Immunology

The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) recommended on October 15 that marketing authorization be granted for Palforzia (Aimmune Therapeutics). The product is intended for desensitizing children and adolescents to peanut allergy.

Palforzia will be available as an oral powder in capsules (0.5, 1, 10, 20, and 100 mg) and as oral powder in sachet (300 mg). The active substance is defatted powder of Arachis hypogaea.

Through use of the product, children with a peanut allergy receive controlled exposure to precise, increasing amounts of peanut protein, mixed with soft food, every day. Over time, this may help to decrease their sensitivity to small amounts of peanuts.

According to the press release from the EMA, Palforzia can mitigate accidental exposure to small amounts of peanut protein. “[A] single dose of a least 1 gram of peanut protein would cause no more than mild allergy symptoms,” the EMA said.

The treatment is indicated for patients aged 4 to 17 years who have received a confirmed diagnosis of peanut allergy. Treatment may be continued for patients aged 18 years or older, according to the press release.

It should be administered under the supervision of a healthcare provider qualified in the diagnosis and treatment of allergic diseases and should be used in conjunction with a peanut-avoidant diet, the EMA notes.

The most common side effects that have been reported are abdominal pain, throat irritation, itch, nausea, vomiting, urticaria, and upper abdominal discomfort.

The next step in the approval process is to obtain market authorization from the European Commission. Detailed recommendations for use will be described in the summary of product characteristics, which will be published in the European public assessment report and will be made available throughout Europe.

“We are encouraged by the CHMP opinion, which recommends Palforzia as the first and only treatment option in the European Union for patients with peanut allergy and their families,” Andrew Oxtoby, president and chief executive officer of Aimmune Therapeutics, said in a statement. “Today’s decision underscores the strong and compelling data from our Palforzia clinical trials and follows the US FDA approval of Palforzia earlier this year. We look forward to the European Commission’s final decision for the marketing approval of Palforzia, which we expect later this year.”

The FDA said in granting its approval that patients, parents, or caregivers must be counseled on the need for always-available injectable epinephrine, the need for continued peanut avoidance, and on how to recognize signs of anaphylaxis.
 

This article originally appeared on Medscape.com.

The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) recommended on October 15 that marketing authorization be granted for Palforzia (Aimmune Therapeutics). The product is intended for desensitizing children and adolescents to peanut allergy.

Palforzia will be available as an oral powder in capsules (0.5, 1, 10, 20, and 100 mg) and as oral powder in sachet (300 mg). The active substance is defatted powder of Arachis hypogaea.

Through use of the product, children with a peanut allergy receive controlled exposure to precise, increasing amounts of peanut protein, mixed with soft food, every day. Over time, this may help to decrease their sensitivity to small amounts of peanuts.

According to the press release from the EMA, Palforzia can mitigate accidental exposure to small amounts of peanut protein. “[A] single dose of a least 1 gram of peanut protein would cause no more than mild allergy symptoms,” the EMA said.

The treatment is indicated for patients aged 4 to 17 years who have received a confirmed diagnosis of peanut allergy. Treatment may be continued for patients aged 18 years or older, according to the press release.

It should be administered under the supervision of a healthcare provider qualified in the diagnosis and treatment of allergic diseases and should be used in conjunction with a peanut-avoidant diet, the EMA notes.

The most common side effects that have been reported are abdominal pain, throat irritation, itch, nausea, vomiting, urticaria, and upper abdominal discomfort.

The next step in the approval process is to obtain market authorization from the European Commission. Detailed recommendations for use will be described in the summary of product characteristics, which will be published in the European public assessment report and will be made available throughout Europe.

“We are encouraged by the CHMP opinion, which recommends Palforzia as the first and only treatment option in the European Union for patients with peanut allergy and their families,” Andrew Oxtoby, president and chief executive officer of Aimmune Therapeutics, said in a statement. “Today’s decision underscores the strong and compelling data from our Palforzia clinical trials and follows the US FDA approval of Palforzia earlier this year. We look forward to the European Commission’s final decision for the marketing approval of Palforzia, which we expect later this year.”

The FDA said in granting its approval that patients, parents, or caregivers must be counseled on the need for always-available injectable epinephrine, the need for continued peanut avoidance, and on how to recognize signs of anaphylaxis.
 

This article originally appeared on Medscape.com.

The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) recommended on October 15 that marketing authorization be granted for Palforzia (Aimmune Therapeutics). The product is intended for desensitizing children and adolescents to peanut allergy.

Palforzia will be available as an oral powder in capsules (0.5, 1, 10, 20, and 100 mg) and as oral powder in sachet (300 mg). The active substance is defatted powder of Arachis hypogaea.

Through use of the product, children with a peanut allergy receive controlled exposure to precise, increasing amounts of peanut protein, mixed with soft food, every day. Over time, this may help to decrease their sensitivity to small amounts of peanuts.

According to the press release from the EMA, Palforzia can mitigate accidental exposure to small amounts of peanut protein. “[A] single dose of a least 1 gram of peanut protein would cause no more than mild allergy symptoms,” the EMA said.

The treatment is indicated for patients aged 4 to 17 years who have received a confirmed diagnosis of peanut allergy. Treatment may be continued for patients aged 18 years or older, according to the press release.

It should be administered under the supervision of a healthcare provider qualified in the diagnosis and treatment of allergic diseases and should be used in conjunction with a peanut-avoidant diet, the EMA notes.

The most common side effects that have been reported are abdominal pain, throat irritation, itch, nausea, vomiting, urticaria, and upper abdominal discomfort.

The next step in the approval process is to obtain market authorization from the European Commission. Detailed recommendations for use will be described in the summary of product characteristics, which will be published in the European public assessment report and will be made available throughout Europe.

“We are encouraged by the CHMP opinion, which recommends Palforzia as the first and only treatment option in the European Union for patients with peanut allergy and their families,” Andrew Oxtoby, president and chief executive officer of Aimmune Therapeutics, said in a statement. “Today’s decision underscores the strong and compelling data from our Palforzia clinical trials and follows the US FDA approval of Palforzia earlier this year. We look forward to the European Commission’s final decision for the marketing approval of Palforzia, which we expect later this year.”

The FDA said in granting its approval that patients, parents, or caregivers must be counseled on the need for always-available injectable epinephrine, the need for continued peanut avoidance, and on how to recognize signs of anaphylaxis.
 

This article originally appeared on Medscape.com.

A 59-year-old man is admitted with abdominal pain. He has a history of pancreatitis. A contrast CT scan is ordered. He reports a history of severe shellfish allergy when the radiology tech checks him in for the procedure. You are paged regarding what to do:

A) Continue with scan as ordered.

B) Switch to MRI scan.

C) Switch to MRI scan with gadolinium.

D) Continue with CT with contrast, give dose of Solu-Medrol.

E) Continue with CT with contrast give IV diphenhydramine.
 

The correct answer here is A, This patient can receive his scan and receive contrast as ordered.

For many years, patients have been asked about shellfish allergy as a proxy for having increased risk when receiving iodine containing contrast. The mistaken thought was that shellfish contains iodine, so allergy to shellfish was likely to portend allergy to iodine.

Allergy to shellfish is caused by individual proteins that are definitely not in iodine-containing contrast.¹ Beaty et al. studied the prevalence of the belief that allergy to shellfish is tied to iodine allergy in a survey given to 231 faculty radiologists and interventional cardiologists.² Almost 70% responded that they inquire about seafood allergy before procedures that require iodine contrast, and 37% reported they would withhold the contrast or premedicate patients if they had a seafood allergy.

In a more recent study, Westermann-Clark and colleagues surveyed 252 health professionals before and after an educational intervention to dispel the myth of shellfish allergy and iodinated contrast reactions.³ Before the intervention, 66% of participants felt it was important to ask about shellfish allergies and 93% felt it was important to ask about iodine allergies; 26% responded that they would withhold iodinated contrast material in patients with a shellfish allergy, and 56% would withhold in patients with an iodine allergy. A total of 62% reported they would premedicate patients with a shellfish allergy and 75% would premedicate patients with an iodine allergy. The numbers declined dramatically after the educational intervention.

Patients who have seafood allergy have a higher rate of reactions to iodinated contrast, but not at a higher rate than do patients with other food allergies or asthma.⁴ Most radiology departments do not screen for other food allergies despite the fact these allergies have the same increased risk as for patients with a seafood/shellfish allergy. These patients are more allergic, and in general, are more likely to have reactions. The American Academy of Allergy, Asthma, and Immunology recommends not routinely ordering low- or iso-osmolar radiocontrast media or pretreating with either antihistamines or steroids in patients with a history of seafood allergy.⁵

• It is unnecessary and unhelpful to ask patients about seafood allergies before ordering radiologic studies involving contrast.
• Iodine allergy does not exist.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Narayan AK et al. Avoiding contrast-enhanced computed tomography scans in patients with shellfish allergies. J Hosp Med. 2016 Jun;11(6):435-7.

2. Beaty AD et al. Seafood allergy and radiocontrast media: Are physicians propagating a myth? Am J Med. 2008 Feb;121(2):158.e1-4.

3. Westermann-Clark E et al. Debunking myths about “allergy” to radiocontrast media in an academic institution. Postgrad Med. 2015 Apr;127(3):295-300.

4. Coakley FV and DM Panicek. Iodine allergy: An oyster without a pearl? AJR Am J Roentgenol. 1997 Oct;169(4):951-2.

5. American Academy of Allergy, Asthma & Immunology recommendations on low- or iso-osmolar radiocontrast media.

6. Schabelman E and M Witting. The relationship of radiocontrast, iodine, and seafood allergies: A medical myth exposed. J Emerg Med. 2010 Nov;39(5):701-7.

7. van Ketel WG and WH van den Berg. Sensitization to povidone-iodine. Dermatol Clin. 1990 Jan;8(1):107-9.

A 59-year-old man is admitted with abdominal pain. He has a history of pancreatitis. A contrast CT scan is ordered. He reports a history of severe shellfish allergy when the radiology tech checks him in for the procedure. You are paged regarding what to do:

A) Continue with scan as ordered.

B) Switch to MRI scan.

C) Switch to MRI scan with gadolinium.

D) Continue with CT with contrast, give dose of Solu-Medrol.

E) Continue with CT with contrast give IV diphenhydramine.
 

The correct answer here is A, This patient can receive his scan and receive contrast as ordered.

For many years, patients have been asked about shellfish allergy as a proxy for having increased risk when receiving iodine containing contrast. The mistaken thought was that shellfish contains iodine, so allergy to shellfish was likely to portend allergy to iodine.

Allergy to shellfish is caused by individual proteins that are definitely not in iodine-containing contrast.¹ Beaty et al. studied the prevalence of the belief that allergy to shellfish is tied to iodine allergy in a survey given to 231 faculty radiologists and interventional cardiologists.² Almost 70% responded that they inquire about seafood allergy before procedures that require iodine contrast, and 37% reported they would withhold the contrast or premedicate patients if they had a seafood allergy.

In a more recent study, Westermann-Clark and colleagues surveyed 252 health professionals before and after an educational intervention to dispel the myth of shellfish allergy and iodinated contrast reactions.³ Before the intervention, 66% of participants felt it was important to ask about shellfish allergies and 93% felt it was important to ask about iodine allergies; 26% responded that they would withhold iodinated contrast material in patients with a shellfish allergy, and 56% would withhold in patients with an iodine allergy. A total of 62% reported they would premedicate patients with a shellfish allergy and 75% would premedicate patients with an iodine allergy. The numbers declined dramatically after the educational intervention.

Patients who have seafood allergy have a higher rate of reactions to iodinated contrast, but not at a higher rate than do patients with other food allergies or asthma.⁴ Most radiology departments do not screen for other food allergies despite the fact these allergies have the same increased risk as for patients with a seafood/shellfish allergy. These patients are more allergic, and in general, are more likely to have reactions. The American Academy of Allergy, Asthma, and Immunology recommends not routinely ordering low- or iso-osmolar radiocontrast media or pretreating with either antihistamines or steroids in patients with a history of seafood allergy.⁵

• It is unnecessary and unhelpful to ask patients about seafood allergies before ordering radiologic studies involving contrast.
• Iodine allergy does not exist.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Narayan AK et al. Avoiding contrast-enhanced computed tomography scans in patients with shellfish allergies. J Hosp Med. 2016 Jun;11(6):435-7.

2. Beaty AD et al. Seafood allergy and radiocontrast media: Are physicians propagating a myth? Am J Med. 2008 Feb;121(2):158.e1-4.

3. Westermann-Clark E et al. Debunking myths about “allergy” to radiocontrast media in an academic institution. Postgrad Med. 2015 Apr;127(3):295-300.

4. Coakley FV and DM Panicek. Iodine allergy: An oyster without a pearl? AJR Am J Roentgenol. 1997 Oct;169(4):951-2.

5. American Academy of Allergy, Asthma & Immunology recommendations on low- or iso-osmolar radiocontrast media.

6. Schabelman E and M Witting. The relationship of radiocontrast, iodine, and seafood allergies: A medical myth exposed. J Emerg Med. 2010 Nov;39(5):701-7.

7. van Ketel WG and WH van den Berg. Sensitization to povidone-iodine. Dermatol Clin. 1990 Jan;8(1):107-9.

A 59-year-old man is admitted with abdominal pain. He has a history of pancreatitis. A contrast CT scan is ordered. He reports a history of severe shellfish allergy when the radiology tech checks him in for the procedure. You are paged regarding what to do:

A) Continue with scan as ordered.

B) Switch to MRI scan.

C) Switch to MRI scan with gadolinium.

D) Continue with CT with contrast, give dose of Solu-Medrol.

E) Continue with CT with contrast give IV diphenhydramine.
 

The correct answer here is A, This patient can receive his scan and receive contrast as ordered.

For many years, patients have been asked about shellfish allergy as a proxy for having increased risk when receiving iodine containing contrast. The mistaken thought was that shellfish contains iodine, so allergy to shellfish was likely to portend allergy to iodine.

Allergy to shellfish is caused by individual proteins that are definitely not in iodine-containing contrast.¹ Beaty et al. studied the prevalence of the belief that allergy to shellfish is tied to iodine allergy in a survey given to 231 faculty radiologists and interventional cardiologists.² Almost 70% responded that they inquire about seafood allergy before procedures that require iodine contrast, and 37% reported they would withhold the contrast or premedicate patients if they had a seafood allergy.

In a more recent study, Westermann-Clark and colleagues surveyed 252 health professionals before and after an educational intervention to dispel the myth of shellfish allergy and iodinated contrast reactions.³ Before the intervention, 66% of participants felt it was important to ask about shellfish allergies and 93% felt it was important to ask about iodine allergies; 26% responded that they would withhold iodinated contrast material in patients with a shellfish allergy, and 56% would withhold in patients with an iodine allergy. A total of 62% reported they would premedicate patients with a shellfish allergy and 75% would premedicate patients with an iodine allergy. The numbers declined dramatically after the educational intervention.

Patients who have seafood allergy have a higher rate of reactions to iodinated contrast, but not at a higher rate than do patients with other food allergies or asthma.⁴ Most radiology departments do not screen for other food allergies despite the fact these allergies have the same increased risk as for patients with a seafood/shellfish allergy. These patients are more allergic, and in general, are more likely to have reactions. The American Academy of Allergy, Asthma, and Immunology recommends not routinely ordering low- or iso-osmolar radiocontrast media or pretreating with either antihistamines or steroids in patients with a history of seafood allergy.⁵

• It is unnecessary and unhelpful to ask patients about seafood allergies before ordering radiologic studies involving contrast.
• Iodine allergy does not exist.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Narayan AK et al. Avoiding contrast-enhanced computed tomography scans in patients with shellfish allergies. J Hosp Med. 2016 Jun;11(6):435-7.

2. Beaty AD et al. Seafood allergy and radiocontrast media: Are physicians propagating a myth? Am J Med. 2008 Feb;121(2):158.e1-4.

3. Westermann-Clark E et al. Debunking myths about “allergy” to radiocontrast media in an academic institution. Postgrad Med. 2015 Apr;127(3):295-300.

4. Coakley FV and DM Panicek. Iodine allergy: An oyster without a pearl? AJR Am J Roentgenol. 1997 Oct;169(4):951-2.

5. American Academy of Allergy, Asthma & Immunology recommendations on low- or iso-osmolar radiocontrast media.

6. Schabelman E and M Witting. The relationship of radiocontrast, iodine, and seafood allergies: A medical myth exposed. J Emerg Med. 2010 Nov;39(5):701-7.

7. van Ketel WG and WH van den Berg. Sensitization to povidone-iodine. Dermatol Clin. 1990 Jan;8(1):107-9.

For children with milk-induced eosinophilic esophagitis (EoE), 9 months of epicutaneous immunotherapy (EPIT) with Viaskin Milk did not significantly improve eosinophil counts or symptoms, compared with placebo, according to the results of an intention-to-treat analysis of a randomized, double-blinded pilot study.

Average maximum eosinophil counts were 50.1 per high-power field in the Viaskin Milk group versus 48.2 in the placebo group, said Jonathan M. Spergel, MD, of the Children’s Hospital of Philadelphia and associates. However, in the per-protocol analysis, the seven patients who received Viaskin Milk had mean eosinophil counts of 25.6 per high-power field, compared with 95.0 for the two children who received placebo (P = .038). Moreover, 47% of patients had fewer than 15 eosinophils per high-power field after an additional 11 months of open-label treatment with Viaskin Milk. Taken together, the findings justify larger, multicenter studies to evaluate EPIT for treating EoE and other non-IgE mediated food diseases, Dr. Spergel and associates wrote in Clinical Gastroenterology and Hepatology.

EoE results from an immune response to specific food allergens, including milk. Classic symptoms include difficulty feeding and failure to thrive in infants, abdominal pain in young children, and dysphagia in older children and adults. Definitive diagnosis requires an esophageal biopsy with an eosinophil count of 15 or more cells per high-power field. “There are no approved therapies [for eosinophilic esophagitis] beyond avoidance of the allergen(s) or treatment of inflammation,” the investigators wrote.

In prior studies, exposure to EPIT was found to mitigate eosinophilic gastrointestinal disease in mice and pigs. In humans, milk is the most common dietary cause of eosinophilic esophagitis. Accordingly, Viaskin Milk is an EPIT containing an allergen extract of milk that is administered epicutaneously using a specialized delivery system. To evaluate its use for the treatment of pediatric milk-induced EoE (at least 15 eosinophils per high-power frame despite at least 2 months of high-dose proton pump–inhibitor therapy at 1-2 mg/kg twice daily), the researchers randomly assigned 20 children on a 3:1 basis to receive either Viaskin Milk or placebo for 9 months. Patients and investigators were double-blinded for this phase of the study, during most of which patients abstained from milk. Toward the end of the 9 months, patients resumed consuming milk and continued doing so if their upper endoscopy biopsy showed resolution of EoE (eosinophil count less than 15 per high-power field).

In the intention-to-treat analysis, Viaskin Milk did not meet the primary endpoint of the difference in least squares mean compared with placebo (8.6; 95% confidence interval, –35.36 to 52.56). Symptom scores also were similar between groups. In contrast, at the end of the 11-month, open-label period, 9 of 19 evaluable patients had eosinophil biopsy counts of fewer than 15 per high-power field, for a response rate of 47%. “The number of adverse events did not differ significantly between the Viaskin Milk and placebo groups,” the researchers added.

Protocol violations might explain why EPIT failed to meet the primary endpoint in the intention-to-treat analysis, they wrote. “For example, the patients on the active therapy wanted to ingest more milk, while the patients in the placebo group wanted less milk,” they reported. “Three patients in the active therapy went on binge milk diets drinking 4 to 8 times the amount of milk compared with baseline.” The use of proton pump inhibitors also was inconsistent between groups, they added. “The major limitation in the [per-protocol] population was the small sample size of this pilot study, raising the possibility of false-positive results.”

The study was funded by DBV Technologies and by the Children’s Hospital of Philadelphia Eosinophilic Esophagitis Family Fund. Dr. Spergel disclosed consulting agreements, grants funding, and stock equity with DBV Technologies. Three coinvestigators also disclosed ties to DBV. The remaining five coinvestigators reported having no conflicts of interest.

SOURCE: Spergel JM et al. Clin Gastroenterol Hepatol. 2019 May 14. doi: 10.1016/j.cgh.2019.05.014.

For children with milk-induced eosinophilic esophagitis (EoE), 9 months of epicutaneous immunotherapy (EPIT) with Viaskin Milk did not significantly improve eosinophil counts or symptoms, compared with placebo, according to the results of an intention-to-treat analysis of a randomized, double-blinded pilot study.

Average maximum eosinophil counts were 50.1 per high-power field in the Viaskin Milk group versus 48.2 in the placebo group, said Jonathan M. Spergel, MD, of the Children’s Hospital of Philadelphia and associates. However, in the per-protocol analysis, the seven patients who received Viaskin Milk had mean eosinophil counts of 25.6 per high-power field, compared with 95.0 for the two children who received placebo (P = .038). Moreover, 47% of patients had fewer than 15 eosinophils per high-power field after an additional 11 months of open-label treatment with Viaskin Milk. Taken together, the findings justify larger, multicenter studies to evaluate EPIT for treating EoE and other non-IgE mediated food diseases, Dr. Spergel and associates wrote in Clinical Gastroenterology and Hepatology.

EoE results from an immune response to specific food allergens, including milk. Classic symptoms include difficulty feeding and failure to thrive in infants, abdominal pain in young children, and dysphagia in older children and adults. Definitive diagnosis requires an esophageal biopsy with an eosinophil count of 15 or more cells per high-power field. “There are no approved therapies [for eosinophilic esophagitis] beyond avoidance of the allergen(s) or treatment of inflammation,” the investigators wrote.

In prior studies, exposure to EPIT was found to mitigate eosinophilic gastrointestinal disease in mice and pigs. In humans, milk is the most common dietary cause of eosinophilic esophagitis. Accordingly, Viaskin Milk is an EPIT containing an allergen extract of milk that is administered epicutaneously using a specialized delivery system. To evaluate its use for the treatment of pediatric milk-induced EoE (at least 15 eosinophils per high-power frame despite at least 2 months of high-dose proton pump–inhibitor therapy at 1-2 mg/kg twice daily), the researchers randomly assigned 20 children on a 3:1 basis to receive either Viaskin Milk or placebo for 9 months. Patients and investigators were double-blinded for this phase of the study, during most of which patients abstained from milk. Toward the end of the 9 months, patients resumed consuming milk and continued doing so if their upper endoscopy biopsy showed resolution of EoE (eosinophil count less than 15 per high-power field).

In the intention-to-treat analysis, Viaskin Milk did not meet the primary endpoint of the difference in least squares mean compared with placebo (8.6; 95% confidence interval, –35.36 to 52.56). Symptom scores also were similar between groups. In contrast, at the end of the 11-month, open-label period, 9 of 19 evaluable patients had eosinophil biopsy counts of fewer than 15 per high-power field, for a response rate of 47%. “The number of adverse events did not differ significantly between the Viaskin Milk and placebo groups,” the researchers added.

Protocol violations might explain why EPIT failed to meet the primary endpoint in the intention-to-treat analysis, they wrote. “For example, the patients on the active therapy wanted to ingest more milk, while the patients in the placebo group wanted less milk,” they reported. “Three patients in the active therapy went on binge milk diets drinking 4 to 8 times the amount of milk compared with baseline.” The use of proton pump inhibitors also was inconsistent between groups, they added. “The major limitation in the [per-protocol] population was the small sample size of this pilot study, raising the possibility of false-positive results.”

The study was funded by DBV Technologies and by the Children’s Hospital of Philadelphia Eosinophilic Esophagitis Family Fund. Dr. Spergel disclosed consulting agreements, grants funding, and stock equity with DBV Technologies. Three coinvestigators also disclosed ties to DBV. The remaining five coinvestigators reported having no conflicts of interest.

SOURCE: Spergel JM et al. Clin Gastroenterol Hepatol. 2019 May 14. doi: 10.1016/j.cgh.2019.05.014.

For children with milk-induced eosinophilic esophagitis (EoE), 9 months of epicutaneous immunotherapy (EPIT) with Viaskin Milk did not significantly improve eosinophil counts or symptoms, compared with placebo, according to the results of an intention-to-treat analysis of a randomized, double-blinded pilot study.

Average maximum eosinophil counts were 50.1 per high-power field in the Viaskin Milk group versus 48.2 in the placebo group, said Jonathan M. Spergel, MD, of the Children’s Hospital of Philadelphia and associates. However, in the per-protocol analysis, the seven patients who received Viaskin Milk had mean eosinophil counts of 25.6 per high-power field, compared with 95.0 for the two children who received placebo (P = .038). Moreover, 47% of patients had fewer than 15 eosinophils per high-power field after an additional 11 months of open-label treatment with Viaskin Milk. Taken together, the findings justify larger, multicenter studies to evaluate EPIT for treating EoE and other non-IgE mediated food diseases, Dr. Spergel and associates wrote in Clinical Gastroenterology and Hepatology.

EoE results from an immune response to specific food allergens, including milk. Classic symptoms include difficulty feeding and failure to thrive in infants, abdominal pain in young children, and dysphagia in older children and adults. Definitive diagnosis requires an esophageal biopsy with an eosinophil count of 15 or more cells per high-power field. “There are no approved therapies [for eosinophilic esophagitis] beyond avoidance of the allergen(s) or treatment of inflammation,” the investigators wrote.

In prior studies, exposure to EPIT was found to mitigate eosinophilic gastrointestinal disease in mice and pigs. In humans, milk is the most common dietary cause of eosinophilic esophagitis. Accordingly, Viaskin Milk is an EPIT containing an allergen extract of milk that is administered epicutaneously using a specialized delivery system. To evaluate its use for the treatment of pediatric milk-induced EoE (at least 15 eosinophils per high-power frame despite at least 2 months of high-dose proton pump–inhibitor therapy at 1-2 mg/kg twice daily), the researchers randomly assigned 20 children on a 3:1 basis to receive either Viaskin Milk or placebo for 9 months. Patients and investigators were double-blinded for this phase of the study, during most of which patients abstained from milk. Toward the end of the 9 months, patients resumed consuming milk and continued doing so if their upper endoscopy biopsy showed resolution of EoE (eosinophil count less than 15 per high-power field).

In the intention-to-treat analysis, Viaskin Milk did not meet the primary endpoint of the difference in least squares mean compared with placebo (8.6; 95% confidence interval, –35.36 to 52.56). Symptom scores also were similar between groups. In contrast, at the end of the 11-month, open-label period, 9 of 19 evaluable patients had eosinophil biopsy counts of fewer than 15 per high-power field, for a response rate of 47%. “The number of adverse events did not differ significantly between the Viaskin Milk and placebo groups,” the researchers added.

Protocol violations might explain why EPIT failed to meet the primary endpoint in the intention-to-treat analysis, they wrote. “For example, the patients on the active therapy wanted to ingest more milk, while the patients in the placebo group wanted less milk,” they reported. “Three patients in the active therapy went on binge milk diets drinking 4 to 8 times the amount of milk compared with baseline.” The use of proton pump inhibitors also was inconsistent between groups, they added. “The major limitation in the [per-protocol] population was the small sample size of this pilot study, raising the possibility of false-positive results.”

The study was funded by DBV Technologies and by the Children’s Hospital of Philadelphia Eosinophilic Esophagitis Family Fund. Dr. Spergel disclosed consulting agreements, grants funding, and stock equity with DBV Technologies. Three coinvestigators also disclosed ties to DBV. The remaining five coinvestigators reported having no conflicts of interest.

SOURCE: Spergel JM et al. Clin Gastroenterol Hepatol. 2019 May 14. doi: 10.1016/j.cgh.2019.05.014.

ATLANTA – Adenosine deaminase 2 above the upper limit of normal is 86% sensitive and 94% specific for distinguishing macrophage activation syndrome from active systemic juvenile idiopathic arthritis, making it perhaps the most potent blood marker yet identified to differentiate the two, according to a report presented at the annual meeting of the American College of Rheumatology.

The upper limit of normal was 27.8 U/L, two standard deviations above the median of 13 U/L (interquartile range, 10.6-16.1) in 174 healthy children. The work was published simultaneously in Annals of the Rheumatic Diseases.

In children with active systemic juvenile idiopathic arthritis (JIA), adenosine deaminase 2 (ADA2) “beyond the upper limit of normal is strong evidence for concomitant” macrophage activation syndrome (MAS). “Our work represents a new method to diagnose this condition,” said lead investigator Pui Y. Lee, MD, PhD, a pediatric rheumatologist at Boston Children’s Hospital.

The hope, he said, is that the finding will lead to quicker recognition and treatment of MAS, a devastating complication of systemic JIA in which rampant inflammation begets further inflammation in a downward spiral that ultimately proves fatal in about 20% of cases. The problem is that the clinical features of MAS overlap with those of active systemic JIA, which makes early diagnosis difficult.

Ferritin and other common markers are not very specific unless “the cutoff is raised significantly to distinguish MAS from general inflammation. Most labs will not tell you ‘this is an active systemic JIA range; this is an MAS-like range.’ It’s hard for them to define that for you. ADA2 is more black and white; if you go above the upper limit, you most likely have MAS,” Dr. Lee explained at the meeting.

Potentially, “we can combine this test with other tests to define a single MAS panel,” he said.

ADA2 is measured by a simple, inexpensive enzyme assay that’s been around for 20 years, but it hasn’t caught on because the protein’s function is unknown and the clinical relevance of ADA2 levels has been uncertain. With the new findings, “it is our hope that ADA2 testing will become more available,” Dr. Lee said.

The protein appears to be a product of monocytes and macrophages, and a genetic deficiency has recently been linked to congenital vasculitis, which made Dr. Lee and colleagues curious about ADA2 in other rheumatic diseases. The first step was to define normal limits in healthy controls; the 13 U/L median in children proved to be a bit higher than in 150 healthy adults.

The team then found that levels were completely normal in 25 children with active Kawasaki disease, and only mildly elevated in 13 children with systemic lupus and 13 with juvenile dermatomyositis. The Kawasaki children, in particular “were highly inflamed, so this protein is not just simply a marker of inflammation,” Dr. Lee said.

They next turned to 120 children with JIA, with a mix of systemic and nonsystemic cases. “The ones with very high levels, far beyond the upper limit of normal, were” almost exclusively the 23 children with systemic JIA and clinically diagnosed MAS. “As long as [JIA children] didn’t have MAS, their levels were pretty much close to normal,” he said.

In eight MAS children with repeat testing, levels fell below the upper limit of normal with treatment and remission, but children prone to repeat MAS seemed to hover closer to the limit even when they were well.

Blood sample testing showed that interleukin-18 and interferon-gamma were the main drivers of ADA2 expression in the periphery, “which makes sense because these two cytokines are very involved in the process of MAS,” Dr. Lee said.

The work was funded by the National Institutes of Health, among others. Dr. Lee didn’t have any disclosures.

[email protected]

SOURCE: Lee PY et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 920.

ATLANTA – Adenosine deaminase 2 above the upper limit of normal is 86% sensitive and 94% specific for distinguishing macrophage activation syndrome from active systemic juvenile idiopathic arthritis, making it perhaps the most potent blood marker yet identified to differentiate the two, according to a report presented at the annual meeting of the American College of Rheumatology.

The upper limit of normal was 27.8 U/L, two standard deviations above the median of 13 U/L (interquartile range, 10.6-16.1) in 174 healthy children. The work was published simultaneously in Annals of the Rheumatic Diseases.

In children with active systemic juvenile idiopathic arthritis (JIA), adenosine deaminase 2 (ADA2) “beyond the upper limit of normal is strong evidence for concomitant” macrophage activation syndrome (MAS). “Our work represents a new method to diagnose this condition,” said lead investigator Pui Y. Lee, MD, PhD, a pediatric rheumatologist at Boston Children’s Hospital.

The hope, he said, is that the finding will lead to quicker recognition and treatment of MAS, a devastating complication of systemic JIA in which rampant inflammation begets further inflammation in a downward spiral that ultimately proves fatal in about 20% of cases. The problem is that the clinical features of MAS overlap with those of active systemic JIA, which makes early diagnosis difficult.

Ferritin and other common markers are not very specific unless “the cutoff is raised significantly to distinguish MAS from general inflammation. Most labs will not tell you ‘this is an active systemic JIA range; this is an MAS-like range.’ It’s hard for them to define that for you. ADA2 is more black and white; if you go above the upper limit, you most likely have MAS,” Dr. Lee explained at the meeting.

Potentially, “we can combine this test with other tests to define a single MAS panel,” he said.

ADA2 is measured by a simple, inexpensive enzyme assay that’s been around for 20 years, but it hasn’t caught on because the protein’s function is unknown and the clinical relevance of ADA2 levels has been uncertain. With the new findings, “it is our hope that ADA2 testing will become more available,” Dr. Lee said.

The protein appears to be a product of monocytes and macrophages, and a genetic deficiency has recently been linked to congenital vasculitis, which made Dr. Lee and colleagues curious about ADA2 in other rheumatic diseases. The first step was to define normal limits in healthy controls; the 13 U/L median in children proved to be a bit higher than in 150 healthy adults.

The team then found that levels were completely normal in 25 children with active Kawasaki disease, and only mildly elevated in 13 children with systemic lupus and 13 with juvenile dermatomyositis. The Kawasaki children, in particular “were highly inflamed, so this protein is not just simply a marker of inflammation,” Dr. Lee said.

They next turned to 120 children with JIA, with a mix of systemic and nonsystemic cases. “The ones with very high levels, far beyond the upper limit of normal, were” almost exclusively the 23 children with systemic JIA and clinically diagnosed MAS. “As long as [JIA children] didn’t have MAS, their levels were pretty much close to normal,” he said.

In eight MAS children with repeat testing, levels fell below the upper limit of normal with treatment and remission, but children prone to repeat MAS seemed to hover closer to the limit even when they were well.

Blood sample testing showed that interleukin-18 and interferon-gamma were the main drivers of ADA2 expression in the periphery, “which makes sense because these two cytokines are very involved in the process of MAS,” Dr. Lee said.

The work was funded by the National Institutes of Health, among others. Dr. Lee didn’t have any disclosures.

[email protected]

SOURCE: Lee PY et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 920.

ATLANTA – Adenosine deaminase 2 above the upper limit of normal is 86% sensitive and 94% specific for distinguishing macrophage activation syndrome from active systemic juvenile idiopathic arthritis, making it perhaps the most potent blood marker yet identified to differentiate the two, according to a report presented at the annual meeting of the American College of Rheumatology.

The upper limit of normal was 27.8 U/L, two standard deviations above the median of 13 U/L (interquartile range, 10.6-16.1) in 174 healthy children. The work was published simultaneously in Annals of the Rheumatic Diseases.

In children with active systemic juvenile idiopathic arthritis (JIA), adenosine deaminase 2 (ADA2) “beyond the upper limit of normal is strong evidence for concomitant” macrophage activation syndrome (MAS). “Our work represents a new method to diagnose this condition,” said lead investigator Pui Y. Lee, MD, PhD, a pediatric rheumatologist at Boston Children’s Hospital.

The hope, he said, is that the finding will lead to quicker recognition and treatment of MAS, a devastating complication of systemic JIA in which rampant inflammation begets further inflammation in a downward spiral that ultimately proves fatal in about 20% of cases. The problem is that the clinical features of MAS overlap with those of active systemic JIA, which makes early diagnosis difficult.

Ferritin and other common markers are not very specific unless “the cutoff is raised significantly to distinguish MAS from general inflammation. Most labs will not tell you ‘this is an active systemic JIA range; this is an MAS-like range.’ It’s hard for them to define that for you. ADA2 is more black and white; if you go above the upper limit, you most likely have MAS,” Dr. Lee explained at the meeting.

Potentially, “we can combine this test with other tests to define a single MAS panel,” he said.

ADA2 is measured by a simple, inexpensive enzyme assay that’s been around for 20 years, but it hasn’t caught on because the protein’s function is unknown and the clinical relevance of ADA2 levels has been uncertain. With the new findings, “it is our hope that ADA2 testing will become more available,” Dr. Lee said.

The protein appears to be a product of monocytes and macrophages, and a genetic deficiency has recently been linked to congenital vasculitis, which made Dr. Lee and colleagues curious about ADA2 in other rheumatic diseases. The first step was to define normal limits in healthy controls; the 13 U/L median in children proved to be a bit higher than in 150 healthy adults.

The team then found that levels were completely normal in 25 children with active Kawasaki disease, and only mildly elevated in 13 children with systemic lupus and 13 with juvenile dermatomyositis. The Kawasaki children, in particular “were highly inflamed, so this protein is not just simply a marker of inflammation,” Dr. Lee said.

They next turned to 120 children with JIA, with a mix of systemic and nonsystemic cases. “The ones with very high levels, far beyond the upper limit of normal, were” almost exclusively the 23 children with systemic JIA and clinically diagnosed MAS. “As long as [JIA children] didn’t have MAS, their levels were pretty much close to normal,” he said.

In eight MAS children with repeat testing, levels fell below the upper limit of normal with treatment and remission, but children prone to repeat MAS seemed to hover closer to the limit even when they were well.

Blood sample testing showed that interleukin-18 and interferon-gamma were the main drivers of ADA2 expression in the periphery, “which makes sense because these two cytokines are very involved in the process of MAS,” Dr. Lee said.

The work was funded by the National Institutes of Health, among others. Dr. Lee didn’t have any disclosures.

[email protected]

SOURCE: Lee PY et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 920.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Is the relationship between A-fib and sleep apnea more than a coincidence stemming from the number of shared associated comorbidities? Significantly, the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) has been shown to decrease the recurrence of A-fib after pharmacologic or electrical conversion and after interventional pulmonary vein interruption.¹ This suggests that at least in some cases, sleep apnea plays an active role in initiating and possibly also maintaining A-fib. The immediate culprit mediators that come to mind are hypoxia and hypercapnea; both are at least partially ameliorated by the successful use of CPAP, and both are reasonable physiologic candidates for induction of A-fib. Hypoxia is supported by clinical observation, and hypercapnea by experimental modeling.²

It is easy for clinicians to conceptualize the organ effects of hypoxia and hypercapnea. We are accustomed to seeing clinical ramifications of these in the emergency department and intensive care unit, particularly those affecting the brain and heart, organs critically dependent on transmembrane ion flow. We may recall from biochemistry classes the effects of hypoxia on intracellular metabolism and the implications on energy stores, mitochondrial function, and ion translocation. Recent work on the cellular effects of hypoxia, including research that resulted in a Nobel prize, has drawn major attention to patterned cellular responses to intermittent and persistent hypoxia. This includes recognition of epigenetic changes resulting in localized cardiac remodeling and fibrosis,³ factors that clearly affect the expression of arrhythmias, including A-fib.

But the interrelationship between A-fib and sleep apnea may be even more convoluted and intriguing. It now seems that most things cardiac are associated with inflammation in some guise, and the A-fib connection with sleep apnea may not be an exception. Almost 20 years ago, it was recognized that A-fib is associated with an elevation in circulating C-reactive protein (CRP),⁴ a biomarker of “inflammation,” although not necessarily an active participant. Recent reviews of this connection have been published,⁵ and successful anti-inflammatory approaches to preventing A-fib using colchicine have been described.⁶ So how does this tie in with sleep apnea?

A number of papers have now demonstrated that sleep apnea is also associated with an elevation in CRP,⁷ perhaps due to increases in tumor necrosis factor (TNF)-alpha in response to the intermittent hypoxia of sleep apnea. TNF can drive the inflammatory response through increased expression of genes regulated by nuclear factor kappa-B.⁸ While it certainly warrants consideration that the elevated biomarkers of inflammation in patients with sleep apnea actually reflect the presence of the frequent comorbidities, including visceral obesity, treating sleep apnea with CPAP (comparable to what I noted above in patients with A-fib) has been shown to reduce circulating CRP levels.⁹

As our understanding of the biologic underpinnings of A-fib and sleep apnea continue to grow, the practical clinical implications of the relationship between them, as described by Ayache et al, may achieve greater clarity. The two conditions commonly coexist, and treating the sleep apnea results in better rhythm-directed outcomes in the A-fib.

Stay tuned, there is certainly more to learn about this.

Is the relationship between A-fib and sleep apnea more than a coincidence stemming from the number of shared associated comorbidities? Significantly, the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) has been shown to decrease the recurrence of A-fib after pharmacologic or electrical conversion and after interventional pulmonary vein interruption.¹ This suggests that at least in some cases, sleep apnea plays an active role in initiating and possibly also maintaining A-fib. The immediate culprit mediators that come to mind are hypoxia and hypercapnea; both are at least partially ameliorated by the successful use of CPAP, and both are reasonable physiologic candidates for induction of A-fib. Hypoxia is supported by clinical observation, and hypercapnea by experimental modeling.²

It is easy for clinicians to conceptualize the organ effects of hypoxia and hypercapnea. We are accustomed to seeing clinical ramifications of these in the emergency department and intensive care unit, particularly those affecting the brain and heart, organs critically dependent on transmembrane ion flow. We may recall from biochemistry classes the effects of hypoxia on intracellular metabolism and the implications on energy stores, mitochondrial function, and ion translocation. Recent work on the cellular effects of hypoxia, including research that resulted in a Nobel prize, has drawn major attention to patterned cellular responses to intermittent and persistent hypoxia. This includes recognition of epigenetic changes resulting in localized cardiac remodeling and fibrosis,³ factors that clearly affect the expression of arrhythmias, including A-fib.

But the interrelationship between A-fib and sleep apnea may be even more convoluted and intriguing. It now seems that most things cardiac are associated with inflammation in some guise, and the A-fib connection with sleep apnea may not be an exception. Almost 20 years ago, it was recognized that A-fib is associated with an elevation in circulating C-reactive protein (CRP),⁴ a biomarker of “inflammation,” although not necessarily an active participant. Recent reviews of this connection have been published,⁵ and successful anti-inflammatory approaches to preventing A-fib using colchicine have been described.⁶ So how does this tie in with sleep apnea?

A number of papers have now demonstrated that sleep apnea is also associated with an elevation in CRP,⁷ perhaps due to increases in tumor necrosis factor (TNF)-alpha in response to the intermittent hypoxia of sleep apnea. TNF can drive the inflammatory response through increased expression of genes regulated by nuclear factor kappa-B.⁸ While it certainly warrants consideration that the elevated biomarkers of inflammation in patients with sleep apnea actually reflect the presence of the frequent comorbidities, including visceral obesity, treating sleep apnea with CPAP (comparable to what I noted above in patients with A-fib) has been shown to reduce circulating CRP levels.⁹

As our understanding of the biologic underpinnings of A-fib and sleep apnea continue to grow, the practical clinical implications of the relationship between them, as described by Ayache et al, may achieve greater clarity. The two conditions commonly coexist, and treating the sleep apnea results in better rhythm-directed outcomes in the A-fib.

Stay tuned, there is certainly more to learn about this.

Is the relationship between A-fib and sleep apnea more than a coincidence stemming from the number of shared associated comorbidities? Significantly, the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) has been shown to decrease the recurrence of A-fib after pharmacologic or electrical conversion and after interventional pulmonary vein interruption.¹ This suggests that at least in some cases, sleep apnea plays an active role in initiating and possibly also maintaining A-fib. The immediate culprit mediators that come to mind are hypoxia and hypercapnea; both are at least partially ameliorated by the successful use of CPAP, and both are reasonable physiologic candidates for induction of A-fib. Hypoxia is supported by clinical observation, and hypercapnea by experimental modeling.²

It is easy for clinicians to conceptualize the organ effects of hypoxia and hypercapnea. We are accustomed to seeing clinical ramifications of these in the emergency department and intensive care unit, particularly those affecting the brain and heart, organs critically dependent on transmembrane ion flow. We may recall from biochemistry classes the effects of hypoxia on intracellular metabolism and the implications on energy stores, mitochondrial function, and ion translocation. Recent work on the cellular effects of hypoxia, including research that resulted in a Nobel prize, has drawn major attention to patterned cellular responses to intermittent and persistent hypoxia. This includes recognition of epigenetic changes resulting in localized cardiac remodeling and fibrosis,³ factors that clearly affect the expression of arrhythmias, including A-fib.

But the interrelationship between A-fib and sleep apnea may be even more convoluted and intriguing. It now seems that most things cardiac are associated with inflammation in some guise, and the A-fib connection with sleep apnea may not be an exception. Almost 20 years ago, it was recognized that A-fib is associated with an elevation in circulating C-reactive protein (CRP),⁴ a biomarker of “inflammation,” although not necessarily an active participant. Recent reviews of this connection have been published,⁵ and successful anti-inflammatory approaches to preventing A-fib using colchicine have been described.⁶ So how does this tie in with sleep apnea?

A number of papers have now demonstrated that sleep apnea is also associated with an elevation in CRP,⁷ perhaps due to increases in tumor necrosis factor (TNF)-alpha in response to the intermittent hypoxia of sleep apnea. TNF can drive the inflammatory response through increased expression of genes regulated by nuclear factor kappa-B.⁸ While it certainly warrants consideration that the elevated biomarkers of inflammation in patients with sleep apnea actually reflect the presence of the frequent comorbidities, including visceral obesity, treating sleep apnea with CPAP (comparable to what I noted above in patients with A-fib) has been shown to reduce circulating CRP levels.⁹

As our understanding of the biologic underpinnings of A-fib and sleep apnea continue to grow, the practical clinical implications of the relationship between them, as described by Ayache et al, may achieve greater clarity. The two conditions commonly coexist, and treating the sleep apnea results in better rhythm-directed outcomes in the A-fib.

Stay tuned, there is certainly more to learn about this.

MADRID – Low-dose azithromycin prophylaxis significantly reduced exacerbations and hospitalizations in patients with primary antibody deficiency relative to placebo, according to a randomized multicenter phase 2 trial.

The study results support routine use of low-dose azithromycin in patients with primary antibody deficiency, according to Cinzia Milito, MD, PhD, department of molecular medicine, Sapienza University, Rome. Perhaps more importantly, the long-term benefits might be even greater.

“In patients with primary antibody deficiency, the respiratory tract is the major target of acute infections, leading to inflammation, increased airway reactivity, and over time to tissue remodeling and chronic lung disease,” Dr. Milito said at the annual congress of the European Respiratory Society. “Chronic lung disease is a major cause of death in this population.”

In this study 89 patients with primary antibody deficiency were randomized at seven centers in Italy to 250 mg per day of azithromycin or placebo administered on three consecutive days of each week for three years. Patients were maintained on other treatments, such as IgG replacement.

At the end of study, 33 of the 44 patients randomized to azithromycin and 34 of the 45 patients randomized to placebo remained on therapy. When compared for the primary endpoint of exacerbations, the median incidence rates were 3.6 episodes in the azithromycin group and 5.2 episodes in the placebo group, providing a 1.6 episode or 31% relative reduction (P=0.02).

The median number of hospitalizations for any cause, which was a secondary endpoint, was also significantly lower in the azithromycin arm (0.1 vs. 0.3 episodes).

In addition, the number of additional courses of antibiotics was significantly lower (2.3 vs. 3.6), and the time to the first course of antibiotic course was significantly longer (181.5 vs. 122.4 days) in the azithromycin group, reported Dr. Milito, whose study is now published (Milito C et al. J Allergy Clin Immunol 2019;144: 584-593).

“In a six-month washout at the end of the study, the relative advantages seen for azithromycin were lost,” Dr. Milito said.

Quality of life measured with the St. George’s Respiratory Questionnaire showed an association between low-dose azithromycin prophylaxis and significant improvement in the symptom domain when evaluated during and at the end of the study. Improvement on the Short-Form 36, which was observed one year into the study, was no longer significant at the end of the study.

Azithromycin was well tolerated with no significant differences in the rate of serious adverse events observed between the experimental and control arms of the study. Over the course of the study, however, azithromycin was associated with a significant protective effect against diarrhea (13% vs. 53%) and acute rhinosinusitus (4% vs. 27%).

There was no observed increase in macrolide resistance associated with azithromycin prophylaxis.

Macrolides have been evaluated for preventing progression of several chronic lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and cystic fibrosis. Like other drugs in its class, “azithromycin, in addition to its antimicrobial effect, has anti-inflammatory properties,” Dr. Milito said. This increases its potential to slow the time to airway damage in patients with primary antibiotic deficiency.

“Chronic lung disease is the result of a vicious cycle that begins with the inflammatory response to infection,” Dr. Milito explained. On the basis of these data, she believes azithromycin “should be considered a valuable addition to usual treatment” for primary antibody deficiencies.
 

SOURCE: EUROPEAN RESPIRATORY SOCIETY 2019 INTERNATIONAL CONGRESS

MADRID – Low-dose azithromycin prophylaxis significantly reduced exacerbations and hospitalizations in patients with primary antibody deficiency relative to placebo, according to a randomized multicenter phase 2 trial.

The study results support routine use of low-dose azithromycin in patients with primary antibody deficiency, according to Cinzia Milito, MD, PhD, department of molecular medicine, Sapienza University, Rome. Perhaps more importantly, the long-term benefits might be even greater.

“In patients with primary antibody deficiency, the respiratory tract is the major target of acute infections, leading to inflammation, increased airway reactivity, and over time to tissue remodeling and chronic lung disease,” Dr. Milito said at the annual congress of the European Respiratory Society. “Chronic lung disease is a major cause of death in this population.”

In this study 89 patients with primary antibody deficiency were randomized at seven centers in Italy to 250 mg per day of azithromycin or placebo administered on three consecutive days of each week for three years. Patients were maintained on other treatments, such as IgG replacement.

At the end of study, 33 of the 44 patients randomized to azithromycin and 34 of the 45 patients randomized to placebo remained on therapy. When compared for the primary endpoint of exacerbations, the median incidence rates were 3.6 episodes in the azithromycin group and 5.2 episodes in the placebo group, providing a 1.6 episode or 31% relative reduction (P=0.02).

The median number of hospitalizations for any cause, which was a secondary endpoint, was also significantly lower in the azithromycin arm (0.1 vs. 0.3 episodes).

In addition, the number of additional courses of antibiotics was significantly lower (2.3 vs. 3.6), and the time to the first course of antibiotic course was significantly longer (181.5 vs. 122.4 days) in the azithromycin group, reported Dr. Milito, whose study is now published (Milito C et al. J Allergy Clin Immunol 2019;144: 584-593).

“In a six-month washout at the end of the study, the relative advantages seen for azithromycin were lost,” Dr. Milito said.

Quality of life measured with the St. George’s Respiratory Questionnaire showed an association between low-dose azithromycin prophylaxis and significant improvement in the symptom domain when evaluated during and at the end of the study. Improvement on the Short-Form 36, which was observed one year into the study, was no longer significant at the end of the study.

Azithromycin was well tolerated with no significant differences in the rate of serious adverse events observed between the experimental and control arms of the study. Over the course of the study, however, azithromycin was associated with a significant protective effect against diarrhea (13% vs. 53%) and acute rhinosinusitus (4% vs. 27%).

There was no observed increase in macrolide resistance associated with azithromycin prophylaxis.

Macrolides have been evaluated for preventing progression of several chronic lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and cystic fibrosis. Like other drugs in its class, “azithromycin, in addition to its antimicrobial effect, has anti-inflammatory properties,” Dr. Milito said. This increases its potential to slow the time to airway damage in patients with primary antibiotic deficiency.

“Chronic lung disease is the result of a vicious cycle that begins with the inflammatory response to infection,” Dr. Milito explained. On the basis of these data, she believes azithromycin “should be considered a valuable addition to usual treatment” for primary antibody deficiencies.
 

SOURCE: EUROPEAN RESPIRATORY SOCIETY 2019 INTERNATIONAL CONGRESS

MADRID – Low-dose azithromycin prophylaxis significantly reduced exacerbations and hospitalizations in patients with primary antibody deficiency relative to placebo, according to a randomized multicenter phase 2 trial.

The study results support routine use of low-dose azithromycin in patients with primary antibody deficiency, according to Cinzia Milito, MD, PhD, department of molecular medicine, Sapienza University, Rome. Perhaps more importantly, the long-term benefits might be even greater.

“In patients with primary antibody deficiency, the respiratory tract is the major target of acute infections, leading to inflammation, increased airway reactivity, and over time to tissue remodeling and chronic lung disease,” Dr. Milito said at the annual congress of the European Respiratory Society. “Chronic lung disease is a major cause of death in this population.”

In this study 89 patients with primary antibody deficiency were randomized at seven centers in Italy to 250 mg per day of azithromycin or placebo administered on three consecutive days of each week for three years. Patients were maintained on other treatments, such as IgG replacement.

At the end of study, 33 of the 44 patients randomized to azithromycin and 34 of the 45 patients randomized to placebo remained on therapy. When compared for the primary endpoint of exacerbations, the median incidence rates were 3.6 episodes in the azithromycin group and 5.2 episodes in the placebo group, providing a 1.6 episode or 31% relative reduction (P=0.02).

The median number of hospitalizations for any cause, which was a secondary endpoint, was also significantly lower in the azithromycin arm (0.1 vs. 0.3 episodes).

In addition, the number of additional courses of antibiotics was significantly lower (2.3 vs. 3.6), and the time to the first course of antibiotic course was significantly longer (181.5 vs. 122.4 days) in the azithromycin group, reported Dr. Milito, whose study is now published (Milito C et al. J Allergy Clin Immunol 2019;144: 584-593).

“In a six-month washout at the end of the study, the relative advantages seen for azithromycin were lost,” Dr. Milito said.

Quality of life measured with the St. George’s Respiratory Questionnaire showed an association between low-dose azithromycin prophylaxis and significant improvement in the symptom domain when evaluated during and at the end of the study. Improvement on the Short-Form 36, which was observed one year into the study, was no longer significant at the end of the study.

Azithromycin was well tolerated with no significant differences in the rate of serious adverse events observed between the experimental and control arms of the study. Over the course of the study, however, azithromycin was associated with a significant protective effect against diarrhea (13% vs. 53%) and acute rhinosinusitus (4% vs. 27%).

There was no observed increase in macrolide resistance associated with azithromycin prophylaxis.

Macrolides have been evaluated for preventing progression of several chronic lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and cystic fibrosis. Like other drugs in its class, “azithromycin, in addition to its antimicrobial effect, has anti-inflammatory properties,” Dr. Milito said. This increases its potential to slow the time to airway damage in patients with primary antibiotic deficiency.

“Chronic lung disease is the result of a vicious cycle that begins with the inflammatory response to infection,” Dr. Milito explained. On the basis of these data, she believes azithromycin “should be considered a valuable addition to usual treatment” for primary antibody deficiencies.
 

SOURCE: EUROPEAN RESPIRATORY SOCIETY 2019 INTERNATIONAL CONGRESS

Recurrent invasive pneumococcal disease in children could be a signal of underlying primary immunodeficiency, according to a systematic review published in JAMA Pediatrics.

Coen Butters, BMed, DCH, of the Royal Children’s Hospital in Melbourne, and coauthors wrote that, even with optimal vaccine coverage, there is still a group of children with increased susceptibility to invasive pneumococcal disease (IPD), and this could be a potential marker of primary immunodeficiency.

They conducted a systematic review of 17 studies of 6,002 children to examine the evidence on the incidence of primary immunodeficiency in children who presented with IPD but without any other risk factors or predisposing conditions.

Overall, the frequency of primary immunodeficiency in children presenting with IPD who did not have any other predisposing condition ranged from 1% to 26%.

One study of 162 children with IPD, which had an overall frequency of primary immunodeficiency of 10%, found that children older than 2 years were significantly more likely to have primary immunodeficiency than those aged under 2 years (26% vs. 3%; P less than .001).

Primary antibody deficiency was the most commonly diagnosed immunodeficiency in these children with IPD, accounting for 71% of cases. These deficiencies presented as hypogammaglobulinemia, specific pneumococcal antibody deficiency, X-linked agammaglobulinemia, and IgG2 deficiency.

The review also included four studies that looked at the frequency of mannose-binding lectin deficiency in 1,493 children with primary IPD. Two of these studies reported a prevalence of mannose-binding lectin deficiency ranging from 31% in children aged younger than 2 years to 41% in children younger than 1 year.

Five studies looked at the rate of primary immunodeficiency in children presenting with recurrent IPD. In addition to other predisposing conditions such as sickle cell disease, cancer, and anatomical breach in the blood-brain barrier, the three studies that screened for primary immunodeficiency found rates ranging from 10% to 67%. The most common conditions were complement deficiency, pneumococcal antibody deficiency, and a single case of TLR-signaling defect.

In a study of 162 children with primary IPD, screening for asplenia identified a single case of congenital asplenia. In another study of 2,498 cases of IPD, 22 patients had asplenia at presentation, half of whom died at presentation.

Dr. Butters and associates concluded that “this review’s findings suggests that existing data support the immune evaluation of children older than 2 years without a known predisposing condition who present with their first episode of Streptococcus pneumoniae meningitis, pneumonia, or recurrent IPD. Immune evaluation should include assessment for immunoglobulin deficiency, pneumococcal antibody deficiency, complement disorders, and asplenia.”

In an accompanying editorial, Stephen I. Pelton, MD, of the Maxwell Finland Laboratory for Infectious Diseases at Boston Medical Center, and coauthors wrote that in children with recurrent episodes of IPD caused by nonvaccine serotypes – particularly those aged over 5 years – evaluation for primary immunodeficiencies could uncover immune defects.

“Once identified, direct and indirect protection, penicillin prophylaxis, or a combination of these offers great potential for disease prevention and reduction of mortality and morbidity in children with [primary immunodeficiency],” they wrote.

No funding or conflicts of interest were declared for the study. Two of the editorialists declared research funding or honoraria from the pharmaceutical sector.

SOURCES: Butters C et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3203; Pelton SI et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3185.

Recurrent invasive pneumococcal disease in children could be a signal of underlying primary immunodeficiency, according to a systematic review published in JAMA Pediatrics.

Coen Butters, BMed, DCH, of the Royal Children’s Hospital in Melbourne, and coauthors wrote that, even with optimal vaccine coverage, there is still a group of children with increased susceptibility to invasive pneumococcal disease (IPD), and this could be a potential marker of primary immunodeficiency.

They conducted a systematic review of 17 studies of 6,002 children to examine the evidence on the incidence of primary immunodeficiency in children who presented with IPD but without any other risk factors or predisposing conditions.

Overall, the frequency of primary immunodeficiency in children presenting with IPD who did not have any other predisposing condition ranged from 1% to 26%.

One study of 162 children with IPD, which had an overall frequency of primary immunodeficiency of 10%, found that children older than 2 years were significantly more likely to have primary immunodeficiency than those aged under 2 years (26% vs. 3%; P less than .001).

Primary antibody deficiency was the most commonly diagnosed immunodeficiency in these children with IPD, accounting for 71% of cases. These deficiencies presented as hypogammaglobulinemia, specific pneumococcal antibody deficiency, X-linked agammaglobulinemia, and IgG2 deficiency.

The review also included four studies that looked at the frequency of mannose-binding lectin deficiency in 1,493 children with primary IPD. Two of these studies reported a prevalence of mannose-binding lectin deficiency ranging from 31% in children aged younger than 2 years to 41% in children younger than 1 year.

Five studies looked at the rate of primary immunodeficiency in children presenting with recurrent IPD. In addition to other predisposing conditions such as sickle cell disease, cancer, and anatomical breach in the blood-brain barrier, the three studies that screened for primary immunodeficiency found rates ranging from 10% to 67%. The most common conditions were complement deficiency, pneumococcal antibody deficiency, and a single case of TLR-signaling defect.

In a study of 162 children with primary IPD, screening for asplenia identified a single case of congenital asplenia. In another study of 2,498 cases of IPD, 22 patients had asplenia at presentation, half of whom died at presentation.

Dr. Butters and associates concluded that “this review’s findings suggests that existing data support the immune evaluation of children older than 2 years without a known predisposing condition who present with their first episode of Streptococcus pneumoniae meningitis, pneumonia, or recurrent IPD. Immune evaluation should include assessment for immunoglobulin deficiency, pneumococcal antibody deficiency, complement disorders, and asplenia.”

In an accompanying editorial, Stephen I. Pelton, MD, of the Maxwell Finland Laboratory for Infectious Diseases at Boston Medical Center, and coauthors wrote that in children with recurrent episodes of IPD caused by nonvaccine serotypes – particularly those aged over 5 years – evaluation for primary immunodeficiencies could uncover immune defects.

“Once identified, direct and indirect protection, penicillin prophylaxis, or a combination of these offers great potential for disease prevention and reduction of mortality and morbidity in children with [primary immunodeficiency],” they wrote.

No funding or conflicts of interest were declared for the study. Two of the editorialists declared research funding or honoraria from the pharmaceutical sector.

SOURCES: Butters C et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3203; Pelton SI et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3185.

Recurrent invasive pneumococcal disease in children could be a signal of underlying primary immunodeficiency, according to a systematic review published in JAMA Pediatrics.

Coen Butters, BMed, DCH, of the Royal Children’s Hospital in Melbourne, and coauthors wrote that, even with optimal vaccine coverage, there is still a group of children with increased susceptibility to invasive pneumococcal disease (IPD), and this could be a potential marker of primary immunodeficiency.

They conducted a systematic review of 17 studies of 6,002 children to examine the evidence on the incidence of primary immunodeficiency in children who presented with IPD but without any other risk factors or predisposing conditions.

Overall, the frequency of primary immunodeficiency in children presenting with IPD who did not have any other predisposing condition ranged from 1% to 26%.

One study of 162 children with IPD, which had an overall frequency of primary immunodeficiency of 10%, found that children older than 2 years were significantly more likely to have primary immunodeficiency than those aged under 2 years (26% vs. 3%; P less than .001).

Primary antibody deficiency was the most commonly diagnosed immunodeficiency in these children with IPD, accounting for 71% of cases. These deficiencies presented as hypogammaglobulinemia, specific pneumococcal antibody deficiency, X-linked agammaglobulinemia, and IgG2 deficiency.

The review also included four studies that looked at the frequency of mannose-binding lectin deficiency in 1,493 children with primary IPD. Two of these studies reported a prevalence of mannose-binding lectin deficiency ranging from 31% in children aged younger than 2 years to 41% in children younger than 1 year.

Five studies looked at the rate of primary immunodeficiency in children presenting with recurrent IPD. In addition to other predisposing conditions such as sickle cell disease, cancer, and anatomical breach in the blood-brain barrier, the three studies that screened for primary immunodeficiency found rates ranging from 10% to 67%. The most common conditions were complement deficiency, pneumococcal antibody deficiency, and a single case of TLR-signaling defect.

In a study of 162 children with primary IPD, screening for asplenia identified a single case of congenital asplenia. In another study of 2,498 cases of IPD, 22 patients had asplenia at presentation, half of whom died at presentation.

Dr. Butters and associates concluded that “this review’s findings suggests that existing data support the immune evaluation of children older than 2 years without a known predisposing condition who present with their first episode of Streptococcus pneumoniae meningitis, pneumonia, or recurrent IPD. Immune evaluation should include assessment for immunoglobulin deficiency, pneumococcal antibody deficiency, complement disorders, and asplenia.”

In an accompanying editorial, Stephen I. Pelton, MD, of the Maxwell Finland Laboratory for Infectious Diseases at Boston Medical Center, and coauthors wrote that in children with recurrent episodes of IPD caused by nonvaccine serotypes – particularly those aged over 5 years – evaluation for primary immunodeficiencies could uncover immune defects.

“Once identified, direct and indirect protection, penicillin prophylaxis, or a combination of these offers great potential for disease prevention and reduction of mortality and morbidity in children with [primary immunodeficiency],” they wrote.

No funding or conflicts of interest were declared for the study. Two of the editorialists declared research funding or honoraria from the pharmaceutical sector.

SOURCES: Butters C et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3203; Pelton SI et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3185.

Autoimmune rheumatic diseases increase the risk of cardiovascular disease. In rheumatoid arthritis and systemic lupus erythematosus, the risk is driven primarily by the inflammatory milieu, leading to accelerated coronary and cerebrovascular atherosclerosis independent of traditional atherosclerotic risk factors.^1–3 The extent of cardiovascular involvement in other rheumatologic diseases has been less well characterized but is an area of growing interest.

In this review, we focus on the cardiovascular complications of systemic sclerosis and review recommendations for monitoring these patients in clinical practice.

SYSTEMIC SCLEROSIS, AN AUTOIMMUNE RHEUMATIC DISEASE

Systemic sclerosis is an autoimmune rheumatic disease characterized by excessive extracellular matrix deposition leading to diffuse fibrosis, endothelial dysfunction, and microvascular injury. It is most common in North America, Southern Europe, and Australia,^4,5 and it affects women more than men in ratios ranging from 3:1 to 14:1.⁶ The mean age at diagnosis is around 50. 

The disease can affect the lungs (interstitial lung disease and pulmonary hypertension), the heart, the kidneys, and the gastrointestinal tract.

Systemic sclerosis has 2 main subtypes: limited cutaneous systemic sclerosis, formerly called CREST syndrome) and diffuse cutaneous systemic sclerosis. The limited cutaneous subtype is characterized by tightening of the skin of the distal extremities (below the elbows and knees) and face, while diffuse cutaneous systemic sclerosis can manifest as more extensive skin tightening also involving proximal extremities and the trunk. Both subtypes can have an effect on the cardiovascular system.

Some cardiovascular risk factors such as dyslipidemia, diabetes mellitus, and high body mass index are less common in patients with systemic sclerosis than in patients with rheumatoid arthritis, while the rates of arterial hypertension, smoking, chronic obstructive pulmonary disease, osteoporosis, and neoplasms are similar between the 2 groups.⁷

HEART INVOLVEMENT HAS SERIOUS CONSEQUENCES

Overt cardiac involvement in systemic sclerosis is associated with a mortality rate of up to 70% over 5 years,^8,9 and about one-fourth of deaths in patients with systemic sclerosis are from cardiac causes.^10,11 Studies in Europe^10,12 showed that many patients with systemic sclerosis have cardiac involvement detectable by magnetic resonance imaging even if they do not have clinical disease. Pulmonary arterial hypertension (PAH) is a complication of both subtypes of systemic sclerosis and portends a higher risk of death.⁸

Thus, it is critical for clinicians to understand the potential comorbid conditions associated with systemic sclerosis, particularly the cardiovascular ones, and to work closely with cardiologists to help optimize the evaluation and management.

MECHANISMS OF CARDIAC DISEASE IN SYSTEMIC SCLEROSIS

Abnormal vasoreactivity, a consequence of an imbalance between endothelium-derived vasoconstrictors and vasodilators, defective angiogenesis, and endothelial injury, leads to tissue ischemia and vascular endothelial growth factor expression, which initiates injury and fibrosis in the myocardium and in other organs.^14–17 Fibrosis involves the myocardium, pericardium, and conduction system.^13,18

Myocardial involvement in systemic sclerosis is thought to be due mainly to abnormal vasoreactivity and microvascular abnormalities such as transient coronary artery spasm leading to repeated focal ischemia.^19,20 Abnormal vasoreactivity has been demonstrated during cardiac catheterization²¹: while mean coronary sinus blood flow in systemic sclerosis patients was normal at rest, vasodilator reserve was significantly reduced in patients with diffuse cutaneous systemic sclerosis after maximal vasodilation with dipyridamole. Additionally, endomyocardial biopsy showed fibrosis and concentric intimal hypertrophy with normal epicardial coronary arteries.²¹

More research into other mechanisms of cardiovascular disease in systemic sclerosis is needed to allow for better preventive care for these patients.

Systemic sclerosis can be associated with World Health Organization (WHO) groups 1, 2, 3, and 4 pulmonary hypertension. WHO group 1, called pulmonary arterial hypertension or PAH, is one of the most common cardiac complications of systemic sclerosis, with a reported prevalence as high as 12%.²² Systemic sclerosis-associated PAH carries a high mortality rate, with a mean survival of only 3 years.²³

With advances in treatments for other complications of systemic sclerosis, the percentage of systemic sclerosis patients who die of PAH has increased from 6% to 33%.²⁴

Compared with patients with idiopathic PAH, those with systemic sclerosis get less of a response from therapy and have poorer outcomes despite lower mean pulmonary artery pressures and similar reductions in cardiac index. However, recent studies have suggested that with aggressive treatment, patients with systemic sclerosis-related PAH can achieve outcomes similar to those with idiopathic PAH.²⁵ Thus, recognizing this condition early is imperative.

Pulmonary arterial hypertension defined

PAH is defined as the combination of all of the following²⁶:

• Mean pulmonary artery pressure > 20 mm Hg at rest
• Normal pulmonary capillary wedge pressure (≤ 15 mm Hg)
• Pulmonary vascular resistance ≥ 3 Wood units on right heart catheterization.

Other causes of pulmonary hypertension such as interstitial lung disease, chronic pulmonary thromboembolic disease, and left heart disease must be excluded.^24,27

Remodeling in the pulmonary arteries

The events that lead to PAH in systemic sclerosis remain unclear but are believed to involve initial inflammation or endothelial injury that leads to a dysequilibrium between proliferative mediators and antiproliferative vasodilators. This dysequilibrium, along with endothelial dysfunction, causes an obliterative vasculopathy in the pulmonary artery branches and arterioles. Sympathetic overactivity, hypoxemia, and ischemia-reperfusion injury additionally promote vascular proliferation, fibrosis, and remodeling, leading to increased pulmonary vascular resistance, PAH, and increased right ventricular pressures.^23,27

The subtype of systemic sclerosis is an important factor in the development and progression of PAH. PAH appears to be the major cause of death in limited cutaneous systemic sclerosis, while interstitial lung disease is the major cause of death in diffuse cutaneous systemic sclerosis.²⁸

Pulmonary arterial hypertension is a late complication of systemic sclerosis

Data from the South Australian Scleroderma Registry²⁹ revealed that PAH tends to be a late complication of systemic sclerosis, occurring around 20 years after disease onset. In this study of 608 patients, no patient with diffuse cutaneous systemic sclerosis developed PAH.

Systemic sclerosis-related PAH initially follows an indolent course with few symptoms until right ventricular function deteriorates. Early in the disease, patients may experience nonspecific symptoms of fatigue, lightheadedness, and dyspnea on exertion.²³ As it progresses, they tend to have worsening dyspnea and may experience exertional syncope, palpitations, and chest pain.

Physical findings may suggest elevated right ventricular pressure and right ventricular failure; these include a loud P2, a prominent jugular a wave, a tricuspid regurgitant murmur, jugular venous distention, and lower-extremity edema.²⁷

Screening for pulmonary arterial hypertension in systemic sclerosis

Significant signs and symptoms usually occur late in the disease; thus, it is important to appropriately screen patients who are at risk so that they can begin aggressive treatment.

Doppler echocardiography is recommended by European and American guidelines to screen for PAH in patients who have systemic sclerosis, and most agree that screening is appropriate even if the patient has no symptoms.³⁰ European consensus documents recommend that transthoracic echocardiography be done annually for the first 5 years of disease and be continued every year in patients at high risk, ie, those with anticentromere antibodies, anti-Th/To antibodies, or interstitial lung disease. Patients not at high risk of developing pulmonary hypertension should also have regular transthoracic echocardiography, though the exact timing is not defined.³¹ While American societies have not issued corresponding recommendations, many experts follow the European recommendations.

Worrisome features on echocardiography in asymptomatic patients should be followed up with right heart catheterization to assess mean right ventricular pressure. These include:

• Estimated right ventricular systolic pressure ≥ 40 mm Hg
• Tricuspid regurgitant jet velocity > 2.8 m/s
• Right atrial enlargement > 53 mm
• Right ventricular enlargement (mid-cavity dimension > 35 mm).³²

Although echocardiography is the most common form of screening, it gives only an estimate of right ventricular systolic pressure, which is imprecise. Other noninvasive markers are helpful and necessary to appropriately screen this population.

Diffusion capacity. The Itinerair study³³ found that a diffusing capacity for carbon monoxide (D_^LCO) of 60% or higher has a high specificity in excluding PAH.

Uric acid has been found to be elevated in patients with systemic sclerosis-related PAH, and levels inversely correlate with 6-minute walking distance.³⁴

Other predictors. N-terminal pro-B-type natriuretic peptide (NT-proBNP), left atrial volume, and the right ventricular myocardial performance index have also been shown to be independent predictors of PAH in patients with systemic sclerosis.³⁵

An algorithm. The DETECT study³⁶ enrolled patients at increased risk who had had systemic sclerosis longer than 3 years and a D_^LCO less than 60%. The investigators developed a 2-step algorithm to determine which patients should be referred for right heart catheterization to try to detect PAH earlier while minimizing the number of missed diagnoses and optimizing the use of invasive diagnostic right heart catheterization.

The first step was to assess serum values of anticentromere antibodies, NT-proBNP, and urate, and clinical features (telangiectasias), forced vital capacity, and electrocardiographic changes of right axis deviation to derive a prediction score. The second step was to assess surface echocardiographic features of the right atrial area and tricuspid regurgitation velocity.

This approach led to right heart catheterization in 62% of patients and was associated with a false-negative rate of 4%. Importantly, of the patients with PAH, 1 in 5 had no symptoms, and 33% had tricuspid regurgitation velocity less than 2.8 m/s. No single measurement performed well in isolation in this study.³⁷

Thus, we recommend that, in addition to routine surface echocardiography, a multimodal approach be used that includes laboratory testing, clinical features, and electrocardiographic findings when screening this high-risk patient population.

Although macrovascular disease has not typically been regarded as a significant systemic feature in systemic sclerosis, myocardial infarction and stroke are more common in patients with systemic sclerosis than in controls.^38,39

Coronary artery disease in systemic sclerosis

Man et al³⁸ reported that the incidence of myocardial infarction in patients with systemic sclerosis was 4.4 per 1,000 persons per year, and the incidence of stroke was 4.8 per 1,000 persons per year, compared with 2.5 per 1,000 persons per year for both myocardial infarction and stroke in healthy controls matched for age, sex, and time of entry.

The Australian Scleroderma Cohort Study³⁹ found a 3-fold higher prevalence of coronary artery disease in systemic sclerosis patients than in controls after factoring in traditional risk factors.

Aviña-Zubieta et al,⁴⁰ in a cohort of 1,239 systemic sclerosis patients, estimated a hazard ratio (HR) of 3.49 for myocardial infarction and 2.35 for stroke compared with age- and sex-matched controls. Not all of these events were related to macrovascular atherosclerosis—vasospasm and microvascular ischemia may have played significant roles in the etiology of clinical manifestations.

Studies of coronary atherosclerosis in systemic sclerosis are limited. An autopsy study⁴¹ of 58 patients with systemic sclerosis and 58 controls matched for age, sex, and ethnicity found that the prevalence of atherosclerosis of small coronary arteries and arterioles was significantly higher in systemic sclerosis patients than in controls (17% vs 2%, P < .01). However, the prevalence of medium-vessel coronary atherosclerosis was similar (48% vs 43%).

Why patients with systemic sclerosis develop atherosclerosis has not yet been determined. Traditional risk factors such as hypertension, dyslipidemia, diabetes mellitus, and obesity are typically no more prevalent in systemic sclerosis patients than in controls,^38,42 and thus do not explain the increased risk of atherosclerotic cardiovascular disease. There is some evidence that novel markers of atherosclerotic risk such as homocysteine,⁴³ lipoprotein[a],⁴⁴ and oxidized low-density lipoprotein⁴⁵ are more prevalent in systemic sclerosis, but these results have not been substantiated in more extensive studies.

Peripheral artery disease

It remains unclear whether peripheral artery disease is more prevalent in systemic sclerosis patients than in controls.

Individual studies have shown mixed results in comparing carotid artery stenosis between systemic sclerosis patients and controls using carotid duplex ultrasonography,⁴⁶ the ankle-brachial index,^46–48 carotid intima-media thickness,^49–54 and brachial flow-mediated dilation.^{51,53,55–58} A meta-analysis found that the carotid intima and media are significantly thicker in systemic sclerosis patients than in controls,⁵⁹ and the magnitude of difference is similar to that in other groups at increased cardiovascular risk, such as those with rheumatoid arthritis, diabetes, and familial hypercholesterolemia.^60–63

A meta-analysis of brachial artery findings showed significantly lower flow-mediated dilation in systemic sclerosis patients than in controls.⁶⁴

Overall, given the inconsistency of study results, systemic sclerosis patients should be screened and managed as in other patients with peripheral artery disease, but the clinician should be aware that there may be a higher risk of peripheral artery disease in these patients.

RIGHT AND LEFT VENTRICULAR DYSFUNCTION

Many patients with systemic sclerosis have right ventricular dysfunction as a consequence of PAH.⁶⁵ It is important to detect diastolic dysfunction in this population, as it may be an even stronger predictor of death than pulmonary hypertension on right heart catheterization (HR 3.7 vs 2.0).⁶⁶

Fewer patients have left ventricular dysfunction. In a multicenter study of 570 systemic sclerosis patients, only 1.4% had left ventricular systolic dysfunction on echocardiography, though 22.6% had left ventricular hypertrophy and 17.7% had left ventricular diastolic dysfunction.⁶⁷ In the European League Against Rheumatism (EULAR) database, the prevalence of reduced left ventricular ejection fraction was 5.4%.⁶⁸

Though traditional echocardiographic screening suggests the prevalence of left ventricular dysfunction in systemic sclerosis patients is low, cardiac magnetic resonance imaging (MRI) may be more sensitive than echocardiography for detecting subclinical myocardial involvement. Cardiac MRI has been shown to detect evidence of myocardial pathology (increased T2 signal, left ventricular thinning, pericardial effusion, reduced left ventricular and right ventricular ejection fraction, left ventricular diastolic dysfunction, and delayed myocardial contrast enhancement) in up to 75% of systemic sclerosis cases studied.⁶⁹

Patients with systemic sclerosis should already be undergoing echocardiography every year to screen for PAH, and screening should also include tissue Doppler imaging to detect various forms of left and right ventricular systolic and diastolic dysfunction that may not be clinically apparent.

Though cardiac MRI can provide useful additional information, it is not currently recommended for routine screening in patients with systemic sclerosis.

Patients with systemic sclerosis are prone to arrhythmias due to both conduction system fibrosis and myocardial damage.

Arrhythmias accounted for 6% of the deaths in the EULAR Scleroderma Trials and Research (EUSTAR) database.¹¹

In the Genetics Versus Environment in Scleroderma Outcome Study (GENISOS),⁷⁰  250 patients who had had systemic sclerosis for at least 3 years were studied during a period of approximately 6 years, during which there were 52 deaths, 29 of which were directly attributable to systemic sclerosis. Multivariable Cox modeling showed that 7 variables predicted mortality:

• Body mass index < 18.5 kg/m²
• Age ≥ 65
• Forced vital capacity < 50% predicted
• Systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mm Hg
• Pulmonary fibrosis
• Positive anticentromere antibodies
• Cardiac arrhythmias.

The hazard ratio for death in patients with arrhythmias in this model was 2.18 (95% CI 1.05–4.50, P = .035). Thus, finding arrhythmias in systemic sclerosis patients can provide important prognostic information.

While resting electrocardiography in patients with systemic sclerosis  most commonly shows sinus rhythm, 24-hour electrocardiographic monitoring has revealed nonsustained supraventricular and ventricular arrhythmias in a significant percentage.^71,72 Although difficult to quantify in routine practice, parameters controlled by the autonomic nervous system including heart rate variability and heart rate turbulence have been shown to be impaired in systemic sclerosis, and these measures are associated with an increased risk of malignant arrhythmias and sudden cardiac death.^73,74

Conduction abnormalities

Conduction abnormalities occur in one-fifth to one-third of patients with systemic sclerosis.^75,76 The most common abnormal conduction finding is left bundle branch block, followed by first-degree atrioventricular block. High-degree atrioventricular block is uncommon,⁷⁶ though a few case reports of complete heart block thought to be related to systemic sclerosis have been published.^77–79 An autopsy study showed that the conduction system is relatively spared from myocardial changes seen in systemic sclerosis patients, and thus it is speculated that the conduction disturbances are a consequence of damaged myocardium rather than damage to conduction tissue.⁸⁰

Given the array of electrophysiologic abnormalities that systemic sclerosis patients can have, it is critical to monitor all patients with routine (annual or biannual) electrocardiography; to take possible arrhythmia-related symptoms seriously; and to evaluate them with further workup such as Holter monitoring for 24 hours or even longer, event monitoring, exercise testing, or tilt-table testing.

PERICARDIAL DISEASE

Pericardial disease is clinically apparent in 5% to 16% of patients with systemic sclerosis⁸¹; patients with limited cutaneous systemic sclerosis have more pericardial disease than those with diffuse cutaneous systemic sclerosis (30% vs 16%).⁸² Forty-one percent of systemic sclerosis patients have been shown to have pericardial effusion by echocardiography,⁸¹ but the effusions are typically small and rarely cause tamponade, though tamponade is associated with a poor prognosis.

Large pericardial effusions can develop before skin thickening and diagnosis of systemic sclerosis.^81,83,84 Thus, systemic sclerosis should be considered in patients with pericardial effusions of unknown etiology.

In a small study,⁸⁵ the pericardial fluid in systemic sclerosis was typically exudative, with lactate dehydrogenase greater than 200 U/L, a fluid-serum lactate dehydrogenase ratio greater than 0.6, and a fluid-serum total protein ratio greater than 0.5.

Pericardial effusion can be a sign of impending scleroderma renal crisis,⁸⁶ and thus renal function should be carefully monitored in systemic sclerosis patients with pericardial effusion. Constrictive pericarditis and restrictive cardiomyopathy can rarely occur in systemic sclerosis and may more commonly present with symptoms.

Pericardial disease in systemic sclerosis should be treated in a standard fashion with nonsteroidal anti-inflammatory drugs. Corticosteroids are generally of limited benefit and should be avoided, especially in the setting of scleroderma renal crisis.⁸¹

VALVULAR HEART DISEASE

Based on limited studies, the prevalence of significant valvular heart disease in systemic sclerosis patients does not seem to be higher than that in the general population. While patients with systemic sclerosis and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) have been shown to have a higher frequency of mitral valve prolapse and mild mitral regurgitation,^87,88 these abnormalities do not often progress in severity, and thus their clinical significance is limited.

It is important for physicians caring for patients with systemic sclerosis to be aware of its most common cardiac manifestations, including left and right ventricular systolic and diastolic dysfunction, pulmonary hypertension, conduction abnormalities, arrhythmias, and cardiomyopathy.

Look for volume overload

On clinical examination, assess for clinical markers of volume overload such as distended neck veins, peripheral edema, or an abnormal blood pressure response to the Valsalva maneuver. These findings should prompt measurement of NT-proBNP,⁸⁹ and may warrant prescription of a diuretic.

Electrocardiography to investigate arrhythmias

Electrocardiography should be done if patients describe symptoms of palpitations, and should also include continuous rhythm monitoring with Holter or event monitoring, depending on the frequency of symptoms. Otherwise, patients should routinely undergo electrocardiography once or twice a year.

Q waves are common in systemic sclerosis patients (especially those with diffuse cutaneous systemic sclerosis), notably in the precordial leads, and can occur without coronary artery disease.⁹⁰ Symptoms such as presyncope should be further investigated with Holter monitoring and tilt-table testing.

Assess, modify traditional risk factors

Subclinical atherosclerosis as detected by carotid intima-media thickness is as common in systemic sclerosis as in rheumatoid arthritis.⁶¹ However, traditional risk indices such as SCORE (Systematic Coronary Risk Evaluation), QRISK2, and the American College of Cardiology/American Heart Association indices may underestimate risk in patients who have systemic sclerosis.

Strict hypertension control should be the goal for all systemic sclerosis patients. Though there are no specific guidelines on which antihypertensive medications are preferred, calcium channel blockers or angiotensin II receptor blockers, which are typically used to treat systemic sclerosis-related Raynaud phenomenon, may be appropriate.

Statins reduce vascular complications and are generally well tolerated in patients with systemic sclerosis.^91,92 

Aspirin is not recommended for routine primary prevention in view of data suggesting that its benefits in diabetic patients are counterbalanced by increased bleeding risk.⁹³

Echocardiography to detect pulmonary arterial hypertension

At this time, guidelines for monitoring for cardiovascular manifestations in systemic sclerosis patients are limited. The only well-defined ones are European consensus guidelines, which suggest annual transthoracic echocardiography for the first 5 years after systemic sclerosis is diagnosed and continued annual screening in patients at risk of developing PAH.³¹

We support this strategy, with annual screening for the first 5 years followed by surveillance echocardiography every 2 to 3 years unless there is a high risk of PAH. Specific attention should be paid to right ventricular diastolic function, right atrial volume, and right ventricular myocardial performance index.

Emerging data suggest that the addition of global longitudinal strain of ventricles to  routine echocardiography can help detect subclinical cardiac risk.⁹⁴ Although further study is needed into the predictive value of global longitudinal strain, it is a low-cost and noninvasive addition to standard echocardiography that can help guide risk stratification, and thus we recommend that it be part of the echocardiographic examination for all systemic sclerosis patients.

Pulmonary function testing. In addition to screening for PAH with echocardiography, we recommend obtaining baseline pulmonary function tests, including D_^LCO, at the time systemic sclerosis is diagnosed, with repeat testing annually.

Magnetic resonance imaging

While echocardiography is the gold standard for monitoring systemic sclerosis patients, cardiovascular MRI may have a role in identifying those at higher risk of dangerous arrhythmias such as ventricular tachycardia and ventricular fibrillation. In addition to assessing ventricular function, MRI can detect myocardial inflammation, ischemia, and fibrosis that may predispose a patient to develop ventricular tachycardia or fibrillation.⁹⁵ Variables such as T1/T2 mapping, extracellular volume fraction, T2 signal ratio, and early vs late gadolinium enhancement can help identify patients who had past ventricular tachycardia or fibrillation.⁹⁶

Finding an increased risk of arrhythmias may prompt a conversation between the patient and the physician about the need for an implantable cardiac defibrillator.

If cardiac MRI is available and is reimbursed by the patient’s insurance carrier, physicians should strongly consider obtaining at least one baseline scan in systemic sclerosis patients to identify those at risk of highly fatal arrhythmias.

Teamwork is needed

Systemic sclerosis has not traditionally been associated with cardiovascular disease to the extent of other rheumatic conditions, but the cardiovascular system can be affected in various ways that can ultimately lead to an early death. These manifestations may be asymptomatic for long periods, and overt clinical disease portends a poorer prognosis.

Primary care physicians managing these patients should be aware of the cardiovascular complications of systemic sclerosis and should implement appropriate screening tests in conjunction with rheumatologists and cardiologists. It is also essential for general and subspecialty cardiologists to understand the broad spectrum of organ system involvement that can affect systemic sclerosis patients and to tailor their investigation and management recommendations accordingly. By designing a multidisciplinary approach to the treatment of systemic sclerosis patients, physicians can help to optimize cardiovascular risk modification in this vulnerable population.

Autoimmune rheumatic diseases increase the risk of cardiovascular disease. In rheumatoid arthritis and systemic lupus erythematosus, the risk is driven primarily by the inflammatory milieu, leading to accelerated coronary and cerebrovascular atherosclerosis independent of traditional atherosclerotic risk factors.^1–3 The extent of cardiovascular involvement in other rheumatologic diseases has been less well characterized but is an area of growing interest.

In this review, we focus on the cardiovascular complications of systemic sclerosis and review recommendations for monitoring these patients in clinical practice.

SYSTEMIC SCLEROSIS, AN AUTOIMMUNE RHEUMATIC DISEASE

Systemic sclerosis is an autoimmune rheumatic disease characterized by excessive extracellular matrix deposition leading to diffuse fibrosis, endothelial dysfunction, and microvascular injury. It is most common in North America, Southern Europe, and Australia,^4,5 and it affects women more than men in ratios ranging from 3:1 to 14:1.⁶ The mean age at diagnosis is around 50. 

The disease can affect the lungs (interstitial lung disease and pulmonary hypertension), the heart, the kidneys, and the gastrointestinal tract.

Systemic sclerosis has 2 main subtypes: limited cutaneous systemic sclerosis, formerly called CREST syndrome) and diffuse cutaneous systemic sclerosis. The limited cutaneous subtype is characterized by tightening of the skin of the distal extremities (below the elbows and knees) and face, while diffuse cutaneous systemic sclerosis can manifest as more extensive skin tightening also involving proximal extremities and the trunk. Both subtypes can have an effect on the cardiovascular system.

Some cardiovascular risk factors such as dyslipidemia, diabetes mellitus, and high body mass index are less common in patients with systemic sclerosis than in patients with rheumatoid arthritis, while the rates of arterial hypertension, smoking, chronic obstructive pulmonary disease, osteoporosis, and neoplasms are similar between the 2 groups.⁷

HEART INVOLVEMENT HAS SERIOUS CONSEQUENCES

Overt cardiac involvement in systemic sclerosis is associated with a mortality rate of up to 70% over 5 years,^8,9 and about one-fourth of deaths in patients with systemic sclerosis are from cardiac causes.^10,11 Studies in Europe^10,12 showed that many patients with systemic sclerosis have cardiac involvement detectable by magnetic resonance imaging even if they do not have clinical disease. Pulmonary arterial hypertension (PAH) is a complication of both subtypes of systemic sclerosis and portends a higher risk of death.⁸

Thus, it is critical for clinicians to understand the potential comorbid conditions associated with systemic sclerosis, particularly the cardiovascular ones, and to work closely with cardiologists to help optimize the evaluation and management.

MECHANISMS OF CARDIAC DISEASE IN SYSTEMIC SCLEROSIS

Abnormal vasoreactivity, a consequence of an imbalance between endothelium-derived vasoconstrictors and vasodilators, defective angiogenesis, and endothelial injury, leads to tissue ischemia and vascular endothelial growth factor expression, which initiates injury and fibrosis in the myocardium and in other organs.^14–17 Fibrosis involves the myocardium, pericardium, and conduction system.^13,18

Myocardial involvement in systemic sclerosis is thought to be due mainly to abnormal vasoreactivity and microvascular abnormalities such as transient coronary artery spasm leading to repeated focal ischemia.^19,20 Abnormal vasoreactivity has been demonstrated during cardiac catheterization²¹: while mean coronary sinus blood flow in systemic sclerosis patients was normal at rest, vasodilator reserve was significantly reduced in patients with diffuse cutaneous systemic sclerosis after maximal vasodilation with dipyridamole. Additionally, endomyocardial biopsy showed fibrosis and concentric intimal hypertrophy with normal epicardial coronary arteries.²¹

More research into other mechanisms of cardiovascular disease in systemic sclerosis is needed to allow for better preventive care for these patients.

Systemic sclerosis can be associated with World Health Organization (WHO) groups 1, 2, 3, and 4 pulmonary hypertension. WHO group 1, called pulmonary arterial hypertension or PAH, is one of the most common cardiac complications of systemic sclerosis, with a reported prevalence as high as 12%.²² Systemic sclerosis-associated PAH carries a high mortality rate, with a mean survival of only 3 years.²³

With advances in treatments for other complications of systemic sclerosis, the percentage of systemic sclerosis patients who die of PAH has increased from 6% to 33%.²⁴

Compared with patients with idiopathic PAH, those with systemic sclerosis get less of a response from therapy and have poorer outcomes despite lower mean pulmonary artery pressures and similar reductions in cardiac index. However, recent studies have suggested that with aggressive treatment, patients with systemic sclerosis-related PAH can achieve outcomes similar to those with idiopathic PAH.²⁵ Thus, recognizing this condition early is imperative.

Pulmonary arterial hypertension defined

PAH is defined as the combination of all of the following²⁶:

• Mean pulmonary artery pressure > 20 mm Hg at rest
• Normal pulmonary capillary wedge pressure (≤ 15 mm Hg)
• Pulmonary vascular resistance ≥ 3 Wood units on right heart catheterization.

Other causes of pulmonary hypertension such as interstitial lung disease, chronic pulmonary thromboembolic disease, and left heart disease must be excluded.^24,27

Remodeling in the pulmonary arteries

The events that lead to PAH in systemic sclerosis remain unclear but are believed to involve initial inflammation or endothelial injury that leads to a dysequilibrium between proliferative mediators and antiproliferative vasodilators. This dysequilibrium, along with endothelial dysfunction, causes an obliterative vasculopathy in the pulmonary artery branches and arterioles. Sympathetic overactivity, hypoxemia, and ischemia-reperfusion injury additionally promote vascular proliferation, fibrosis, and remodeling, leading to increased pulmonary vascular resistance, PAH, and increased right ventricular pressures.^23,27

The subtype of systemic sclerosis is an important factor in the development and progression of PAH. PAH appears to be the major cause of death in limited cutaneous systemic sclerosis, while interstitial lung disease is the major cause of death in diffuse cutaneous systemic sclerosis.²⁸

Pulmonary arterial hypertension is a late complication of systemic sclerosis

Data from the South Australian Scleroderma Registry²⁹ revealed that PAH tends to be a late complication of systemic sclerosis, occurring around 20 years after disease onset. In this study of 608 patients, no patient with diffuse cutaneous systemic sclerosis developed PAH.

Systemic sclerosis-related PAH initially follows an indolent course with few symptoms until right ventricular function deteriorates. Early in the disease, patients may experience nonspecific symptoms of fatigue, lightheadedness, and dyspnea on exertion.²³ As it progresses, they tend to have worsening dyspnea and may experience exertional syncope, palpitations, and chest pain.

Physical findings may suggest elevated right ventricular pressure and right ventricular failure; these include a loud P2, a prominent jugular a wave, a tricuspid regurgitant murmur, jugular venous distention, and lower-extremity edema.²⁷

Screening for pulmonary arterial hypertension in systemic sclerosis

Significant signs and symptoms usually occur late in the disease; thus, it is important to appropriately screen patients who are at risk so that they can begin aggressive treatment.

Doppler echocardiography is recommended by European and American guidelines to screen for PAH in patients who have systemic sclerosis, and most agree that screening is appropriate even if the patient has no symptoms.³⁰ European consensus documents recommend that transthoracic echocardiography be done annually for the first 5 years of disease and be continued every year in patients at high risk, ie, those with anticentromere antibodies, anti-Th/To antibodies, or interstitial lung disease. Patients not at high risk of developing pulmonary hypertension should also have regular transthoracic echocardiography, though the exact timing is not defined.³¹ While American societies have not issued corresponding recommendations, many experts follow the European recommendations.

Worrisome features on echocardiography in asymptomatic patients should be followed up with right heart catheterization to assess mean right ventricular pressure. These include:

• Estimated right ventricular systolic pressure ≥ 40 mm Hg
• Tricuspid regurgitant jet velocity > 2.8 m/s
• Right atrial enlargement > 53 mm
• Right ventricular enlargement (mid-cavity dimension > 35 mm).³²

Although echocardiography is the most common form of screening, it gives only an estimate of right ventricular systolic pressure, which is imprecise. Other noninvasive markers are helpful and necessary to appropriately screen this population.

Diffusion capacity. The Itinerair study³³ found that a diffusing capacity for carbon monoxide (D_^LCO) of 60% or higher has a high specificity in excluding PAH.

Uric acid has been found to be elevated in patients with systemic sclerosis-related PAH, and levels inversely correlate with 6-minute walking distance.³⁴

Other predictors. N-terminal pro-B-type natriuretic peptide (NT-proBNP), left atrial volume, and the right ventricular myocardial performance index have also been shown to be independent predictors of PAH in patients with systemic sclerosis.³⁵

An algorithm. The DETECT study³⁶ enrolled patients at increased risk who had had systemic sclerosis longer than 3 years and a D_^LCO less than 60%. The investigators developed a 2-step algorithm to determine which patients should be referred for right heart catheterization to try to detect PAH earlier while minimizing the number of missed diagnoses and optimizing the use of invasive diagnostic right heart catheterization.

The first step was to assess serum values of anticentromere antibodies, NT-proBNP, and urate, and clinical features (telangiectasias), forced vital capacity, and electrocardiographic changes of right axis deviation to derive a prediction score. The second step was to assess surface echocardiographic features of the right atrial area and tricuspid regurgitation velocity.

This approach led to right heart catheterization in 62% of patients and was associated with a false-negative rate of 4%. Importantly, of the patients with PAH, 1 in 5 had no symptoms, and 33% had tricuspid regurgitation velocity less than 2.8 m/s. No single measurement performed well in isolation in this study.³⁷

Thus, we recommend that, in addition to routine surface echocardiography, a multimodal approach be used that includes laboratory testing, clinical features, and electrocardiographic findings when screening this high-risk patient population.

Although macrovascular disease has not typically been regarded as a significant systemic feature in systemic sclerosis, myocardial infarction and stroke are more common in patients with systemic sclerosis than in controls.^38,39

Coronary artery disease in systemic sclerosis

Man et al³⁸ reported that the incidence of myocardial infarction in patients with systemic sclerosis was 4.4 per 1,000 persons per year, and the incidence of stroke was 4.8 per 1,000 persons per year, compared with 2.5 per 1,000 persons per year for both myocardial infarction and stroke in healthy controls matched for age, sex, and time of entry.

The Australian Scleroderma Cohort Study³⁹ found a 3-fold higher prevalence of coronary artery disease in systemic sclerosis patients than in controls after factoring in traditional risk factors.

Aviña-Zubieta et al,⁴⁰ in a cohort of 1,239 systemic sclerosis patients, estimated a hazard ratio (HR) of 3.49 for myocardial infarction and 2.35 for stroke compared with age- and sex-matched controls. Not all of these events were related to macrovascular atherosclerosis—vasospasm and microvascular ischemia may have played significant roles in the etiology of clinical manifestations.

Studies of coronary atherosclerosis in systemic sclerosis are limited. An autopsy study⁴¹ of 58 patients with systemic sclerosis and 58 controls matched for age, sex, and ethnicity found that the prevalence of atherosclerosis of small coronary arteries and arterioles was significantly higher in systemic sclerosis patients than in controls (17% vs 2%, P < .01). However, the prevalence of medium-vessel coronary atherosclerosis was similar (48% vs 43%).

Why patients with systemic sclerosis develop atherosclerosis has not yet been determined. Traditional risk factors such as hypertension, dyslipidemia, diabetes mellitus, and obesity are typically no more prevalent in systemic sclerosis patients than in controls,^38,42 and thus do not explain the increased risk of atherosclerotic cardiovascular disease. There is some evidence that novel markers of atherosclerotic risk such as homocysteine,⁴³ lipoprotein[a],⁴⁴ and oxidized low-density lipoprotein⁴⁵ are more prevalent in systemic sclerosis, but these results have not been substantiated in more extensive studies.

Peripheral artery disease

It remains unclear whether peripheral artery disease is more prevalent in systemic sclerosis patients than in controls.

Individual studies have shown mixed results in comparing carotid artery stenosis between systemic sclerosis patients and controls using carotid duplex ultrasonography,⁴⁶ the ankle-brachial index,^46–48 carotid intima-media thickness,^49–54 and brachial flow-mediated dilation.^{51,53,55–58} A meta-analysis found that the carotid intima and media are significantly thicker in systemic sclerosis patients than in controls,⁵⁹ and the magnitude of difference is similar to that in other groups at increased cardiovascular risk, such as those with rheumatoid arthritis, diabetes, and familial hypercholesterolemia.^60–63

A meta-analysis of brachial artery findings showed significantly lower flow-mediated dilation in systemic sclerosis patients than in controls.⁶⁴

Overall, given the inconsistency of study results, systemic sclerosis patients should be screened and managed as in other patients with peripheral artery disease, but the clinician should be aware that there may be a higher risk of peripheral artery disease in these patients.

RIGHT AND LEFT VENTRICULAR DYSFUNCTION

Many patients with systemic sclerosis have right ventricular dysfunction as a consequence of PAH.⁶⁵ It is important to detect diastolic dysfunction in this population, as it may be an even stronger predictor of death than pulmonary hypertension on right heart catheterization (HR 3.7 vs 2.0).⁶⁶

Fewer patients have left ventricular dysfunction. In a multicenter study of 570 systemic sclerosis patients, only 1.4% had left ventricular systolic dysfunction on echocardiography, though 22.6% had left ventricular hypertrophy and 17.7% had left ventricular diastolic dysfunction.⁶⁷ In the European League Against Rheumatism (EULAR) database, the prevalence of reduced left ventricular ejection fraction was 5.4%.⁶⁸

Though traditional echocardiographic screening suggests the prevalence of left ventricular dysfunction in systemic sclerosis patients is low, cardiac magnetic resonance imaging (MRI) may be more sensitive than echocardiography for detecting subclinical myocardial involvement. Cardiac MRI has been shown to detect evidence of myocardial pathology (increased T2 signal, left ventricular thinning, pericardial effusion, reduced left ventricular and right ventricular ejection fraction, left ventricular diastolic dysfunction, and delayed myocardial contrast enhancement) in up to 75% of systemic sclerosis cases studied.⁶⁹

Patients with systemic sclerosis should already be undergoing echocardiography every year to screen for PAH, and screening should also include tissue Doppler imaging to detect various forms of left and right ventricular systolic and diastolic dysfunction that may not be clinically apparent.

Though cardiac MRI can provide useful additional information, it is not currently recommended for routine screening in patients with systemic sclerosis.

Patients with systemic sclerosis are prone to arrhythmias due to both conduction system fibrosis and myocardial damage.

Arrhythmias accounted for 6% of the deaths in the EULAR Scleroderma Trials and Research (EUSTAR) database.¹¹

In the Genetics Versus Environment in Scleroderma Outcome Study (GENISOS),⁷⁰  250 patients who had had systemic sclerosis for at least 3 years were studied during a period of approximately 6 years, during which there were 52 deaths, 29 of which were directly attributable to systemic sclerosis. Multivariable Cox modeling showed that 7 variables predicted mortality:

• Body mass index < 18.5 kg/m²
• Age ≥ 65
• Forced vital capacity < 50% predicted
• Systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mm Hg
• Pulmonary fibrosis
• Positive anticentromere antibodies
• Cardiac arrhythmias.

The hazard ratio for death in patients with arrhythmias in this model was 2.18 (95% CI 1.05–4.50, P = .035). Thus, finding arrhythmias in systemic sclerosis patients can provide important prognostic information.

While resting electrocardiography in patients with systemic sclerosis  most commonly shows sinus rhythm, 24-hour electrocardiographic monitoring has revealed nonsustained supraventricular and ventricular arrhythmias in a significant percentage.^71,72 Although difficult to quantify in routine practice, parameters controlled by the autonomic nervous system including heart rate variability and heart rate turbulence have been shown to be impaired in systemic sclerosis, and these measures are associated with an increased risk of malignant arrhythmias and sudden cardiac death.^73,74

Conduction abnormalities

Conduction abnormalities occur in one-fifth to one-third of patients with systemic sclerosis.^75,76 The most common abnormal conduction finding is left bundle branch block, followed by first-degree atrioventricular block. High-degree atrioventricular block is uncommon,⁷⁶ though a few case reports of complete heart block thought to be related to systemic sclerosis have been published.^77–79 An autopsy study showed that the conduction system is relatively spared from myocardial changes seen in systemic sclerosis patients, and thus it is speculated that the conduction disturbances are a consequence of damaged myocardium rather than damage to conduction tissue.⁸⁰

Given the array of electrophysiologic abnormalities that systemic sclerosis patients can have, it is critical to monitor all patients with routine (annual or biannual) electrocardiography; to take possible arrhythmia-related symptoms seriously; and to evaluate them with further workup such as Holter monitoring for 24 hours or even longer, event monitoring, exercise testing, or tilt-table testing.

PERICARDIAL DISEASE

Pericardial disease is clinically apparent in 5% to 16% of patients with systemic sclerosis⁸¹; patients with limited cutaneous systemic sclerosis have more pericardial disease than those with diffuse cutaneous systemic sclerosis (30% vs 16%).⁸² Forty-one percent of systemic sclerosis patients have been shown to have pericardial effusion by echocardiography,⁸¹ but the effusions are typically small and rarely cause tamponade, though tamponade is associated with a poor prognosis.

Large pericardial effusions can develop before skin thickening and diagnosis of systemic sclerosis.^81,83,84 Thus, systemic sclerosis should be considered in patients with pericardial effusions of unknown etiology.

In a small study,⁸⁵ the pericardial fluid in systemic sclerosis was typically exudative, with lactate dehydrogenase greater than 200 U/L, a fluid-serum lactate dehydrogenase ratio greater than 0.6, and a fluid-serum total protein ratio greater than 0.5.

Pericardial effusion can be a sign of impending scleroderma renal crisis,⁸⁶ and thus renal function should be carefully monitored in systemic sclerosis patients with pericardial effusion. Constrictive pericarditis and restrictive cardiomyopathy can rarely occur in systemic sclerosis and may more commonly present with symptoms.

Pericardial disease in systemic sclerosis should be treated in a standard fashion with nonsteroidal anti-inflammatory drugs. Corticosteroids are generally of limited benefit and should be avoided, especially in the setting of scleroderma renal crisis.⁸¹

VALVULAR HEART DISEASE

Based on limited studies, the prevalence of significant valvular heart disease in systemic sclerosis patients does not seem to be higher than that in the general population. While patients with systemic sclerosis and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) have been shown to have a higher frequency of mitral valve prolapse and mild mitral regurgitation,^87,88 these abnormalities do not often progress in severity, and thus their clinical significance is limited.

It is important for physicians caring for patients with systemic sclerosis to be aware of its most common cardiac manifestations, including left and right ventricular systolic and diastolic dysfunction, pulmonary hypertension, conduction abnormalities, arrhythmias, and cardiomyopathy.

Look for volume overload

On clinical examination, assess for clinical markers of volume overload such as distended neck veins, peripheral edema, or an abnormal blood pressure response to the Valsalva maneuver. These findings should prompt measurement of NT-proBNP,⁸⁹ and may warrant prescription of a diuretic.

Electrocardiography to investigate arrhythmias

Electrocardiography should be done if patients describe symptoms of palpitations, and should also include continuous rhythm monitoring with Holter or event monitoring, depending on the frequency of symptoms. Otherwise, patients should routinely undergo electrocardiography once or twice a year.

Q waves are common in systemic sclerosis patients (especially those with diffuse cutaneous systemic sclerosis), notably in the precordial leads, and can occur without coronary artery disease.⁹⁰ Symptoms such as presyncope should be further investigated with Holter monitoring and tilt-table testing.

Assess, modify traditional risk factors

Subclinical atherosclerosis as detected by carotid intima-media thickness is as common in systemic sclerosis as in rheumatoid arthritis.⁶¹ However, traditional risk indices such as SCORE (Systematic Coronary Risk Evaluation), QRISK2, and the American College of Cardiology/American Heart Association indices may underestimate risk in patients who have systemic sclerosis.

Strict hypertension control should be the goal for all systemic sclerosis patients. Though there are no specific guidelines on which antihypertensive medications are preferred, calcium channel blockers or angiotensin II receptor blockers, which are typically used to treat systemic sclerosis-related Raynaud phenomenon, may be appropriate.

Statins reduce vascular complications and are generally well tolerated in patients with systemic sclerosis.^91,92 

Aspirin is not recommended for routine primary prevention in view of data suggesting that its benefits in diabetic patients are counterbalanced by increased bleeding risk.⁹³

Echocardiography to detect pulmonary arterial hypertension

At this time, guidelines for monitoring for cardiovascular manifestations in systemic sclerosis patients are limited. The only well-defined ones are European consensus guidelines, which suggest annual transthoracic echocardiography for the first 5 years after systemic sclerosis is diagnosed and continued annual screening in patients at risk of developing PAH.³¹

We support this strategy, with annual screening for the first 5 years followed by surveillance echocardiography every 2 to 3 years unless there is a high risk of PAH. Specific attention should be paid to right ventricular diastolic function, right atrial volume, and right ventricular myocardial performance index.

Emerging data suggest that the addition of global longitudinal strain of ventricles to  routine echocardiography can help detect subclinical cardiac risk.⁹⁴ Although further study is needed into the predictive value of global longitudinal strain, it is a low-cost and noninvasive addition to standard echocardiography that can help guide risk stratification, and thus we recommend that it be part of the echocardiographic examination for all systemic sclerosis patients.

Pulmonary function testing. In addition to screening for PAH with echocardiography, we recommend obtaining baseline pulmonary function tests, including D_^LCO, at the time systemic sclerosis is diagnosed, with repeat testing annually.

Magnetic resonance imaging

While echocardiography is the gold standard for monitoring systemic sclerosis patients, cardiovascular MRI may have a role in identifying those at higher risk of dangerous arrhythmias such as ventricular tachycardia and ventricular fibrillation. In addition to assessing ventricular function, MRI can detect myocardial inflammation, ischemia, and fibrosis that may predispose a patient to develop ventricular tachycardia or fibrillation.⁹⁵ Variables such as T1/T2 mapping, extracellular volume fraction, T2 signal ratio, and early vs late gadolinium enhancement can help identify patients who had past ventricular tachycardia or fibrillation.⁹⁶

Finding an increased risk of arrhythmias may prompt a conversation between the patient and the physician about the need for an implantable cardiac defibrillator.

If cardiac MRI is available and is reimbursed by the patient’s insurance carrier, physicians should strongly consider obtaining at least one baseline scan in systemic sclerosis patients to identify those at risk of highly fatal arrhythmias.

Teamwork is needed

Systemic sclerosis has not traditionally been associated with cardiovascular disease to the extent of other rheumatic conditions, but the cardiovascular system can be affected in various ways that can ultimately lead to an early death. These manifestations may be asymptomatic for long periods, and overt clinical disease portends a poorer prognosis.

Primary care physicians managing these patients should be aware of the cardiovascular complications of systemic sclerosis and should implement appropriate screening tests in conjunction with rheumatologists and cardiologists. It is also essential for general and subspecialty cardiologists to understand the broad spectrum of organ system involvement that can affect systemic sclerosis patients and to tailor their investigation and management recommendations accordingly. By designing a multidisciplinary approach to the treatment of systemic sclerosis patients, physicians can help to optimize cardiovascular risk modification in this vulnerable population.

Autoimmune rheumatic diseases increase the risk of cardiovascular disease. In rheumatoid arthritis and systemic lupus erythematosus, the risk is driven primarily by the inflammatory milieu, leading to accelerated coronary and cerebrovascular atherosclerosis independent of traditional atherosclerotic risk factors.^1–3 The extent of cardiovascular involvement in other rheumatologic diseases has been less well characterized but is an area of growing interest.

In this review, we focus on the cardiovascular complications of systemic sclerosis and review recommendations for monitoring these patients in clinical practice.

SYSTEMIC SCLEROSIS, AN AUTOIMMUNE RHEUMATIC DISEASE

Systemic sclerosis is an autoimmune rheumatic disease characterized by excessive extracellular matrix deposition leading to diffuse fibrosis, endothelial dysfunction, and microvascular injury. It is most common in North America, Southern Europe, and Australia,^4,5 and it affects women more than men in ratios ranging from 3:1 to 14:1.⁶ The mean age at diagnosis is around 50. 

The disease can affect the lungs (interstitial lung disease and pulmonary hypertension), the heart, the kidneys, and the gastrointestinal tract.

Systemic sclerosis has 2 main subtypes: limited cutaneous systemic sclerosis, formerly called CREST syndrome) and diffuse cutaneous systemic sclerosis. The limited cutaneous subtype is characterized by tightening of the skin of the distal extremities (below the elbows and knees) and face, while diffuse cutaneous systemic sclerosis can manifest as more extensive skin tightening also involving proximal extremities and the trunk. Both subtypes can have an effect on the cardiovascular system.

Some cardiovascular risk factors such as dyslipidemia, diabetes mellitus, and high body mass index are less common in patients with systemic sclerosis than in patients with rheumatoid arthritis, while the rates of arterial hypertension, smoking, chronic obstructive pulmonary disease, osteoporosis, and neoplasms are similar between the 2 groups.⁷

HEART INVOLVEMENT HAS SERIOUS CONSEQUENCES

Overt cardiac involvement in systemic sclerosis is associated with a mortality rate of up to 70% over 5 years,^8,9 and about one-fourth of deaths in patients with systemic sclerosis are from cardiac causes.^10,11 Studies in Europe^10,12 showed that many patients with systemic sclerosis have cardiac involvement detectable by magnetic resonance imaging even if they do not have clinical disease. Pulmonary arterial hypertension (PAH) is a complication of both subtypes of systemic sclerosis and portends a higher risk of death.⁸

Thus, it is critical for clinicians to understand the potential comorbid conditions associated with systemic sclerosis, particularly the cardiovascular ones, and to work closely with cardiologists to help optimize the evaluation and management.

MECHANISMS OF CARDIAC DISEASE IN SYSTEMIC SCLEROSIS

Abnormal vasoreactivity, a consequence of an imbalance between endothelium-derived vasoconstrictors and vasodilators, defective angiogenesis, and endothelial injury, leads to tissue ischemia and vascular endothelial growth factor expression, which initiates injury and fibrosis in the myocardium and in other organs.^14–17 Fibrosis involves the myocardium, pericardium, and conduction system.^13,18

Myocardial involvement in systemic sclerosis is thought to be due mainly to abnormal vasoreactivity and microvascular abnormalities such as transient coronary artery spasm leading to repeated focal ischemia.^19,20 Abnormal vasoreactivity has been demonstrated during cardiac catheterization²¹: while mean coronary sinus blood flow in systemic sclerosis patients was normal at rest, vasodilator reserve was significantly reduced in patients with diffuse cutaneous systemic sclerosis after maximal vasodilation with dipyridamole. Additionally, endomyocardial biopsy showed fibrosis and concentric intimal hypertrophy with normal epicardial coronary arteries.²¹

More research into other mechanisms of cardiovascular disease in systemic sclerosis is needed to allow for better preventive care for these patients.

Systemic sclerosis can be associated with World Health Organization (WHO) groups 1, 2, 3, and 4 pulmonary hypertension. WHO group 1, called pulmonary arterial hypertension or PAH, is one of the most common cardiac complications of systemic sclerosis, with a reported prevalence as high as 12%.²² Systemic sclerosis-associated PAH carries a high mortality rate, with a mean survival of only 3 years.²³

With advances in treatments for other complications of systemic sclerosis, the percentage of systemic sclerosis patients who die of PAH has increased from 6% to 33%.²⁴

Compared with patients with idiopathic PAH, those with systemic sclerosis get less of a response from therapy and have poorer outcomes despite lower mean pulmonary artery pressures and similar reductions in cardiac index. However, recent studies have suggested that with aggressive treatment, patients with systemic sclerosis-related PAH can achieve outcomes similar to those with idiopathic PAH.²⁵ Thus, recognizing this condition early is imperative.

Pulmonary arterial hypertension defined

PAH is defined as the combination of all of the following²⁶:

• Mean pulmonary artery pressure > 20 mm Hg at rest
• Normal pulmonary capillary wedge pressure (≤ 15 mm Hg)
• Pulmonary vascular resistance ≥ 3 Wood units on right heart catheterization.

Other causes of pulmonary hypertension such as interstitial lung disease, chronic pulmonary thromboembolic disease, and left heart disease must be excluded.^24,27

Remodeling in the pulmonary arteries

The events that lead to PAH in systemic sclerosis remain unclear but are believed to involve initial inflammation or endothelial injury that leads to a dysequilibrium between proliferative mediators and antiproliferative vasodilators. This dysequilibrium, along with endothelial dysfunction, causes an obliterative vasculopathy in the pulmonary artery branches and arterioles. Sympathetic overactivity, hypoxemia, and ischemia-reperfusion injury additionally promote vascular proliferation, fibrosis, and remodeling, leading to increased pulmonary vascular resistance, PAH, and increased right ventricular pressures.^23,27

The subtype of systemic sclerosis is an important factor in the development and progression of PAH. PAH appears to be the major cause of death in limited cutaneous systemic sclerosis, while interstitial lung disease is the major cause of death in diffuse cutaneous systemic sclerosis.²⁸

Pulmonary arterial hypertension is a late complication of systemic sclerosis

Data from the South Australian Scleroderma Registry²⁹ revealed that PAH tends to be a late complication of systemic sclerosis, occurring around 20 years after disease onset. In this study of 608 patients, no patient with diffuse cutaneous systemic sclerosis developed PAH.

Systemic sclerosis-related PAH initially follows an indolent course with few symptoms until right ventricular function deteriorates. Early in the disease, patients may experience nonspecific symptoms of fatigue, lightheadedness, and dyspnea on exertion.²³ As it progresses, they tend to have worsening dyspnea and may experience exertional syncope, palpitations, and chest pain.

Physical findings may suggest elevated right ventricular pressure and right ventricular failure; these include a loud P2, a prominent jugular a wave, a tricuspid regurgitant murmur, jugular venous distention, and lower-extremity edema.²⁷

Screening for pulmonary arterial hypertension in systemic sclerosis

Significant signs and symptoms usually occur late in the disease; thus, it is important to appropriately screen patients who are at risk so that they can begin aggressive treatment.

Doppler echocardiography is recommended by European and American guidelines to screen for PAH in patients who have systemic sclerosis, and most agree that screening is appropriate even if the patient has no symptoms.³⁰ European consensus documents recommend that transthoracic echocardiography be done annually for the first 5 years of disease and be continued every year in patients at high risk, ie, those with anticentromere antibodies, anti-Th/To antibodies, or interstitial lung disease. Patients not at high risk of developing pulmonary hypertension should also have regular transthoracic echocardiography, though the exact timing is not defined.³¹ While American societies have not issued corresponding recommendations, many experts follow the European recommendations.

Worrisome features on echocardiography in asymptomatic patients should be followed up with right heart catheterization to assess mean right ventricular pressure. These include:

• Estimated right ventricular systolic pressure ≥ 40 mm Hg
• Tricuspid regurgitant jet velocity > 2.8 m/s
• Right atrial enlargement > 53 mm
• Right ventricular enlargement (mid-cavity dimension > 35 mm).³²

Although echocardiography is the most common form of screening, it gives only an estimate of right ventricular systolic pressure, which is imprecise. Other noninvasive markers are helpful and necessary to appropriately screen this population.

Diffusion capacity. The Itinerair study³³ found that a diffusing capacity for carbon monoxide (D_^LCO) of 60% or higher has a high specificity in excluding PAH.

Uric acid has been found to be elevated in patients with systemic sclerosis-related PAH, and levels inversely correlate with 6-minute walking distance.³⁴

Other predictors. N-terminal pro-B-type natriuretic peptide (NT-proBNP), left atrial volume, and the right ventricular myocardial performance index have also been shown to be independent predictors of PAH in patients with systemic sclerosis.³⁵

An algorithm. The DETECT study³⁶ enrolled patients at increased risk who had had systemic sclerosis longer than 3 years and a D_^LCO less than 60%. The investigators developed a 2-step algorithm to determine which patients should be referred for right heart catheterization to try to detect PAH earlier while minimizing the number of missed diagnoses and optimizing the use of invasive diagnostic right heart catheterization.

The first step was to assess serum values of anticentromere antibodies, NT-proBNP, and urate, and clinical features (telangiectasias), forced vital capacity, and electrocardiographic changes of right axis deviation to derive a prediction score. The second step was to assess surface echocardiographic features of the right atrial area and tricuspid regurgitation velocity.

This approach led to right heart catheterization in 62% of patients and was associated with a false-negative rate of 4%. Importantly, of the patients with PAH, 1 in 5 had no symptoms, and 33% had tricuspid regurgitation velocity less than 2.8 m/s. No single measurement performed well in isolation in this study.³⁷

Thus, we recommend that, in addition to routine surface echocardiography, a multimodal approach be used that includes laboratory testing, clinical features, and electrocardiographic findings when screening this high-risk patient population.

Although macrovascular disease has not typically been regarded as a significant systemic feature in systemic sclerosis, myocardial infarction and stroke are more common in patients with systemic sclerosis than in controls.^38,39

Coronary artery disease in systemic sclerosis

Man et al³⁸ reported that the incidence of myocardial infarction in patients with systemic sclerosis was 4.4 per 1,000 persons per year, and the incidence of stroke was 4.8 per 1,000 persons per year, compared with 2.5 per 1,000 persons per year for both myocardial infarction and stroke in healthy controls matched for age, sex, and time of entry.

The Australian Scleroderma Cohort Study³⁹ found a 3-fold higher prevalence of coronary artery disease in systemic sclerosis patients than in controls after factoring in traditional risk factors.

Aviña-Zubieta et al,⁴⁰ in a cohort of 1,239 systemic sclerosis patients, estimated a hazard ratio (HR) of 3.49 for myocardial infarction and 2.35 for stroke compared with age- and sex-matched controls. Not all of these events were related to macrovascular atherosclerosis—vasospasm and microvascular ischemia may have played significant roles in the etiology of clinical manifestations.

Studies of coronary atherosclerosis in systemic sclerosis are limited. An autopsy study⁴¹ of 58 patients with systemic sclerosis and 58 controls matched for age, sex, and ethnicity found that the prevalence of atherosclerosis of small coronary arteries and arterioles was significantly higher in systemic sclerosis patients than in controls (17% vs 2%, P < .01). However, the prevalence of medium-vessel coronary atherosclerosis was similar (48% vs 43%).

Why patients with systemic sclerosis develop atherosclerosis has not yet been determined. Traditional risk factors such as hypertension, dyslipidemia, diabetes mellitus, and obesity are typically no more prevalent in systemic sclerosis patients than in controls,^38,42 and thus do not explain the increased risk of atherosclerotic cardiovascular disease. There is some evidence that novel markers of atherosclerotic risk such as homocysteine,⁴³ lipoprotein[a],⁴⁴ and oxidized low-density lipoprotein⁴⁵ are more prevalent in systemic sclerosis, but these results have not been substantiated in more extensive studies.

Peripheral artery disease

It remains unclear whether peripheral artery disease is more prevalent in systemic sclerosis patients than in controls.

Individual studies have shown mixed results in comparing carotid artery stenosis between systemic sclerosis patients and controls using carotid duplex ultrasonography,⁴⁶ the ankle-brachial index,^46–48 carotid intima-media thickness,^49–54 and brachial flow-mediated dilation.^{51,53,55–58} A meta-analysis found that the carotid intima and media are significantly thicker in systemic sclerosis patients than in controls,⁵⁹ and the magnitude of difference is similar to that in other groups at increased cardiovascular risk, such as those with rheumatoid arthritis, diabetes, and familial hypercholesterolemia.^60–63

A meta-analysis of brachial artery findings showed significantly lower flow-mediated dilation in systemic sclerosis patients than in controls.⁶⁴

Overall, given the inconsistency of study results, systemic sclerosis patients should be screened and managed as in other patients with peripheral artery disease, but the clinician should be aware that there may be a higher risk of peripheral artery disease in these patients.

RIGHT AND LEFT VENTRICULAR DYSFUNCTION

Many patients with systemic sclerosis have right ventricular dysfunction as a consequence of PAH.⁶⁵ It is important to detect diastolic dysfunction in this population, as it may be an even stronger predictor of death than pulmonary hypertension on right heart catheterization (HR 3.7 vs 2.0).⁶⁶

Fewer patients have left ventricular dysfunction. In a multicenter study of 570 systemic sclerosis patients, only 1.4% had left ventricular systolic dysfunction on echocardiography, though 22.6% had left ventricular hypertrophy and 17.7% had left ventricular diastolic dysfunction.⁶⁷ In the European League Against Rheumatism (EULAR) database, the prevalence of reduced left ventricular ejection fraction was 5.4%.⁶⁸

Though traditional echocardiographic screening suggests the prevalence of left ventricular dysfunction in systemic sclerosis patients is low, cardiac magnetic resonance imaging (MRI) may be more sensitive than echocardiography for detecting subclinical myocardial involvement. Cardiac MRI has been shown to detect evidence of myocardial pathology (increased T2 signal, left ventricular thinning, pericardial effusion, reduced left ventricular and right ventricular ejection fraction, left ventricular diastolic dysfunction, and delayed myocardial contrast enhancement) in up to 75% of systemic sclerosis cases studied.⁶⁹

Patients with systemic sclerosis should already be undergoing echocardiography every year to screen for PAH, and screening should also include tissue Doppler imaging to detect various forms of left and right ventricular systolic and diastolic dysfunction that may not be clinically apparent.

Though cardiac MRI can provide useful additional information, it is not currently recommended for routine screening in patients with systemic sclerosis.

Patients with systemic sclerosis are prone to arrhythmias due to both conduction system fibrosis and myocardial damage.

Arrhythmias accounted for 6% of the deaths in the EULAR Scleroderma Trials and Research (EUSTAR) database.¹¹

In the Genetics Versus Environment in Scleroderma Outcome Study (GENISOS),⁷⁰  250 patients who had had systemic sclerosis for at least 3 years were studied during a period of approximately 6 years, during which there were 52 deaths, 29 of which were directly attributable to systemic sclerosis. Multivariable Cox modeling showed that 7 variables predicted mortality:

• Body mass index < 18.5 kg/m²
• Age ≥ 65
• Forced vital capacity < 50% predicted
• Systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mm Hg
• Pulmonary fibrosis
• Positive anticentromere antibodies
• Cardiac arrhythmias.

The hazard ratio for death in patients with arrhythmias in this model was 2.18 (95% CI 1.05–4.50, P = .035). Thus, finding arrhythmias in systemic sclerosis patients can provide important prognostic information.

While resting electrocardiography in patients with systemic sclerosis  most commonly shows sinus rhythm, 24-hour electrocardiographic monitoring has revealed nonsustained supraventricular and ventricular arrhythmias in a significant percentage.^71,72 Although difficult to quantify in routine practice, parameters controlled by the autonomic nervous system including heart rate variability and heart rate turbulence have been shown to be impaired in systemic sclerosis, and these measures are associated with an increased risk of malignant arrhythmias and sudden cardiac death.^73,74

Conduction abnormalities

Conduction abnormalities occur in one-fifth to one-third of patients with systemic sclerosis.^75,76 The most common abnormal conduction finding is left bundle branch block, followed by first-degree atrioventricular block. High-degree atrioventricular block is uncommon,⁷⁶ though a few case reports of complete heart block thought to be related to systemic sclerosis have been published.^77–79 An autopsy study showed that the conduction system is relatively spared from myocardial changes seen in systemic sclerosis patients, and thus it is speculated that the conduction disturbances are a consequence of damaged myocardium rather than damage to conduction tissue.⁸⁰

Given the array of electrophysiologic abnormalities that systemic sclerosis patients can have, it is critical to monitor all patients with routine (annual or biannual) electrocardiography; to take possible arrhythmia-related symptoms seriously; and to evaluate them with further workup such as Holter monitoring for 24 hours or even longer, event monitoring, exercise testing, or tilt-table testing.

PERICARDIAL DISEASE

Pericardial disease is clinically apparent in 5% to 16% of patients with systemic sclerosis⁸¹; patients with limited cutaneous systemic sclerosis have more pericardial disease than those with diffuse cutaneous systemic sclerosis (30% vs 16%).⁸² Forty-one percent of systemic sclerosis patients have been shown to have pericardial effusion by echocardiography,⁸¹ but the effusions are typically small and rarely cause tamponade, though tamponade is associated with a poor prognosis.

Large pericardial effusions can develop before skin thickening and diagnosis of systemic sclerosis.^81,83,84 Thus, systemic sclerosis should be considered in patients with pericardial effusions of unknown etiology.

In a small study,⁸⁵ the pericardial fluid in systemic sclerosis was typically exudative, with lactate dehydrogenase greater than 200 U/L, a fluid-serum lactate dehydrogenase ratio greater than 0.6, and a fluid-serum total protein ratio greater than 0.5.

Pericardial effusion can be a sign of impending scleroderma renal crisis,⁸⁶ and thus renal function should be carefully monitored in systemic sclerosis patients with pericardial effusion. Constrictive pericarditis and restrictive cardiomyopathy can rarely occur in systemic sclerosis and may more commonly present with symptoms.

Pericardial disease in systemic sclerosis should be treated in a standard fashion with nonsteroidal anti-inflammatory drugs. Corticosteroids are generally of limited benefit and should be avoided, especially in the setting of scleroderma renal crisis.⁸¹

VALVULAR HEART DISEASE

Based on limited studies, the prevalence of significant valvular heart disease in systemic sclerosis patients does not seem to be higher than that in the general population. While patients with systemic sclerosis and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) have been shown to have a higher frequency of mitral valve prolapse and mild mitral regurgitation,^87,88 these abnormalities do not often progress in severity, and thus their clinical significance is limited.

It is important for physicians caring for patients with systemic sclerosis to be aware of its most common cardiac manifestations, including left and right ventricular systolic and diastolic dysfunction, pulmonary hypertension, conduction abnormalities, arrhythmias, and cardiomyopathy.

Look for volume overload

On clinical examination, assess for clinical markers of volume overload such as distended neck veins, peripheral edema, or an abnormal blood pressure response to the Valsalva maneuver. These findings should prompt measurement of NT-proBNP,⁸⁹ and may warrant prescription of a diuretic.

Electrocardiography to investigate arrhythmias

Electrocardiography should be done if patients describe symptoms of palpitations, and should also include continuous rhythm monitoring with Holter or event monitoring, depending on the frequency of symptoms. Otherwise, patients should routinely undergo electrocardiography once or twice a year.

Q waves are common in systemic sclerosis patients (especially those with diffuse cutaneous systemic sclerosis), notably in the precordial leads, and can occur without coronary artery disease.⁹⁰ Symptoms such as presyncope should be further investigated with Holter monitoring and tilt-table testing.

Assess, modify traditional risk factors

Subclinical atherosclerosis as detected by carotid intima-media thickness is as common in systemic sclerosis as in rheumatoid arthritis.⁶¹ However, traditional risk indices such as SCORE (Systematic Coronary Risk Evaluation), QRISK2, and the American College of Cardiology/American Heart Association indices may underestimate risk in patients who have systemic sclerosis.

Strict hypertension control should be the goal for all systemic sclerosis patients. Though there are no specific guidelines on which antihypertensive medications are preferred, calcium channel blockers or angiotensin II receptor blockers, which are typically used to treat systemic sclerosis-related Raynaud phenomenon, may be appropriate.

Statins reduce vascular complications and are generally well tolerated in patients with systemic sclerosis.^91,92 

Aspirin is not recommended for routine primary prevention in view of data suggesting that its benefits in diabetic patients are counterbalanced by increased bleeding risk.⁹³

Echocardiography to detect pulmonary arterial hypertension

At this time, guidelines for monitoring for cardiovascular manifestations in systemic sclerosis patients are limited. The only well-defined ones are European consensus guidelines, which suggest annual transthoracic echocardiography for the first 5 years after systemic sclerosis is diagnosed and continued annual screening in patients at risk of developing PAH.³¹

We support this strategy, with annual screening for the first 5 years followed by surveillance echocardiography every 2 to 3 years unless there is a high risk of PAH. Specific attention should be paid to right ventricular diastolic function, right atrial volume, and right ventricular myocardial performance index.

Emerging data suggest that the addition of global longitudinal strain of ventricles to  routine echocardiography can help detect subclinical cardiac risk.⁹⁴ Although further study is needed into the predictive value of global longitudinal strain, it is a low-cost and noninvasive addition to standard echocardiography that can help guide risk stratification, and thus we recommend that it be part of the echocardiographic examination for all systemic sclerosis patients.

Pulmonary function testing. In addition to screening for PAH with echocardiography, we recommend obtaining baseline pulmonary function tests, including D_^LCO, at the time systemic sclerosis is diagnosed, with repeat testing annually.

Magnetic resonance imaging

While echocardiography is the gold standard for monitoring systemic sclerosis patients, cardiovascular MRI may have a role in identifying those at higher risk of dangerous arrhythmias such as ventricular tachycardia and ventricular fibrillation. In addition to assessing ventricular function, MRI can detect myocardial inflammation, ischemia, and fibrosis that may predispose a patient to develop ventricular tachycardia or fibrillation.⁹⁵ Variables such as T1/T2 mapping, extracellular volume fraction, T2 signal ratio, and early vs late gadolinium enhancement can help identify patients who had past ventricular tachycardia or fibrillation.⁹⁶

Finding an increased risk of arrhythmias may prompt a conversation between the patient and the physician about the need for an implantable cardiac defibrillator.

If cardiac MRI is available and is reimbursed by the patient’s insurance carrier, physicians should strongly consider obtaining at least one baseline scan in systemic sclerosis patients to identify those at risk of highly fatal arrhythmias.

Teamwork is needed

Systemic sclerosis has not traditionally been associated with cardiovascular disease to the extent of other rheumatic conditions, but the cardiovascular system can be affected in various ways that can ultimately lead to an early death. These manifestations may be asymptomatic for long periods, and overt clinical disease portends a poorer prognosis.

Primary care physicians managing these patients should be aware of the cardiovascular complications of systemic sclerosis and should implement appropriate screening tests in conjunction with rheumatologists and cardiologists. It is also essential for general and subspecialty cardiologists to understand the broad spectrum of organ system involvement that can affect systemic sclerosis patients and to tailor their investigation and management recommendations accordingly. By designing a multidisciplinary approach to the treatment of systemic sclerosis patients, physicians can help to optimize cardiovascular risk modification in this vulnerable population.

We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.

The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.

Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.

Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.

Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.

We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.

Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.

An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.

A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.

When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.

I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.

We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.

The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.

Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.

Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.

Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.

We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.

Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.

An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.

A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.

When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.

I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.

We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.

The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.

Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.

Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.

Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.

We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.

Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.

An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.

A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.

When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.

I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.