vs noninitiation, and statin initiation vs noninitiation.
• The estimated 12-month risk difference was 0.04% (95% CI, 0.03%-0.05%) for SSRIs vs mirtazapine.
• Results were similar for 24-month risk differences. Several medications such as SSRIs were also associated with increased risk for undergoing colonoscopy with a normal colorectal mucosa biopsy result.

“We think it’s unlikely that stopping these medications will improve symptoms of MC,” Khalili said. 

Commenting on the paper but not involved in it, Jordan E. Axelrad, MD, MPH, codirector of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City, said, “This study strengthens the argument that MC is an immune-mediated disease, not primarily driven by drug exposures. But future studies in diverse cohorts are required to validate these findings.” He said the study nevertheless provides reassurance that previously reported associations may have been overstated or confounded by factors such as reverse causation and increased healthcare utilization preceding the MC diagnosis.

In the meantime, Axelrad added, the findings “may reduce the inclination to promptly discontinue medications historically associated with MC in newly diagnosed cases. Also, these data help shift the clinical focus away from medication cessation alone and toward a needed and broader MC management strategy. US-based validation would likely highlight these changes in our patients.”

Despite concerns about the study’s unmeasured confounding because of differential healthcare utilization or surveillance, the modest association observed between SSRI and MC is supported by literature linking catecholamine and serotonin to gut innate immunity and microbiota, Khalili’s group wrote. “However, this finding may also be confounded by other factors including persisting surveillance and protopathic bias, especially since an association was also seen for risk for receipt of a colonoscopy with normal mucosa.”

Khalili believes the Swedish results are applicable even to the more diverse US population. He noted that lack of primary care data limited measurement of and adjustment for symptoms and medical diagnoses that increase risk. But according to Axelrad, MC is more prevalent in White, older patients, who are well-represented in Swedish cohorts but to a lesser extent in US populations. “Additionally, environmental factors and medication use patterns differ between Sweden and the US, particularly in regard to over-the-counter medication access.”

The findings have implications for future research in pharmacoepidemiologic studies of gastrointestinal-related outcomes. Since many routinely prescribed medications such as SSRIs were associated with an apparent increased risk for colonoscopies with normal colorectal biopsy results, future studies that examine gastrointestinal-specific adverse events should carefully consider potential surveillance bias.

In the meantime, Khalili stressed, it’s important to highlight that while some of these medications cause diarrhea in a small subset of patients, stopping medications in these patients is unnecessary.

This study was supported by the National Institutes of Health (NIH) and the Swedish Research Council. Khalili disclosed grants from the Crohn’s & Coiltis Foundation, the NIH and the Helmsley CharitableTrust, as well as stock ownership in Cylinder Health. One coauthor is employed by Massachusetts General Hospital. Axelrad had no relevant competing interests.







 

No evidence of a causal relationship between previously suspected pharmacologic triggers and increased risk of microscopic colitis (MC) emerged from a nationwide longitudinal study of older Swedish individuals in a national database.

“Sensitivity analyses suggest that previously reported associations and persistent association with SSRI [selective serotonin reuptake inhibitor] initiation may be due to surveillance bias,” wrote gastroenterologist Hamed Khalili, MD, MPH, of Massachusetts General Hospital, Boston, and colleagues in Annals of Internal Medicine, advising clinicians to carefully balance the benefits of these medication classes against the very low likelihood of a causal relationship with MC.

While two smaller studies had challenged the belief that these medications can cause MC, Khalili told GI & Hepatology News, “the quality of the data that supported or refuted this hypothesis were low. Nevertheless, most in the field consider MC to be largely related to medications so we thought it was important to systematically answer this question.”

While most medications thought to trigger MC were found not to be causally linked, he added, “we did observe a marginal association with SSRIs but could not rule out the possibility that the association is related to residual bias.”

The authors noted that the incidence of MC in older persons is rising rapidly and is thought to account for more than 30% of chronic diarrhea cases in this group.

Despite weak evidence in the literature, the treatment guidelines of several societies, including the American Gastroenterological Association, recommend discontinuing potential pharmacologic triggers as first-line prevention or as an adjunct therapy, particularly in recurrent or refractory MC. But this approach may be ineffective in patients with established disease and could lead to inappropriate discontinuation of medication such as antihypertensives, the authors argued.

As to proposed mechanisms of action, said Khalili, “for PPIs [proton-pump inhibitors,] people thought it was related to changes in the gut microbiome. For NSAIDs [nonsteroidal anti-inflammatory drugs], people thought it could be related to changes in the gut barrier function. But overall, not a single mechanism would have explained all the prior associations that were observed.”

While medications such as PPIs and SSRIs can cause diarrhea in a small subset of users, Khalili added, “most patients generally catch these side effects very quickly and realize that stopping these medications will improve their diarrhea. This is very different than most patients we as gastroenterologists see with a new diagnosis of MC. Many of them may have been on these medications for a long time. We believe that stopping medications in these patients is unnecessary.” 

 

Study Details

The investigators looked at eligible residents in Sweden age 65 years or older in the years 2006 to 2017 (n = 191,482 to 2,634,777). Participants had no history of inflammatory bowel disease and different cohorts were examined for various common medications from calcium channel blockers to statins.

With a primary outcome of biopsy-verified MC, dates of diagnosis were obtained from Sweden’s national histopathology cohort ESPRESSO (Epidemiology Strengthened by Histopathology Reports in Sweden). Among the findings:

• The 12- and 24-month cumulative incidences of MC were less than 0.05% under all treatment strategies.
• Estimated 12-month risk differences were close to null under angiotensin-converting enzyme vs calcium-channel blocker (CCB) initiation, angiotensin-receptor blocker vs CCB initiation, NSAID initiation vs noninitiation, PPI inhibitor initiation vs noninitiation, and statin initiation vs noninitiation.
• The estimated 12-month risk difference was 0.04% (95% CI, 0.03%-0.05%) for SSRIs vs mirtazapine.
• Results were similar for 24-month risk differences. Several medications such as SSRIs were also associated with increased risk for undergoing colonoscopy with a normal colorectal mucosa biopsy result.

“We think it’s unlikely that stopping these medications will improve symptoms of MC,” Khalili said. 

Commenting on the paper but not involved in it, Jordan E. Axelrad, MD, MPH, codirector of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City, said, “This study strengthens the argument that MC is an immune-mediated disease, not primarily driven by drug exposures. But future studies in diverse cohorts are required to validate these findings.” He said the study nevertheless provides reassurance that previously reported associations may have been overstated or confounded by factors such as reverse causation and increased healthcare utilization preceding the MC diagnosis.

In the meantime, Axelrad added, the findings “may reduce the inclination to promptly discontinue medications historically associated with MC in newly diagnosed cases. Also, these data help shift the clinical focus away from medication cessation alone and toward a needed and broader MC management strategy. US-based validation would likely highlight these changes in our patients.”

Despite concerns about the study’s unmeasured confounding because of differential healthcare utilization or surveillance, the modest association observed between SSRI and MC is supported by literature linking catecholamine and serotonin to gut innate immunity and microbiota, Khalili’s group wrote. “However, this finding may also be confounded by other factors including persisting surveillance and protopathic bias, especially since an association was also seen for risk for receipt of a colonoscopy with normal mucosa.”

Khalili believes the Swedish results are applicable even to the more diverse US population. He noted that lack of primary care data limited measurement of and adjustment for symptoms and medical diagnoses that increase risk. But according to Axelrad, MC is more prevalent in White, older patients, who are well-represented in Swedish cohorts but to a lesser extent in US populations. “Additionally, environmental factors and medication use patterns differ between Sweden and the US, particularly in regard to over-the-counter medication access.”

The findings have implications for future research in pharmacoepidemiologic studies of gastrointestinal-related outcomes. Since many routinely prescribed medications such as SSRIs were associated with an apparent increased risk for colonoscopies with normal colorectal biopsy results, future studies that examine gastrointestinal-specific adverse events should carefully consider potential surveillance bias.

In the meantime, Khalili stressed, it’s important to highlight that while some of these medications cause diarrhea in a small subset of patients, stopping medications in these patients is unnecessary.

This study was supported by the National Institutes of Health (NIH) and the Swedish Research Council. Khalili disclosed grants from the Crohn’s & Coiltis Foundation, the NIH and the Helmsley CharitableTrust, as well as stock ownership in Cylinder Health. One coauthor is employed by Massachusetts General Hospital. Axelrad had no relevant competing interests.