Autoimmune Diseases

All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.

The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.

“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.

It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.

“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.

Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.

“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.

With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”

Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”

Recommendation highlights

Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.

“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.

Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.

“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.

There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
 

Separate cancer screening guidelines on cards

“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.

“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”

Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.

The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.

“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.

Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.

“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.

“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.

“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”

Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.

All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.

The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.

“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.

It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.

“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.

Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.

“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.

With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”

Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”

Recommendation highlights

Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.

“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.

Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.

“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.

There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
 

Separate cancer screening guidelines on cards

“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.

“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”

Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.

The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.

“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.

Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.

“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.

“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.

“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”

Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.

All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.

The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.

“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.

It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.

“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.

Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.

“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.

With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”

Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”

Recommendation highlights

Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.

“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.

Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.

“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.

There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
 

Separate cancer screening guidelines on cards

“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.

“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”

Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.

The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.

“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.

Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.

“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.

“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.

“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”

Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.

Women with systemic lupus erythematosus (SLE) experience worse outcomes after an acute stroke than does the general population, but men with SLE do not, according to an analysis of the U.S. National Inpatient Sample presented at the annual meeting of the British Society for Rheumatology.

In a study of more than 1.5 million cases of acute stroke recorded in the United States between 2015 and 2018, women with SLE were more likely to be hospitalized for longer and less likely to be routinely discharged into their home environment than were those without SLE. No such association was found for men with SLE.

“The findings imply that primary stroke prevention is of utmost importance, especially in females with SLE,” said Sona Jesenakova, a fourth-year medical student at the University of Aberdeen (Scotland).

“There might be a need to explore more effective and targeted treatment strategies to try and minimize these excessive adverse acute stroke outcomes, especially in females with SLE suffering from stroke,” she suggested.

“Even though males form only a minority of the SLE patient population, some studies have shown that they are prone to suffer from worse disease outcomes,” Ms. Jesenakova said.

Importantly, “male sex has been identified as a risk factor for death early in the course of SLE,” she added, highlighting that sex differences do seem to exist in SLE.

Stroke is an important outcome to look at because people with SLE are known to be at higher risk for developing atherosclerosis, which is a widely known risk factor for ischemic stroke, and with antiphospholipid antibody positivity and uncontrolled disease activity, that risk can be increased. A meta-analysis of older studies has suggested that the risk for death after a stroke is 68% higher in people with SLE than in those without.

To examine the risk for death and other in-hospital outcomes in a more contemporary population, Ms. Jesenakova and associates used data from the National Inpatient Sample, a large, publicly available database that contains inpatient health care information from across the United States. Their sample population consisted of 1,581,430 individuals who had been hospitalized for stroke. Of these, there were 6,100 women and 940 men who had SLE; the remainder served as the ‘no-SLE’ control population.

As might be expected, patients with SLE were about 10 years younger than those without SLE; the median age of women and men with SLE and those without SLE were a respective 60, 61, and 71 years.

There was no difference in the type of stroke between the SLE and no-SLE groups; most had an ischemic stroke (around 89%) rather than a hemorrhagic stroke (around 11%).

The researchers analyzed three key outcomes: mortality at discharge, hospitalization prolonged to a stay of more than 4 days, and routine home discharge, meaning that the patient was able to be discharged home versus more specialist facilities such as a nursing home.

They conducted a multivariate analysis with adjustments made for potential confounding factors such as age, ethnicity, type of stroke, and revascularization treatment. Comorbidities, including major cardiovascular disease, were also accounted for.

Although women with SLE were 21% more likely to die than patients without SLE, men with SLE were 24% less likely to die than was the no-SLE population. However, these differences were not statistically significant.

Women with SLE were 20% more likely to have a prolonged hospital stay and 28% less likely to have a routine home discharge, compared with patients who did not have SLE. The 95% confidence intervals were statistically significant, which was not seen when comparing the same outcomes in men with SLE (odds ratios of 1.06 and 1.18, respectively).

“As for males, even though we didn’t find anything of statistical significance, we have to bear in mind that the sample we had was quite small, and thus these results need to be interpreted with caution,” Ms. Jesenakova said. “We also think that we identified a gap in the current knowledge, and as such, further research is needed to help us understand the influence of male sex on acute stroke outcomes in patients with comorbid SLE.”

The researchers performed a secondary analysis looking at the use of revascularization treatments for ischemic stroke and found that there were no differences between individuals with and without SLE. This analysis considered the use of intravenous thrombolysis and endovascular thrombectomy in just over 1.4 million cases but did not look at sex-specific differences.

Ms. Jesenakova had no conflicts of interest to disclose.

Women with systemic lupus erythematosus (SLE) experience worse outcomes after an acute stroke than does the general population, but men with SLE do not, according to an analysis of the U.S. National Inpatient Sample presented at the annual meeting of the British Society for Rheumatology.

In a study of more than 1.5 million cases of acute stroke recorded in the United States between 2015 and 2018, women with SLE were more likely to be hospitalized for longer and less likely to be routinely discharged into their home environment than were those without SLE. No such association was found for men with SLE.

“The findings imply that primary stroke prevention is of utmost importance, especially in females with SLE,” said Sona Jesenakova, a fourth-year medical student at the University of Aberdeen (Scotland).

“There might be a need to explore more effective and targeted treatment strategies to try and minimize these excessive adverse acute stroke outcomes, especially in females with SLE suffering from stroke,” she suggested.

“Even though males form only a minority of the SLE patient population, some studies have shown that they are prone to suffer from worse disease outcomes,” Ms. Jesenakova said.

Importantly, “male sex has been identified as a risk factor for death early in the course of SLE,” she added, highlighting that sex differences do seem to exist in SLE.

Stroke is an important outcome to look at because people with SLE are known to be at higher risk for developing atherosclerosis, which is a widely known risk factor for ischemic stroke, and with antiphospholipid antibody positivity and uncontrolled disease activity, that risk can be increased. A meta-analysis of older studies has suggested that the risk for death after a stroke is 68% higher in people with SLE than in those without.

To examine the risk for death and other in-hospital outcomes in a more contemporary population, Ms. Jesenakova and associates used data from the National Inpatient Sample, a large, publicly available database that contains inpatient health care information from across the United States. Their sample population consisted of 1,581,430 individuals who had been hospitalized for stroke. Of these, there were 6,100 women and 940 men who had SLE; the remainder served as the ‘no-SLE’ control population.

As might be expected, patients with SLE were about 10 years younger than those without SLE; the median age of women and men with SLE and those without SLE were a respective 60, 61, and 71 years.

There was no difference in the type of stroke between the SLE and no-SLE groups; most had an ischemic stroke (around 89%) rather than a hemorrhagic stroke (around 11%).

The researchers analyzed three key outcomes: mortality at discharge, hospitalization prolonged to a stay of more than 4 days, and routine home discharge, meaning that the patient was able to be discharged home versus more specialist facilities such as a nursing home.

They conducted a multivariate analysis with adjustments made for potential confounding factors such as age, ethnicity, type of stroke, and revascularization treatment. Comorbidities, including major cardiovascular disease, were also accounted for.

Although women with SLE were 21% more likely to die than patients without SLE, men with SLE were 24% less likely to die than was the no-SLE population. However, these differences were not statistically significant.

Women with SLE were 20% more likely to have a prolonged hospital stay and 28% less likely to have a routine home discharge, compared with patients who did not have SLE. The 95% confidence intervals were statistically significant, which was not seen when comparing the same outcomes in men with SLE (odds ratios of 1.06 and 1.18, respectively).

“As for males, even though we didn’t find anything of statistical significance, we have to bear in mind that the sample we had was quite small, and thus these results need to be interpreted with caution,” Ms. Jesenakova said. “We also think that we identified a gap in the current knowledge, and as such, further research is needed to help us understand the influence of male sex on acute stroke outcomes in patients with comorbid SLE.”

The researchers performed a secondary analysis looking at the use of revascularization treatments for ischemic stroke and found that there were no differences between individuals with and without SLE. This analysis considered the use of intravenous thrombolysis and endovascular thrombectomy in just over 1.4 million cases but did not look at sex-specific differences.

Ms. Jesenakova had no conflicts of interest to disclose.

Women with systemic lupus erythematosus (SLE) experience worse outcomes after an acute stroke than does the general population, but men with SLE do not, according to an analysis of the U.S. National Inpatient Sample presented at the annual meeting of the British Society for Rheumatology.

In a study of more than 1.5 million cases of acute stroke recorded in the United States between 2015 and 2018, women with SLE were more likely to be hospitalized for longer and less likely to be routinely discharged into their home environment than were those without SLE. No such association was found for men with SLE.

“The findings imply that primary stroke prevention is of utmost importance, especially in females with SLE,” said Sona Jesenakova, a fourth-year medical student at the University of Aberdeen (Scotland).

“There might be a need to explore more effective and targeted treatment strategies to try and minimize these excessive adverse acute stroke outcomes, especially in females with SLE suffering from stroke,” she suggested.

“Even though males form only a minority of the SLE patient population, some studies have shown that they are prone to suffer from worse disease outcomes,” Ms. Jesenakova said.

Importantly, “male sex has been identified as a risk factor for death early in the course of SLE,” she added, highlighting that sex differences do seem to exist in SLE.

Stroke is an important outcome to look at because people with SLE are known to be at higher risk for developing atherosclerosis, which is a widely known risk factor for ischemic stroke, and with antiphospholipid antibody positivity and uncontrolled disease activity, that risk can be increased. A meta-analysis of older studies has suggested that the risk for death after a stroke is 68% higher in people with SLE than in those without.

To examine the risk for death and other in-hospital outcomes in a more contemporary population, Ms. Jesenakova and associates used data from the National Inpatient Sample, a large, publicly available database that contains inpatient health care information from across the United States. Their sample population consisted of 1,581,430 individuals who had been hospitalized for stroke. Of these, there were 6,100 women and 940 men who had SLE; the remainder served as the ‘no-SLE’ control population.

As might be expected, patients with SLE were about 10 years younger than those without SLE; the median age of women and men with SLE and those without SLE were a respective 60, 61, and 71 years.

There was no difference in the type of stroke between the SLE and no-SLE groups; most had an ischemic stroke (around 89%) rather than a hemorrhagic stroke (around 11%).

The researchers analyzed three key outcomes: mortality at discharge, hospitalization prolonged to a stay of more than 4 days, and routine home discharge, meaning that the patient was able to be discharged home versus more specialist facilities such as a nursing home.

They conducted a multivariate analysis with adjustments made for potential confounding factors such as age, ethnicity, type of stroke, and revascularization treatment. Comorbidities, including major cardiovascular disease, were also accounted for.

Although women with SLE were 21% more likely to die than patients without SLE, men with SLE were 24% less likely to die than was the no-SLE population. However, these differences were not statistically significant.

Women with SLE were 20% more likely to have a prolonged hospital stay and 28% less likely to have a routine home discharge, compared with patients who did not have SLE. The 95% confidence intervals were statistically significant, which was not seen when comparing the same outcomes in men with SLE (odds ratios of 1.06 and 1.18, respectively).

“As for males, even though we didn’t find anything of statistical significance, we have to bear in mind that the sample we had was quite small, and thus these results need to be interpreted with caution,” Ms. Jesenakova said. “We also think that we identified a gap in the current knowledge, and as such, further research is needed to help us understand the influence of male sex on acute stroke outcomes in patients with comorbid SLE.”

The researchers performed a secondary analysis looking at the use of revascularization treatments for ischemic stroke and found that there were no differences between individuals with and without SLE. This analysis considered the use of intravenous thrombolysis and endovascular thrombectomy in just over 1.4 million cases but did not look at sex-specific differences.

Ms. Jesenakova had no conflicts of interest to disclose.

The Diagnosis: Acquired Lymphangioma Circumscriptum

A skin biopsy of the plaque on the right labium majus showed a proliferation of well-formed, dilated lymphatic vessels lined by benign-appearing endothelial cells in the papillary dermis (Figure). These findings were consistent with a diagnosis of acquired lymphangioma circumscriptum (ALC) in the setting of severe hidradenitis suppurativa (HS).

Image courtesy of Alicia Schnebelen, MD (Dallas, Texas).

Acquired lymphangioma circumscriptum (also known as acquired lymphangiectasia or secondary lymphangioma¹) is a rare skin finding resulting from chronic lymphatic obstruction that leads to dilated lymphatic vessels within the dermis.^2,3 There also is a distinct congenital form of lymphangioma circumscriptum caused by lymphatic malformations present at birth.^2,4 Acquired lymphangioma circumscriptum of the vulva is a rare phenomenon.³ Identified causes include radiation or surgery for carcinoma, solid gynecologic tumors, lymphadenectomy, Crohn disease, and tuberculosis and other infections, all of which can disrupt normal lymphatics to cause ALC.^2-4 Hidradenitis suppurativa is not a widely recognized cause of ALC; however, this phenomenon is reported in the literature. A long-standing history of severe HS complicated by lymphedema seems to precede the development of ALC in the reported cases, as in our patient.^5-7

Acquired lymphangioma circumscriptum of the vulva can appear in women of all ages as frog spawn or cobblestone papules or vesicles, sometimes with a hyperkeratotic or verrucous appearance.^2,4 Associated symptoms include serous drainage, edema, pruritus, and discomfort. The lesions may become eroded, which can predispose patients to secondary infections.^1,2 Acquired lymphangioma circumscriptum of the vulva can be difficult to diagnose, as the time interval between the initial cause and the appearance of skin findings can be years, leading to the misdiagnosis of ALC as other similar-appearing genital skin conditions such as squamous cell carcinoma or condyloma.^4,8 When misidentified as an infection, diagnosis can lead to substantial distress, abstinence from sexual activity, and unnecessary and painful treatments.

Skin biopsy is helpful in distinguishing ALC from other differential diagnoses such as condylomata acuminata, squamous cell carcinoma, and condyloma lata. Histopathology in ALC is notable for dilated lymphatic vessels filled with hypocellular fluid and lined with endothelial cells in the superficial dermis; the epidermis can appear hyperplastic, hyperkeratotic, or eroded.^3-5,9 These lymphatic vessels stain positively for CD31 and D2-40, markers for endothelial cells and lymphatic endothelium, respectively, and negative for CD34, a marker for vascular endothelium.^3,4,9 Features suggestive of condylomata acuminata such as rounded parakeratosis, hypergranulosis, and vacuolated keratinocytes⁹ are not present. The giant condyloma of Buschke-Löwenstein, a clinical variant of verrucous squamous cell carcinoma, also can present as a warty ulcerated papule or plaque in the genital region, but the characteristic rounded eosinophilic keratinocytes pushing down into the dermis⁹ are not seen in ALC. Secondary syphilis is associated with condyloma lata, which are verrucous or fleshy-appearing papules often coalescing into plaques located in the anogenital region. Pathologic features of secondary syphilis include vacuolar interface dermatitis and acanthosis with long slender rete ridges.⁹ Squamous cell carcinoma, which can arise from inflammation associated with long-standing HS, must be ruled out, as it is associated with a high risk of mortality in patients with HS.¹⁰

It is noteworthy to recognize the various, often confusing nomenclature used to describe cutaneous lymphatic conditions. The terms acquired lymphangioma circumscriptum, secondary lymphangioma, and lymphangiectasia are used interchangeably to describe dilated lymphatic vessels in the skin.¹ The term atypical vascular lesion refers to lymphectasias of the skin of the breast due to prior radiation therapy most often used in the treatment of breast carcinoma; clinically, these present as red-brown or flesh-colored papules or telangiectatic plaques on the breast.^11,12 Lymphedema also may occur alongside atypical vascular lesions, as prior radiation or surgical lymph node dissection can predispose patients to impaired lymphatic drainage.¹³ The lymphatic histopathologic subtype of atypical vascular lesions may appear similar to ALC; however, the vascular subtype will demonstrate collections of capillary-sized vessels and extravasated erythrocytes.^11,12 Unlike ALC, the benign nature of atypical vascular lesions has been questioned, as they may be associated with a small risk for progression to angiosarcoma.^11-13 It also is important to distinguish ALC from lymphangiomatosis, a generalized lymphatic anomaly that is characterized by extensive lymphatic malformations involving numerous internal organs, including the lungs and gastrointestinal tract. This condition is associated with notable morbidity and mortality.¹³

Although the suffix of the term lymphangioma suggests a neoplastic process, ALC is not a neoplasm and can be managed expectantly in many cases.^2,3,8 However, due to cosmetic appearance, pain, discomfort, and recurrent bacterial superinfections, many patients pursue treatment. Treatment options for ALC include sclerotherapy, electrocautery, radiofrequency or carbon dioxide laser ablation, and excision, though recurrence can arise.^3-5,7,8 Our patient elected to manage her asymptomatic ALC expectantly.

The Diagnosis: Acquired Lymphangioma Circumscriptum

A skin biopsy of the plaque on the right labium majus showed a proliferation of well-formed, dilated lymphatic vessels lined by benign-appearing endothelial cells in the papillary dermis (Figure). These findings were consistent with a diagnosis of acquired lymphangioma circumscriptum (ALC) in the setting of severe hidradenitis suppurativa (HS).

Image courtesy of Alicia Schnebelen, MD (Dallas, Texas).

Acquired lymphangioma circumscriptum (also known as acquired lymphangiectasia or secondary lymphangioma¹) is a rare skin finding resulting from chronic lymphatic obstruction that leads to dilated lymphatic vessels within the dermis.^2,3 There also is a distinct congenital form of lymphangioma circumscriptum caused by lymphatic malformations present at birth.^2,4 Acquired lymphangioma circumscriptum of the vulva is a rare phenomenon.³ Identified causes include radiation or surgery for carcinoma, solid gynecologic tumors, lymphadenectomy, Crohn disease, and tuberculosis and other infections, all of which can disrupt normal lymphatics to cause ALC.^2-4 Hidradenitis suppurativa is not a widely recognized cause of ALC; however, this phenomenon is reported in the literature. A long-standing history of severe HS complicated by lymphedema seems to precede the development of ALC in the reported cases, as in our patient.^5-7

Acquired lymphangioma circumscriptum of the vulva can appear in women of all ages as frog spawn or cobblestone papules or vesicles, sometimes with a hyperkeratotic or verrucous appearance.^2,4 Associated symptoms include serous drainage, edema, pruritus, and discomfort. The lesions may become eroded, which can predispose patients to secondary infections.^1,2 Acquired lymphangioma circumscriptum of the vulva can be difficult to diagnose, as the time interval between the initial cause and the appearance of skin findings can be years, leading to the misdiagnosis of ALC as other similar-appearing genital skin conditions such as squamous cell carcinoma or condyloma.^4,8 When misidentified as an infection, diagnosis can lead to substantial distress, abstinence from sexual activity, and unnecessary and painful treatments.

Skin biopsy is helpful in distinguishing ALC from other differential diagnoses such as condylomata acuminata, squamous cell carcinoma, and condyloma lata. Histopathology in ALC is notable for dilated lymphatic vessels filled with hypocellular fluid and lined with endothelial cells in the superficial dermis; the epidermis can appear hyperplastic, hyperkeratotic, or eroded.^3-5,9 These lymphatic vessels stain positively for CD31 and D2-40, markers for endothelial cells and lymphatic endothelium, respectively, and negative for CD34, a marker for vascular endothelium.^3,4,9 Features suggestive of condylomata acuminata such as rounded parakeratosis, hypergranulosis, and vacuolated keratinocytes⁹ are not present. The giant condyloma of Buschke-Löwenstein, a clinical variant of verrucous squamous cell carcinoma, also can present as a warty ulcerated papule or plaque in the genital region, but the characteristic rounded eosinophilic keratinocytes pushing down into the dermis⁹ are not seen in ALC. Secondary syphilis is associated with condyloma lata, which are verrucous or fleshy-appearing papules often coalescing into plaques located in the anogenital region. Pathologic features of secondary syphilis include vacuolar interface dermatitis and acanthosis with long slender rete ridges.⁹ Squamous cell carcinoma, which can arise from inflammation associated with long-standing HS, must be ruled out, as it is associated with a high risk of mortality in patients with HS.¹⁰

It is noteworthy to recognize the various, often confusing nomenclature used to describe cutaneous lymphatic conditions. The terms acquired lymphangioma circumscriptum, secondary lymphangioma, and lymphangiectasia are used interchangeably to describe dilated lymphatic vessels in the skin.¹ The term atypical vascular lesion refers to lymphectasias of the skin of the breast due to prior radiation therapy most often used in the treatment of breast carcinoma; clinically, these present as red-brown or flesh-colored papules or telangiectatic plaques on the breast.^11,12 Lymphedema also may occur alongside atypical vascular lesions, as prior radiation or surgical lymph node dissection can predispose patients to impaired lymphatic drainage.¹³ The lymphatic histopathologic subtype of atypical vascular lesions may appear similar to ALC; however, the vascular subtype will demonstrate collections of capillary-sized vessels and extravasated erythrocytes.^11,12 Unlike ALC, the benign nature of atypical vascular lesions has been questioned, as they may be associated with a small risk for progression to angiosarcoma.^11-13 It also is important to distinguish ALC from lymphangiomatosis, a generalized lymphatic anomaly that is characterized by extensive lymphatic malformations involving numerous internal organs, including the lungs and gastrointestinal tract. This condition is associated with notable morbidity and mortality.¹³

Although the suffix of the term lymphangioma suggests a neoplastic process, ALC is not a neoplasm and can be managed expectantly in many cases.^2,3,8 However, due to cosmetic appearance, pain, discomfort, and recurrent bacterial superinfections, many patients pursue treatment. Treatment options for ALC include sclerotherapy, electrocautery, radiofrequency or carbon dioxide laser ablation, and excision, though recurrence can arise.^3-5,7,8 Our patient elected to manage her asymptomatic ALC expectantly.

The Diagnosis: Acquired Lymphangioma Circumscriptum

A skin biopsy of the plaque on the right labium majus showed a proliferation of well-formed, dilated lymphatic vessels lined by benign-appearing endothelial cells in the papillary dermis (Figure). These findings were consistent with a diagnosis of acquired lymphangioma circumscriptum (ALC) in the setting of severe hidradenitis suppurativa (HS).

Image courtesy of Alicia Schnebelen, MD (Dallas, Texas).

Acquired lymphangioma circumscriptum (also known as acquired lymphangiectasia or secondary lymphangioma¹) is a rare skin finding resulting from chronic lymphatic obstruction that leads to dilated lymphatic vessels within the dermis.^2,3 There also is a distinct congenital form of lymphangioma circumscriptum caused by lymphatic malformations present at birth.^2,4 Acquired lymphangioma circumscriptum of the vulva is a rare phenomenon.³ Identified causes include radiation or surgery for carcinoma, solid gynecologic tumors, lymphadenectomy, Crohn disease, and tuberculosis and other infections, all of which can disrupt normal lymphatics to cause ALC.^2-4 Hidradenitis suppurativa is not a widely recognized cause of ALC; however, this phenomenon is reported in the literature. A long-standing history of severe HS complicated by lymphedema seems to precede the development of ALC in the reported cases, as in our patient.^5-7

Acquired lymphangioma circumscriptum of the vulva can appear in women of all ages as frog spawn or cobblestone papules or vesicles, sometimes with a hyperkeratotic or verrucous appearance.^2,4 Associated symptoms include serous drainage, edema, pruritus, and discomfort. The lesions may become eroded, which can predispose patients to secondary infections.^1,2 Acquired lymphangioma circumscriptum of the vulva can be difficult to diagnose, as the time interval between the initial cause and the appearance of skin findings can be years, leading to the misdiagnosis of ALC as other similar-appearing genital skin conditions such as squamous cell carcinoma or condyloma.^4,8 When misidentified as an infection, diagnosis can lead to substantial distress, abstinence from sexual activity, and unnecessary and painful treatments.

Skin biopsy is helpful in distinguishing ALC from other differential diagnoses such as condylomata acuminata, squamous cell carcinoma, and condyloma lata. Histopathology in ALC is notable for dilated lymphatic vessels filled with hypocellular fluid and lined with endothelial cells in the superficial dermis; the epidermis can appear hyperplastic, hyperkeratotic, or eroded.^3-5,9 These lymphatic vessels stain positively for CD31 and D2-40, markers for endothelial cells and lymphatic endothelium, respectively, and negative for CD34, a marker for vascular endothelium.^3,4,9 Features suggestive of condylomata acuminata such as rounded parakeratosis, hypergranulosis, and vacuolated keratinocytes⁹ are not present. The giant condyloma of Buschke-Löwenstein, a clinical variant of verrucous squamous cell carcinoma, also can present as a warty ulcerated papule or plaque in the genital region, but the characteristic rounded eosinophilic keratinocytes pushing down into the dermis⁹ are not seen in ALC. Secondary syphilis is associated with condyloma lata, which are verrucous or fleshy-appearing papules often coalescing into plaques located in the anogenital region. Pathologic features of secondary syphilis include vacuolar interface dermatitis and acanthosis with long slender rete ridges.⁹ Squamous cell carcinoma, which can arise from inflammation associated with long-standing HS, must be ruled out, as it is associated with a high risk of mortality in patients with HS.¹⁰

It is noteworthy to recognize the various, often confusing nomenclature used to describe cutaneous lymphatic conditions. The terms acquired lymphangioma circumscriptum, secondary lymphangioma, and lymphangiectasia are used interchangeably to describe dilated lymphatic vessels in the skin.¹ The term atypical vascular lesion refers to lymphectasias of the skin of the breast due to prior radiation therapy most often used in the treatment of breast carcinoma; clinically, these present as red-brown or flesh-colored papules or telangiectatic plaques on the breast.^11,12 Lymphedema also may occur alongside atypical vascular lesions, as prior radiation or surgical lymph node dissection can predispose patients to impaired lymphatic drainage.¹³ The lymphatic histopathologic subtype of atypical vascular lesions may appear similar to ALC; however, the vascular subtype will demonstrate collections of capillary-sized vessels and extravasated erythrocytes.^11,12 Unlike ALC, the benign nature of atypical vascular lesions has been questioned, as they may be associated with a small risk for progression to angiosarcoma.^11-13 It also is important to distinguish ALC from lymphangiomatosis, a generalized lymphatic anomaly that is characterized by extensive lymphatic malformations involving numerous internal organs, including the lungs and gastrointestinal tract. This condition is associated with notable morbidity and mortality.¹³

Although the suffix of the term lymphangioma suggests a neoplastic process, ALC is not a neoplasm and can be managed expectantly in many cases.^2,3,8 However, due to cosmetic appearance, pain, discomfort, and recurrent bacterial superinfections, many patients pursue treatment. Treatment options for ALC include sclerotherapy, electrocautery, radiofrequency or carbon dioxide laser ablation, and excision, though recurrence can arise.^3-5,7,8 Our patient elected to manage her asymptomatic ALC expectantly.

BOSTON – Following infection with SARS-CoV-2 infection, patients between the ages of 18 and 65 were at a significantly increased for developing certain cutaneous autoimmune and vascular diseases. This predominately favored systemic disease states with cutaneous involvement, rather than skin-limited processes.

The findings come from a large multicenter analysis that Zachary Holcomb, MD, presented during a late-breaking abstract session at the annual meeting of the American Academy of Dermatology.

Doug Brunk, MDedge News

“Viral triggers have been implicated in the pathogenesis of rheumatologic disease, but information regarding development of autoimmune disease following SARS-CoV-2 infection is limited,” said Dr. Holcomb, chief resident in the Harvard Combined Internal Medicine–Dermatology Residency, Boston. “Given its proposed thromboinflammatory pathobiology, we hypothesized that SARS-CoV-2 infection increases the risk of development of autoimmune disease with cutaneous manifestations and sought to define incidence rates of newly-diagnosed autoimmune diseases following SARS-CoV-2 infection.”

The researchers drew from the TriNetX Dataworks platform, an online cloud-based system that contains aggregated and deidentified patient information from about 75 million patients across 48 health care organizations. The infected cohort was defined as having a positive lab test for severe SARS-CoV-2 within the study window using Logical Observation Identifiers Names and Codes (LOINCs). Healthy controls consisted of a documented health care contact (inpatient or outpatient visit) during the study window without a positive SARS-CoV-2 lab test. Each cohort included patients aged 18-65 at the time of the study, and patients with previously diagnosed cutaneous autoimmune or vascular diseases were excluded from the analysis.

After propensity matching, the COVID-19 infected cohort and the healthy cohort included 1,904,864 patients each, with no baseline differences in age at index event, ethnicity, race, or sex. The study window was between April 1, 2020, and Oct. 1, 2020. The index event was a COVID-19 infection for the infected group and first documented health care contact in the healthy control group. The researchers looked at a window of 60 days following this index event for new incidence of cutaneous or vascular disease.

In the realm of connective tissue and related diseases, they found the incidence was increased among the COVID-19 infected group compared with controls for dermatomyositis (risk ratio, 2.273; P = .0196), scleroderma (RR, 1.959; P = .0001), and systemic lupus erythematosus (RR, 1.401; P < .0001). They also noted a significant decrease in the new incidence of alopecia areata in the COVID-19 infected group compared with controls (RR, 0.527; P < .0001).

No significant differences in the incidence of bullous and papulosquamous diseases were observed between the two groups. However, sarcoidosis was significantly more common in the COVID-19–infected group compared with controls (RR, 2.086; P < .001). “When taking all of these autoinflammatory diseases as a whole, there was an increased incidence in the COVID-19 infected group overall with a RR of 1.168 (P < .0001),” Dr. Holcomb said.

In the realm of vascular skin diseases, there was an increased incidence in the COVID-19 infected group in acrocyanosis (RR, 2.825; P < .001), Raynaud’s phenomenon (RR, 1.462; P < .0001), cutaneous small vessel vasculitis (RR, 1.714; P < .0001), granulomatosis with polyangiitis (RR, 2.667; P = .0002), and temporal arteritis (RR, 1.900; P = .0038).

“Interestingly, despite the academic and lay press reports of COVID toes, we did not see that in our data related to the COVID-infected group,” he said.

Dr. Holcomb acknowledged certain limitations of the study, including a narrow study window with a relatively short follow-up. “We were able to propensity match based on baseline demographics but not necessarily so based on health status and prior autoimmune disease,” he said. In addition, since the study was limited to those aged 18-65, the results may not be generalizable to pediatric and elderly patients, he said.

He described the study findings as “somewhat hypothesis-generating.” For instance, “why would we have more of a systemic process [at play?]. Our theory is that the severe inflammatory nature of COVID-19 leads to a lot of internal organ damage and exposure of autoantigens in that process, with relative skin sparing.”

One of the session moderators, Robert Paul Dellavalle, MD, PhD, professor of dermatology at the University of Colorado, Aurora, characterized the findings as “intriguing” but preliminary. “It would be interesting to look at more recent cohorts and see how vaccination for COVID-19 would impact the incidence rates of some of these diseases,” he said.

When asked for comment, Jeffrey A. Sparks, MD, MMSc, a rheumatologist at Brigham and Women's Hospital and assistant professor of medicine at Harvard Medical School, both in Boston, said, "This is an interesting study that should be followed up. Viral triggers have been known to precede autoimmune diseases so it will be very important to understand whether COVID-19 also impacts systemic autoimmune rheumatic diseases. I would be interested in differences in surveillance between the infection and control groups early in the pandemic. Many patients were avoiding interaction with the health care system at that point." 

Dr. Holcomb reported having no financial disclosures. Dr. Dellavalle disclosed that he is a consultant for Altus Labs and ParaPRO LLC. He has received grants and research funding from Pfizer.

* This story was updated on 3/29/22.

BOSTON – Following infection with SARS-CoV-2 infection, patients between the ages of 18 and 65 were at a significantly increased for developing certain cutaneous autoimmune and vascular diseases. This predominately favored systemic disease states with cutaneous involvement, rather than skin-limited processes.

The findings come from a large multicenter analysis that Zachary Holcomb, MD, presented during a late-breaking abstract session at the annual meeting of the American Academy of Dermatology.

Doug Brunk, MDedge News

“Viral triggers have been implicated in the pathogenesis of rheumatologic disease, but information regarding development of autoimmune disease following SARS-CoV-2 infection is limited,” said Dr. Holcomb, chief resident in the Harvard Combined Internal Medicine–Dermatology Residency, Boston. “Given its proposed thromboinflammatory pathobiology, we hypothesized that SARS-CoV-2 infection increases the risk of development of autoimmune disease with cutaneous manifestations and sought to define incidence rates of newly-diagnosed autoimmune diseases following SARS-CoV-2 infection.”

The researchers drew from the TriNetX Dataworks platform, an online cloud-based system that contains aggregated and deidentified patient information from about 75 million patients across 48 health care organizations. The infected cohort was defined as having a positive lab test for severe SARS-CoV-2 within the study window using Logical Observation Identifiers Names and Codes (LOINCs). Healthy controls consisted of a documented health care contact (inpatient or outpatient visit) during the study window without a positive SARS-CoV-2 lab test. Each cohort included patients aged 18-65 at the time of the study, and patients with previously diagnosed cutaneous autoimmune or vascular diseases were excluded from the analysis.

After propensity matching, the COVID-19 infected cohort and the healthy cohort included 1,904,864 patients each, with no baseline differences in age at index event, ethnicity, race, or sex. The study window was between April 1, 2020, and Oct. 1, 2020. The index event was a COVID-19 infection for the infected group and first documented health care contact in the healthy control group. The researchers looked at a window of 60 days following this index event for new incidence of cutaneous or vascular disease.

In the realm of connective tissue and related diseases, they found the incidence was increased among the COVID-19 infected group compared with controls for dermatomyositis (risk ratio, 2.273; P = .0196), scleroderma (RR, 1.959; P = .0001), and systemic lupus erythematosus (RR, 1.401; P < .0001). They also noted a significant decrease in the new incidence of alopecia areata in the COVID-19 infected group compared with controls (RR, 0.527; P < .0001).

No significant differences in the incidence of bullous and papulosquamous diseases were observed between the two groups. However, sarcoidosis was significantly more common in the COVID-19–infected group compared with controls (RR, 2.086; P < .001). “When taking all of these autoinflammatory diseases as a whole, there was an increased incidence in the COVID-19 infected group overall with a RR of 1.168 (P < .0001),” Dr. Holcomb said.

In the realm of vascular skin diseases, there was an increased incidence in the COVID-19 infected group in acrocyanosis (RR, 2.825; P < .001), Raynaud’s phenomenon (RR, 1.462; P < .0001), cutaneous small vessel vasculitis (RR, 1.714; P < .0001), granulomatosis with polyangiitis (RR, 2.667; P = .0002), and temporal arteritis (RR, 1.900; P = .0038).

“Interestingly, despite the academic and lay press reports of COVID toes, we did not see that in our data related to the COVID-infected group,” he said.

Dr. Holcomb acknowledged certain limitations of the study, including a narrow study window with a relatively short follow-up. “We were able to propensity match based on baseline demographics but not necessarily so based on health status and prior autoimmune disease,” he said. In addition, since the study was limited to those aged 18-65, the results may not be generalizable to pediatric and elderly patients, he said.

He described the study findings as “somewhat hypothesis-generating.” For instance, “why would we have more of a systemic process [at play?]. Our theory is that the severe inflammatory nature of COVID-19 leads to a lot of internal organ damage and exposure of autoantigens in that process, with relative skin sparing.”

One of the session moderators, Robert Paul Dellavalle, MD, PhD, professor of dermatology at the University of Colorado, Aurora, characterized the findings as “intriguing” but preliminary. “It would be interesting to look at more recent cohorts and see how vaccination for COVID-19 would impact the incidence rates of some of these diseases,” he said.

When asked for comment, Jeffrey A. Sparks, MD, MMSc, a rheumatologist at Brigham and Women's Hospital and assistant professor of medicine at Harvard Medical School, both in Boston, said, "This is an interesting study that should be followed up. Viral triggers have been known to precede autoimmune diseases so it will be very important to understand whether COVID-19 also impacts systemic autoimmune rheumatic diseases. I would be interested in differences in surveillance between the infection and control groups early in the pandemic. Many patients were avoiding interaction with the health care system at that point." 

Dr. Holcomb reported having no financial disclosures. Dr. Dellavalle disclosed that he is a consultant for Altus Labs and ParaPRO LLC. He has received grants and research funding from Pfizer.

* This story was updated on 3/29/22.

BOSTON – Following infection with SARS-CoV-2 infection, patients between the ages of 18 and 65 were at a significantly increased for developing certain cutaneous autoimmune and vascular diseases. This predominately favored systemic disease states with cutaneous involvement, rather than skin-limited processes.

The findings come from a large multicenter analysis that Zachary Holcomb, MD, presented during a late-breaking abstract session at the annual meeting of the American Academy of Dermatology.

Doug Brunk, MDedge News

“Viral triggers have been implicated in the pathogenesis of rheumatologic disease, but information regarding development of autoimmune disease following SARS-CoV-2 infection is limited,” said Dr. Holcomb, chief resident in the Harvard Combined Internal Medicine–Dermatology Residency, Boston. “Given its proposed thromboinflammatory pathobiology, we hypothesized that SARS-CoV-2 infection increases the risk of development of autoimmune disease with cutaneous manifestations and sought to define incidence rates of newly-diagnosed autoimmune diseases following SARS-CoV-2 infection.”

The researchers drew from the TriNetX Dataworks platform, an online cloud-based system that contains aggregated and deidentified patient information from about 75 million patients across 48 health care organizations. The infected cohort was defined as having a positive lab test for severe SARS-CoV-2 within the study window using Logical Observation Identifiers Names and Codes (LOINCs). Healthy controls consisted of a documented health care contact (inpatient or outpatient visit) during the study window without a positive SARS-CoV-2 lab test. Each cohort included patients aged 18-65 at the time of the study, and patients with previously diagnosed cutaneous autoimmune or vascular diseases were excluded from the analysis.

After propensity matching, the COVID-19 infected cohort and the healthy cohort included 1,904,864 patients each, with no baseline differences in age at index event, ethnicity, race, or sex. The study window was between April 1, 2020, and Oct. 1, 2020. The index event was a COVID-19 infection for the infected group and first documented health care contact in the healthy control group. The researchers looked at a window of 60 days following this index event for new incidence of cutaneous or vascular disease.

In the realm of connective tissue and related diseases, they found the incidence was increased among the COVID-19 infected group compared with controls for dermatomyositis (risk ratio, 2.273; P = .0196), scleroderma (RR, 1.959; P = .0001), and systemic lupus erythematosus (RR, 1.401; P < .0001). They also noted a significant decrease in the new incidence of alopecia areata in the COVID-19 infected group compared with controls (RR, 0.527; P < .0001).

No significant differences in the incidence of bullous and papulosquamous diseases were observed between the two groups. However, sarcoidosis was significantly more common in the COVID-19–infected group compared with controls (RR, 2.086; P < .001). “When taking all of these autoinflammatory diseases as a whole, there was an increased incidence in the COVID-19 infected group overall with a RR of 1.168 (P < .0001),” Dr. Holcomb said.

In the realm of vascular skin diseases, there was an increased incidence in the COVID-19 infected group in acrocyanosis (RR, 2.825; P < .001), Raynaud’s phenomenon (RR, 1.462; P < .0001), cutaneous small vessel vasculitis (RR, 1.714; P < .0001), granulomatosis with polyangiitis (RR, 2.667; P = .0002), and temporal arteritis (RR, 1.900; P = .0038).

“Interestingly, despite the academic and lay press reports of COVID toes, we did not see that in our data related to the COVID-infected group,” he said.

Dr. Holcomb acknowledged certain limitations of the study, including a narrow study window with a relatively short follow-up. “We were able to propensity match based on baseline demographics but not necessarily so based on health status and prior autoimmune disease,” he said. In addition, since the study was limited to those aged 18-65, the results may not be generalizable to pediatric and elderly patients, he said.

He described the study findings as “somewhat hypothesis-generating.” For instance, “why would we have more of a systemic process [at play?]. Our theory is that the severe inflammatory nature of COVID-19 leads to a lot of internal organ damage and exposure of autoantigens in that process, with relative skin sparing.”

One of the session moderators, Robert Paul Dellavalle, MD, PhD, professor of dermatology at the University of Colorado, Aurora, characterized the findings as “intriguing” but preliminary. “It would be interesting to look at more recent cohorts and see how vaccination for COVID-19 would impact the incidence rates of some of these diseases,” he said.

When asked for comment, Jeffrey A. Sparks, MD, MMSc, a rheumatologist at Brigham and Women's Hospital and assistant professor of medicine at Harvard Medical School, both in Boston, said, "This is an interesting study that should be followed up. Viral triggers have been known to precede autoimmune diseases so it will be very important to understand whether COVID-19 also impacts systemic autoimmune rheumatic diseases. I would be interested in differences in surveillance between the infection and control groups early in the pandemic. Many patients were avoiding interaction with the health care system at that point." 

Dr. Holcomb reported having no financial disclosures. Dr. Dellavalle disclosed that he is a consultant for Altus Labs and ParaPRO LLC. He has received grants and research funding from Pfizer.

* This story was updated on 3/29/22.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with hyperandrogenism and is caused by occlusion or rupture of follicular units and inflammation of the apocrine glands.^1-3 The disease most commonly affects women (female to male ratio of 3:1) of childbearing age.^1,2,4,5 Body areas affected include the axillae and groin, and less commonly the perineum; perianal region; and skin folds, such as gluteal, inframammary, and infraumbilical folds.^1,2 Symptoms manifest as painful subcutaneous nodules with possible accompanying purulent drainage, sinus tracts, and/or dermal contractures. Although the pathophysiology is unclear, androgens affect the course of HS during pregnancy by stimulating the affected glands and altering cytokines.^1,2,6

During pregnancy, maternal immune function switches from cell-mediated T helper cell (T_H1) to humoral T_H2 cytokine production. The activity of sebaceous and eccrine glands increases while the activity of apocrine glands decreases, thus changing the inflammatory course of HS during pregnancy.³ Approximately 20% of women with HS experience improvement of symptoms during pregnancy, while the remainder either experience no relief or deterioration of symptoms.¹ Improvement in symptoms during pregnancy was found to occur more frequently in those who had worsening symptoms during menses owing to the possible hormonal effect estrogen has on inhibiting T_H1 and T_H17 proinflammatory cytokines, which promotes an immunosuppressive environment.⁴

Lactation and breastfeeding abilities may be hindered if a woman has HS affecting the apocrine glands of breast tissue and a symptom flare in the postpartum period. If HS causes notable inflammation in the nipple-areolar complex during pregnancy, the patient may experience difficulties with lactation and milk fistula formation, leading to inability to breastfeed.² Another reason why mothers with HS may not be able to breastfeed is that the medications required to treat the disease are unsafe if passed to the infant via breast milk. In addition, the teratogenic effects of HS medications may necessitate therapy adjustments in pregnancy.¹ Here, we provide a brief overview of the medical management considerations of HS in the setting of pregnancy and the impact on breastfeeding.

MEDICAL MANAGEMENT AND DRUG SAFETY

Dermatologists prescribe a myriad of topical and systemic medications to ameliorate symptoms of HS. Therapy regimens often are multimodal and include antibiotics, biologics, and immunosuppressants.^1,3

Antibiotics

First-line antibiotics include clindamycin, metronidazole, tetracyclines, erythromycin, rifampin, dapsone, and fluoroquinolones. Topical clindamycin 1%, metronidazole 0.75%, and erythromycin 2% are used for open or active HS lesions and are all safe to use in pregnancy since there is minimal systemic absorption and minimal excretion into breast milk.¹ Topical antimicrobial washes such as benzoyl peroxide and chlorhexidine often are used in combination with systemic medications to treat HS. These washes are safe during pregnancy and lactation, as they have minimal systemic absorption.⁷

Of these first-line antibiotics, only tetracyclines are contraindicated during pregnancy and lactation, as they are deemed to be in category D by the US Food and Drug Administration (FDA).¹ Aside from tetracyclines, these antibiotics do not cause birth defects and are safe for nursing infants.^1,8 Systemic clindamycin is safe during pregnancy and breastfeeding. Systemic metronidazole also is safe for use in pregnant patients but needs to be discontinued 12 to 24 hours prior to breastfeeding, which often prohibits appropriate dosing.¹

Systemic Erythromycin—There are several forms of systemic erythromycin, including erythromycin base, erythromycin estolate, erythromycin ethylsuccinate (EES), and erythromycin stearate. Erythromycin estolate is contraindicated in pregnancy because it is associated with reversible maternal hepatoxicity and jaundice.^9-11 Erythromycin ethylsuccinate is the preferred form for pregnant patients. Providers should exercise caution when prescribing EES to lactating mothers, as small amounts are still secreted through breast milk.¹¹ Some studies have shown an increased risk for development of infantile hypertrophic pyloric stenosis with systemic erythromycin use, especially if a neonate is exposed in the first 14 days of life. Thus, we recommend withholding EES for 2 weeks after delivery if the patient is breastfeeding. A follow-up study did not find any association between erythromycin and infantile hypertrophic pyloric stenosis; however, the American Academy of Pediatrics still recommends short-term use only of erythromycin if it is to be used in the systemic form.⁸

Rifampin—Rifampin is excreted into breast milk but without adverse effects to the infant. Rifampin also is safe in pregnancy but should be used on a case-by-case basis in pregnant or nursing women because it is a cytochrome P450 inducer.

Dapsone—Dapsone has no increased risk for congenital anomalies. However, it is associated with hemolytic anemia and neonatal hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹² Newborns exposed to dapsone are at an increased risk for methemoglobinemia owing to increased sensitivity of fetal erythrocytes to oxidizing agents.¹³ If dapsone use is necessary, stopping dapsone treatment in the last month of gestation is recommended to minimize risk for kernicterus.⁹ Dapsone can be found in high concentrations in breast milk at 14.3% of the maternal dose. It is still safe to use during breastfeeding, but there is a risk of the infant developing hyperbilirubinemia/G6PD deficiency.^1,8 Thus, physicians may consider performing a G6PD screen on infants to determine if breastfeeding is safe.¹²

Fluoroquinolones—Quinolones are not contraindicated during pregnancy, but they can damage fetal cartilage and thus should be reserved for use in complicated infections when the benefits outweigh the risks.¹² Quinolones are believed to increase risk for arthropathy but are safe for use in lactation. When quinolones are digested with milk, exposure decreases below pediatric doses because of the ionized property of calcium in milk.⁸

Tumor Necrosis Factor α Inhibitors—The safety of anti–tumor necrosis factor (TNF) α biologics in pregnancy is less certain when compared with antibiotics.¹ Anti–TNF-α inhibitors such as etanercept, adalimumab, and infliximab are all labeled as FDA category B, meaning there are no well-controlled human studies of the drugs.⁹ There are limited data that support safe use of TNF-α inhibitors prior to the third trimester before maternal IgG antibodies are transferred to the fetus via the placenta.^1,13 Anti–TNF-α inhibitors may be safe when breastfeeding because the drugs have large molecular weights that prevent them from entering breast milk in large amounts. Absorption also is limited due to the infant’s digestive acids and enzymes breaking down the protein structure of the medication.⁸ Overall, TNF-α inhibitor use is still controversial and only used if the benefits outweigh the risks during pregnancy or if there is no alternative treatment.^1,3,9

Ustekinumab and Anakinra—Ustekinumab (an IL-12/IL-23 inhibitor) and anakinra (an IL-1α and IL-1β inhibitor) also are FDA category B drugs and have limited data supporting their use as HS treatment in pregnancy. Anakinra may have evidence of compatibility with breastfeeding, as endogenous IL-1α inhibitor is found in colostrum and mature breast milk.¹

Immunosuppressants

Immunosuppressants that are used to treat HS include corticosteroids and cyclosporine.

Corticosteroids—Topical corticosteroids can be used safely in lactation if they are not applied directly to the nipple or any area that makes direct contact with the infant’s mouth. Intralesional corticosteroid injections are safe for use during both pregnancy and breastfeeding to decrease inflammation of acutely flaring lesions and can be considered first-line treatment.¹ Oral glucocorticoids also can be safely used for acute flares during pregnancy; however, prolonged use is associated with pregnancy complications such as preeclampsia, eclampsia, premature delivery, and gestational diabetes.¹² There also is a small risk of oral cleft deformity in the infant; thus, potent corticosteroids are recommended in short durations during pregnancy, and there are no adverse effects if the maternal dose is less than 10 mg daily.^8,12 Systemic steroids are safe to use with breastfeeding, but patients should be advised to wait 4 hours after ingesting medication before breastfeeding.^1,8

Cyclosporine—Topical and oral calcineurin inhibitors such as cyclosporine have low risk for transmission into breast milk; however, potential effects of exposure through breast milk are unknown. For that reason, manufacturers state that cyclosporine use is contraindicated during lactation.⁸ If cyclosporine is to be used by a breastfeeding woman, monitoring cyclosporine concentrations in the infant is suggested to ensure that the exposure is less than 5% to 10% of the therapeutic dose.¹³ The use of cyclosporine has been extensively studied in pregnant transplant patients and is considered relatively safe for use in pregnancy.¹⁴ Cyclosporine is lipid soluble and thus is quickly metabolized and spread throughout the body; it can easily cross the placenta.^9,13 Blood concentration in the fetus is 30% to 64% that of the maternal circulation. However, cyclosporine is only toxic to the fetus at maternally toxic doses, which can result in low birth weight and increased prenatal and postnatal mortality.¹³

Isotretinoin, Oral Contraceptive Pills, and Spironolactone

Isotretinoin and hormonal treatments such as oral contraceptive pills and spironolactone (an androgen receptor blocker) commonly are used to treat HS, but all are contraindicated in pregnancy and lactation. Isotretinoin is a well-established teratogen, but adverse effects on nursing babies have not been described. However, the manufacturer of isotretinoin advises against its use in lactation. Oral contraceptive pill use in early pregnancy is associated with increased risk for Down syndrome. Oral contraceptive pill use also is contraindicated in lactation for 2 reasons: decreased milk production and risk for fetal feminization. Antiandrogenic agents such as spironolactone have been shown to be associated with hypospadias and feminization of the male fetus.⁷

COMMENT

Women with HS usually require ongoing medical treatment during pregnancy and immediately postpartum; thus, it is important that treatments are proven to be safe for use in this specific population. Current management guidelines are not entirely suitable for pregnant and breastfeeding women given that many HS drugs have teratogenic effects and/or can be excreted into breast milk.¹ Several treatments have uncertain safety profiles in pregnancy and breastfeeding, which calls for dermatologists to change or create new regimens for their patients. Close management also is necessary to prevent excess inflammation of breast tissue and milk fistula formation, which would hinder normal breastfeeding.

The eTable lists medications used to treat HS. The FDA category is listed next to each drug. However, it should be noted that these FDA letter categories were replaced with the Pregnancy and Lactation Labeling Rule in 2015. The letter ratings were deemed overly simplistic and replaced with narrative-based labeling that provides more detailed adverse effects and clinical considerations.⁹

Risk Factors of HS—Predisposing risk factors for HS flares that are controllable include obesity and smoking.² Pregnancy weight gain may cause increased skin maceration at intertriginous sites, which can contribute to worsening HS symptoms.^1,5 Adipocytes play a role in HS exacerbation by promoting secretion of TNF-α, leading to increased inflammation.⁵ Dermatologists can help prevent postpartum HS flares by monitoring weight gain during pregnancy, encouraging smoking cessation, and promoting weight and nutrition goals as set by an obstetrician.¹ In addition to medications, management of HS should include emotional support and education on wearing loose-fitting clothing to avoid irritation of the affected areas.³ An emphasis on dermatologist counseling for all patients with HS, even for those with milder disease, can reduce exacerbations during pregnancy.⁵

CONCLUSION

The selection of dermatologic drugs for the treatment of HS in the setting of pregnancy involves complex decision-making. Dermatologists need more guidelines and proven safety data in human trials, especially regarding use of biologics and immunosuppressants to better treat HS in pregnancy. With more data, they can create more evidence-based treatment regimens to help prevent postpartum exacerbations of HS. Thus, patients can breastfeed their infants comfortably and without any risks of impaired child development. In the meantime, dermatologists can continue to work together with obstetricians and psychiatrists to decrease disease flares through counseling patients on nutrition and weight gain and providing emotional support.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with hyperandrogenism and is caused by occlusion or rupture of follicular units and inflammation of the apocrine glands.^1-3 The disease most commonly affects women (female to male ratio of 3:1) of childbearing age.^1,2,4,5 Body areas affected include the axillae and groin, and less commonly the perineum; perianal region; and skin folds, such as gluteal, inframammary, and infraumbilical folds.^1,2 Symptoms manifest as painful subcutaneous nodules with possible accompanying purulent drainage, sinus tracts, and/or dermal contractures. Although the pathophysiology is unclear, androgens affect the course of HS during pregnancy by stimulating the affected glands and altering cytokines.^1,2,6

During pregnancy, maternal immune function switches from cell-mediated T helper cell (T_H1) to humoral T_H2 cytokine production. The activity of sebaceous and eccrine glands increases while the activity of apocrine glands decreases, thus changing the inflammatory course of HS during pregnancy.³ Approximately 20% of women with HS experience improvement of symptoms during pregnancy, while the remainder either experience no relief or deterioration of symptoms.¹ Improvement in symptoms during pregnancy was found to occur more frequently in those who had worsening symptoms during menses owing to the possible hormonal effect estrogen has on inhibiting T_H1 and T_H17 proinflammatory cytokines, which promotes an immunosuppressive environment.⁴

Lactation and breastfeeding abilities may be hindered if a woman has HS affecting the apocrine glands of breast tissue and a symptom flare in the postpartum period. If HS causes notable inflammation in the nipple-areolar complex during pregnancy, the patient may experience difficulties with lactation and milk fistula formation, leading to inability to breastfeed.² Another reason why mothers with HS may not be able to breastfeed is that the medications required to treat the disease are unsafe if passed to the infant via breast milk. In addition, the teratogenic effects of HS medications may necessitate therapy adjustments in pregnancy.¹ Here, we provide a brief overview of the medical management considerations of HS in the setting of pregnancy and the impact on breastfeeding.

MEDICAL MANAGEMENT AND DRUG SAFETY

Dermatologists prescribe a myriad of topical and systemic medications to ameliorate symptoms of HS. Therapy regimens often are multimodal and include antibiotics, biologics, and immunosuppressants.^1,3

Antibiotics

First-line antibiotics include clindamycin, metronidazole, tetracyclines, erythromycin, rifampin, dapsone, and fluoroquinolones. Topical clindamycin 1%, metronidazole 0.75%, and erythromycin 2% are used for open or active HS lesions and are all safe to use in pregnancy since there is minimal systemic absorption and minimal excretion into breast milk.¹ Topical antimicrobial washes such as benzoyl peroxide and chlorhexidine often are used in combination with systemic medications to treat HS. These washes are safe during pregnancy and lactation, as they have minimal systemic absorption.⁷

Of these first-line antibiotics, only tetracyclines are contraindicated during pregnancy and lactation, as they are deemed to be in category D by the US Food and Drug Administration (FDA).¹ Aside from tetracyclines, these antibiotics do not cause birth defects and are safe for nursing infants.^1,8 Systemic clindamycin is safe during pregnancy and breastfeeding. Systemic metronidazole also is safe for use in pregnant patients but needs to be discontinued 12 to 24 hours prior to breastfeeding, which often prohibits appropriate dosing.¹

Systemic Erythromycin—There are several forms of systemic erythromycin, including erythromycin base, erythromycin estolate, erythromycin ethylsuccinate (EES), and erythromycin stearate. Erythromycin estolate is contraindicated in pregnancy because it is associated with reversible maternal hepatoxicity and jaundice.^9-11 Erythromycin ethylsuccinate is the preferred form for pregnant patients. Providers should exercise caution when prescribing EES to lactating mothers, as small amounts are still secreted through breast milk.¹¹ Some studies have shown an increased risk for development of infantile hypertrophic pyloric stenosis with systemic erythromycin use, especially if a neonate is exposed in the first 14 days of life. Thus, we recommend withholding EES for 2 weeks after delivery if the patient is breastfeeding. A follow-up study did not find any association between erythromycin and infantile hypertrophic pyloric stenosis; however, the American Academy of Pediatrics still recommends short-term use only of erythromycin if it is to be used in the systemic form.⁸

Rifampin—Rifampin is excreted into breast milk but without adverse effects to the infant. Rifampin also is safe in pregnancy but should be used on a case-by-case basis in pregnant or nursing women because it is a cytochrome P450 inducer.

Dapsone—Dapsone has no increased risk for congenital anomalies. However, it is associated with hemolytic anemia and neonatal hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹² Newborns exposed to dapsone are at an increased risk for methemoglobinemia owing to increased sensitivity of fetal erythrocytes to oxidizing agents.¹³ If dapsone use is necessary, stopping dapsone treatment in the last month of gestation is recommended to minimize risk for kernicterus.⁹ Dapsone can be found in high concentrations in breast milk at 14.3% of the maternal dose. It is still safe to use during breastfeeding, but there is a risk of the infant developing hyperbilirubinemia/G6PD deficiency.^1,8 Thus, physicians may consider performing a G6PD screen on infants to determine if breastfeeding is safe.¹²

Fluoroquinolones—Quinolones are not contraindicated during pregnancy, but they can damage fetal cartilage and thus should be reserved for use in complicated infections when the benefits outweigh the risks.¹² Quinolones are believed to increase risk for arthropathy but are safe for use in lactation. When quinolones are digested with milk, exposure decreases below pediatric doses because of the ionized property of calcium in milk.⁸

Tumor Necrosis Factor α Inhibitors—The safety of anti–tumor necrosis factor (TNF) α biologics in pregnancy is less certain when compared with antibiotics.¹ Anti–TNF-α inhibitors such as etanercept, adalimumab, and infliximab are all labeled as FDA category B, meaning there are no well-controlled human studies of the drugs.⁹ There are limited data that support safe use of TNF-α inhibitors prior to the third trimester before maternal IgG antibodies are transferred to the fetus via the placenta.^1,13 Anti–TNF-α inhibitors may be safe when breastfeeding because the drugs have large molecular weights that prevent them from entering breast milk in large amounts. Absorption also is limited due to the infant’s digestive acids and enzymes breaking down the protein structure of the medication.⁸ Overall, TNF-α inhibitor use is still controversial and only used if the benefits outweigh the risks during pregnancy or if there is no alternative treatment.^1,3,9

Ustekinumab and Anakinra—Ustekinumab (an IL-12/IL-23 inhibitor) and anakinra (an IL-1α and IL-1β inhibitor) also are FDA category B drugs and have limited data supporting their use as HS treatment in pregnancy. Anakinra may have evidence of compatibility with breastfeeding, as endogenous IL-1α inhibitor is found in colostrum and mature breast milk.¹

Immunosuppressants

Immunosuppressants that are used to treat HS include corticosteroids and cyclosporine.

Corticosteroids—Topical corticosteroids can be used safely in lactation if they are not applied directly to the nipple or any area that makes direct contact with the infant’s mouth. Intralesional corticosteroid injections are safe for use during both pregnancy and breastfeeding to decrease inflammation of acutely flaring lesions and can be considered first-line treatment.¹ Oral glucocorticoids also can be safely used for acute flares during pregnancy; however, prolonged use is associated with pregnancy complications such as preeclampsia, eclampsia, premature delivery, and gestational diabetes.¹² There also is a small risk of oral cleft deformity in the infant; thus, potent corticosteroids are recommended in short durations during pregnancy, and there are no adverse effects if the maternal dose is less than 10 mg daily.^8,12 Systemic steroids are safe to use with breastfeeding, but patients should be advised to wait 4 hours after ingesting medication before breastfeeding.^1,8

Cyclosporine—Topical and oral calcineurin inhibitors such as cyclosporine have low risk for transmission into breast milk; however, potential effects of exposure through breast milk are unknown. For that reason, manufacturers state that cyclosporine use is contraindicated during lactation.⁸ If cyclosporine is to be used by a breastfeeding woman, monitoring cyclosporine concentrations in the infant is suggested to ensure that the exposure is less than 5% to 10% of the therapeutic dose.¹³ The use of cyclosporine has been extensively studied in pregnant transplant patients and is considered relatively safe for use in pregnancy.¹⁴ Cyclosporine is lipid soluble and thus is quickly metabolized and spread throughout the body; it can easily cross the placenta.^9,13 Blood concentration in the fetus is 30% to 64% that of the maternal circulation. However, cyclosporine is only toxic to the fetus at maternally toxic doses, which can result in low birth weight and increased prenatal and postnatal mortality.¹³

Isotretinoin, Oral Contraceptive Pills, and Spironolactone

Isotretinoin and hormonal treatments such as oral contraceptive pills and spironolactone (an androgen receptor blocker) commonly are used to treat HS, but all are contraindicated in pregnancy and lactation. Isotretinoin is a well-established teratogen, but adverse effects on nursing babies have not been described. However, the manufacturer of isotretinoin advises against its use in lactation. Oral contraceptive pill use in early pregnancy is associated with increased risk for Down syndrome. Oral contraceptive pill use also is contraindicated in lactation for 2 reasons: decreased milk production and risk for fetal feminization. Antiandrogenic agents such as spironolactone have been shown to be associated with hypospadias and feminization of the male fetus.⁷

COMMENT

Women with HS usually require ongoing medical treatment during pregnancy and immediately postpartum; thus, it is important that treatments are proven to be safe for use in this specific population. Current management guidelines are not entirely suitable for pregnant and breastfeeding women given that many HS drugs have teratogenic effects and/or can be excreted into breast milk.¹ Several treatments have uncertain safety profiles in pregnancy and breastfeeding, which calls for dermatologists to change or create new regimens for their patients. Close management also is necessary to prevent excess inflammation of breast tissue and milk fistula formation, which would hinder normal breastfeeding.

The eTable lists medications used to treat HS. The FDA category is listed next to each drug. However, it should be noted that these FDA letter categories were replaced with the Pregnancy and Lactation Labeling Rule in 2015. The letter ratings were deemed overly simplistic and replaced with narrative-based labeling that provides more detailed adverse effects and clinical considerations.⁹

Risk Factors of HS—Predisposing risk factors for HS flares that are controllable include obesity and smoking.² Pregnancy weight gain may cause increased skin maceration at intertriginous sites, which can contribute to worsening HS symptoms.^1,5 Adipocytes play a role in HS exacerbation by promoting secretion of TNF-α, leading to increased inflammation.⁵ Dermatologists can help prevent postpartum HS flares by monitoring weight gain during pregnancy, encouraging smoking cessation, and promoting weight and nutrition goals as set by an obstetrician.¹ In addition to medications, management of HS should include emotional support and education on wearing loose-fitting clothing to avoid irritation of the affected areas.³ An emphasis on dermatologist counseling for all patients with HS, even for those with milder disease, can reduce exacerbations during pregnancy.⁵

CONCLUSION

The selection of dermatologic drugs for the treatment of HS in the setting of pregnancy involves complex decision-making. Dermatologists need more guidelines and proven safety data in human trials, especially regarding use of biologics and immunosuppressants to better treat HS in pregnancy. With more data, they can create more evidence-based treatment regimens to help prevent postpartum exacerbations of HS. Thus, patients can breastfeed their infants comfortably and without any risks of impaired child development. In the meantime, dermatologists can continue to work together with obstetricians and psychiatrists to decrease disease flares through counseling patients on nutrition and weight gain and providing emotional support.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with hyperandrogenism and is caused by occlusion or rupture of follicular units and inflammation of the apocrine glands.^1-3 The disease most commonly affects women (female to male ratio of 3:1) of childbearing age.^1,2,4,5 Body areas affected include the axillae and groin, and less commonly the perineum; perianal region; and skin folds, such as gluteal, inframammary, and infraumbilical folds.^1,2 Symptoms manifest as painful subcutaneous nodules with possible accompanying purulent drainage, sinus tracts, and/or dermal contractures. Although the pathophysiology is unclear, androgens affect the course of HS during pregnancy by stimulating the affected glands and altering cytokines.^1,2,6

During pregnancy, maternal immune function switches from cell-mediated T helper cell (T_H1) to humoral T_H2 cytokine production. The activity of sebaceous and eccrine glands increases while the activity of apocrine glands decreases, thus changing the inflammatory course of HS during pregnancy.³ Approximately 20% of women with HS experience improvement of symptoms during pregnancy, while the remainder either experience no relief or deterioration of symptoms.¹ Improvement in symptoms during pregnancy was found to occur more frequently in those who had worsening symptoms during menses owing to the possible hormonal effect estrogen has on inhibiting T_H1 and T_H17 proinflammatory cytokines, which promotes an immunosuppressive environment.⁴

Lactation and breastfeeding abilities may be hindered if a woman has HS affecting the apocrine glands of breast tissue and a symptom flare in the postpartum period. If HS causes notable inflammation in the nipple-areolar complex during pregnancy, the patient may experience difficulties with lactation and milk fistula formation, leading to inability to breastfeed.² Another reason why mothers with HS may not be able to breastfeed is that the medications required to treat the disease are unsafe if passed to the infant via breast milk. In addition, the teratogenic effects of HS medications may necessitate therapy adjustments in pregnancy.¹ Here, we provide a brief overview of the medical management considerations of HS in the setting of pregnancy and the impact on breastfeeding.

MEDICAL MANAGEMENT AND DRUG SAFETY

Dermatologists prescribe a myriad of topical and systemic medications to ameliorate symptoms of HS. Therapy regimens often are multimodal and include antibiotics, biologics, and immunosuppressants.^1,3

Antibiotics

First-line antibiotics include clindamycin, metronidazole, tetracyclines, erythromycin, rifampin, dapsone, and fluoroquinolones. Topical clindamycin 1%, metronidazole 0.75%, and erythromycin 2% are used for open or active HS lesions and are all safe to use in pregnancy since there is minimal systemic absorption and minimal excretion into breast milk.¹ Topical antimicrobial washes such as benzoyl peroxide and chlorhexidine often are used in combination with systemic medications to treat HS. These washes are safe during pregnancy and lactation, as they have minimal systemic absorption.⁷

Of these first-line antibiotics, only tetracyclines are contraindicated during pregnancy and lactation, as they are deemed to be in category D by the US Food and Drug Administration (FDA).¹ Aside from tetracyclines, these antibiotics do not cause birth defects and are safe for nursing infants.^1,8 Systemic clindamycin is safe during pregnancy and breastfeeding. Systemic metronidazole also is safe for use in pregnant patients but needs to be discontinued 12 to 24 hours prior to breastfeeding, which often prohibits appropriate dosing.¹

Systemic Erythromycin—There are several forms of systemic erythromycin, including erythromycin base, erythromycin estolate, erythromycin ethylsuccinate (EES), and erythromycin stearate. Erythromycin estolate is contraindicated in pregnancy because it is associated with reversible maternal hepatoxicity and jaundice.^9-11 Erythromycin ethylsuccinate is the preferred form for pregnant patients. Providers should exercise caution when prescribing EES to lactating mothers, as small amounts are still secreted through breast milk.¹¹ Some studies have shown an increased risk for development of infantile hypertrophic pyloric stenosis with systemic erythromycin use, especially if a neonate is exposed in the first 14 days of life. Thus, we recommend withholding EES for 2 weeks after delivery if the patient is breastfeeding. A follow-up study did not find any association between erythromycin and infantile hypertrophic pyloric stenosis; however, the American Academy of Pediatrics still recommends short-term use only of erythromycin if it is to be used in the systemic form.⁸

Rifampin—Rifampin is excreted into breast milk but without adverse effects to the infant. Rifampin also is safe in pregnancy but should be used on a case-by-case basis in pregnant or nursing women because it is a cytochrome P450 inducer.

Dapsone—Dapsone has no increased risk for congenital anomalies. However, it is associated with hemolytic anemia and neonatal hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹² Newborns exposed to dapsone are at an increased risk for methemoglobinemia owing to increased sensitivity of fetal erythrocytes to oxidizing agents.¹³ If dapsone use is necessary, stopping dapsone treatment in the last month of gestation is recommended to minimize risk for kernicterus.⁹ Dapsone can be found in high concentrations in breast milk at 14.3% of the maternal dose. It is still safe to use during breastfeeding, but there is a risk of the infant developing hyperbilirubinemia/G6PD deficiency.^1,8 Thus, physicians may consider performing a G6PD screen on infants to determine if breastfeeding is safe.¹²

Fluoroquinolones—Quinolones are not contraindicated during pregnancy, but they can damage fetal cartilage and thus should be reserved for use in complicated infections when the benefits outweigh the risks.¹² Quinolones are believed to increase risk for arthropathy but are safe for use in lactation. When quinolones are digested with milk, exposure decreases below pediatric doses because of the ionized property of calcium in milk.⁸

Tumor Necrosis Factor α Inhibitors—The safety of anti–tumor necrosis factor (TNF) α biologics in pregnancy is less certain when compared with antibiotics.¹ Anti–TNF-α inhibitors such as etanercept, adalimumab, and infliximab are all labeled as FDA category B, meaning there are no well-controlled human studies of the drugs.⁹ There are limited data that support safe use of TNF-α inhibitors prior to the third trimester before maternal IgG antibodies are transferred to the fetus via the placenta.^1,13 Anti–TNF-α inhibitors may be safe when breastfeeding because the drugs have large molecular weights that prevent them from entering breast milk in large amounts. Absorption also is limited due to the infant’s digestive acids and enzymes breaking down the protein structure of the medication.⁸ Overall, TNF-α inhibitor use is still controversial and only used if the benefits outweigh the risks during pregnancy or if there is no alternative treatment.^1,3,9

Ustekinumab and Anakinra—Ustekinumab (an IL-12/IL-23 inhibitor) and anakinra (an IL-1α and IL-1β inhibitor) also are FDA category B drugs and have limited data supporting their use as HS treatment in pregnancy. Anakinra may have evidence of compatibility with breastfeeding, as endogenous IL-1α inhibitor is found in colostrum and mature breast milk.¹

Immunosuppressants

Immunosuppressants that are used to treat HS include corticosteroids and cyclosporine.

Corticosteroids—Topical corticosteroids can be used safely in lactation if they are not applied directly to the nipple or any area that makes direct contact with the infant’s mouth. Intralesional corticosteroid injections are safe for use during both pregnancy and breastfeeding to decrease inflammation of acutely flaring lesions and can be considered first-line treatment.¹ Oral glucocorticoids also can be safely used for acute flares during pregnancy; however, prolonged use is associated with pregnancy complications such as preeclampsia, eclampsia, premature delivery, and gestational diabetes.¹² There also is a small risk of oral cleft deformity in the infant; thus, potent corticosteroids are recommended in short durations during pregnancy, and there are no adverse effects if the maternal dose is less than 10 mg daily.^8,12 Systemic steroids are safe to use with breastfeeding, but patients should be advised to wait 4 hours after ingesting medication before breastfeeding.^1,8

Cyclosporine—Topical and oral calcineurin inhibitors such as cyclosporine have low risk for transmission into breast milk; however, potential effects of exposure through breast milk are unknown. For that reason, manufacturers state that cyclosporine use is contraindicated during lactation.⁸ If cyclosporine is to be used by a breastfeeding woman, monitoring cyclosporine concentrations in the infant is suggested to ensure that the exposure is less than 5% to 10% of the therapeutic dose.¹³ The use of cyclosporine has been extensively studied in pregnant transplant patients and is considered relatively safe for use in pregnancy.¹⁴ Cyclosporine is lipid soluble and thus is quickly metabolized and spread throughout the body; it can easily cross the placenta.^9,13 Blood concentration in the fetus is 30% to 64% that of the maternal circulation. However, cyclosporine is only toxic to the fetus at maternally toxic doses, which can result in low birth weight and increased prenatal and postnatal mortality.¹³

Isotretinoin, Oral Contraceptive Pills, and Spironolactone

Isotretinoin and hormonal treatments such as oral contraceptive pills and spironolactone (an androgen receptor blocker) commonly are used to treat HS, but all are contraindicated in pregnancy and lactation. Isotretinoin is a well-established teratogen, but adverse effects on nursing babies have not been described. However, the manufacturer of isotretinoin advises against its use in lactation. Oral contraceptive pill use in early pregnancy is associated with increased risk for Down syndrome. Oral contraceptive pill use also is contraindicated in lactation for 2 reasons: decreased milk production and risk for fetal feminization. Antiandrogenic agents such as spironolactone have been shown to be associated with hypospadias and feminization of the male fetus.⁷

COMMENT

Women with HS usually require ongoing medical treatment during pregnancy and immediately postpartum; thus, it is important that treatments are proven to be safe for use in this specific population. Current management guidelines are not entirely suitable for pregnant and breastfeeding women given that many HS drugs have teratogenic effects and/or can be excreted into breast milk.¹ Several treatments have uncertain safety profiles in pregnancy and breastfeeding, which calls for dermatologists to change or create new regimens for their patients. Close management also is necessary to prevent excess inflammation of breast tissue and milk fistula formation, which would hinder normal breastfeeding.

The eTable lists medications used to treat HS. The FDA category is listed next to each drug. However, it should be noted that these FDA letter categories were replaced with the Pregnancy and Lactation Labeling Rule in 2015. The letter ratings were deemed overly simplistic and replaced with narrative-based labeling that provides more detailed adverse effects and clinical considerations.⁹

Risk Factors of HS—Predisposing risk factors for HS flares that are controllable include obesity and smoking.² Pregnancy weight gain may cause increased skin maceration at intertriginous sites, which can contribute to worsening HS symptoms.^1,5 Adipocytes play a role in HS exacerbation by promoting secretion of TNF-α, leading to increased inflammation.⁵ Dermatologists can help prevent postpartum HS flares by monitoring weight gain during pregnancy, encouraging smoking cessation, and promoting weight and nutrition goals as set by an obstetrician.¹ In addition to medications, management of HS should include emotional support and education on wearing loose-fitting clothing to avoid irritation of the affected areas.³ An emphasis on dermatologist counseling for all patients with HS, even for those with milder disease, can reduce exacerbations during pregnancy.⁵

CONCLUSION

The selection of dermatologic drugs for the treatment of HS in the setting of pregnancy involves complex decision-making. Dermatologists need more guidelines and proven safety data in human trials, especially regarding use of biologics and immunosuppressants to better treat HS in pregnancy. With more data, they can create more evidence-based treatment regimens to help prevent postpartum exacerbations of HS. Thus, patients can breastfeed their infants comfortably and without any risks of impaired child development. In the meantime, dermatologists can continue to work together with obstetricians and psychiatrists to decrease disease flares through counseling patients on nutrition and weight gain and providing emotional support.

Lichen planus is a chronic inflammatory mucocutaneous disease that usually affects the skin and/or the genital and oral mucosae.^1,2 This disease classically presents with clinical relapses or outbreaks that alternate with periods of remission or latency. Oral lichen planus (OLP) can present with or without extraoral manifestation. It sometimes is difficult to differentiate OLP from oral lichenoid reactions, which can be related to dental materials, some drugs, and systemic conditions or can be idiopathic.^1,2

Oral lichen planus is one of the most common noninfectious diseases of the oral cavity, with a reported prevalence of 1% worldwide and marked geographical differences. In Europe, the prevalence of OLP ranges from 1% to 2%.^3,4 It is more frequent in women (1.5:1 to 2:1) and usually appears in the fourth and fifth decades of life.^1-4

The causes of OLP have not been entirely elucidated, but it is broadly accepted that there is a deregulation on different T lymphocytes that in turn causes effects on CD8 lymphocytes in response to an external noxa. This unknown “trigger” or starting factor also produces an impact on basal keratinocytes. Therefore, the pathogenesis of lichen planus is influenced by a series of cellular events mediated by different cytokines.^2,5,6 Among these, tumor necrosis factor α and IL-1 are known to have important roles in the disease. More recently, other cytokines, such as IL-4, secreted by type 2 helper T cells, also have been related to the development and progression of the oral lesions.^5,6 In addition to the factors that generate the onset of the disease, there are others that may precipitate clinical outbreaks. Different factors have been related to the progression of the disease, influencing the initiation, perpetuation, and/or worsening of OLP lesions.^1,2 Exactly how these factors affect disease progression is another challenging question. The list of possible or potential factors related to disease progression is long; nonetheless, in the vast majority, a clear explanation at a molecular level has not been clearly demonstrated.^2,5

Conventionally, 6 clinical presentations of OLP lesions divided into 2 main groups have been described in the oral cavity: white forms (reticular, papular, and plaquelike) and red forms (erythematous, atrophic-erosive, and bullous).^1,7-9

Oral lichen planus mainly is treated with topically or systemically administered steroids based on the presence of symptoms such as pain and inability to perform daily activities (eg, eating, talking).^5,10 The treatment of choice often is based on the professional’s experience, as there are no broadly accepted national or international clinical practice guidelines on steroid type, administration route, dose, vehicle for administration, or maintenance.¹¹ Despite this lack of unified criteria, different topical and systemic steroid administration protocols allow a reduction in the symptoms or even the disappearance of the red lesions to be achieved in many cases. Unfortunately, there are many patients with lesions refractory to standard treatments for OLP.¹² Several alternatives for these patients have been described in the literature, though on many occasions these alternatives present substantial side effects for the patient.¹³ The search for an effective treatment without side effects is still challenging. One of the treatments tested under this premise has been the application of plasma rich in growth factors (PRGF) by means of infiltration or topical application, in both cases obtaining good results without side effects.¹⁴

We sought to analyze the information from a case series of patients treated at the Eduardo Anitua Clinic (Vitoria-Gasteiz, Spain) and describe the results and follow-up of patients with erosive OLP refractory to standard therapy who have been successfully treated by local infiltration of PRGF as the only treatment.

Material and Methods

Patients—We included data from the database of the clinical center with de-identified information of patients with erosive OLP diagnosed clinically and histopathologically who did not respond to conventional treatment (ie, topical and/or systemic corticosteroids [depending on the case]) as well as patients who presented with extensive erosive OLP with systemic involvement and whose systemic treatment was not effective in resolving oral manifestations.

Therapies Administered and Evaluations—Lesions refractory to conventional corticosteroid protocols had been previously treated for 30 days with 0.5% triamcinolone acetonide mouth rinse followed by a cycle of 1% triamcinolone acetonide mouth rinse. Subsequently, a cycle of oral corticosteroids (prednisone for 30 days: 1 mg/kg/d in a single morning dose with staged reduction after the first week) had been administered. One dayafter the corticosteroid treatment was suspended, the patients were treated by PRGF-Endoret (BTI Biotechnology Institute) infiltration following the protocol described by Anitua et al.^15,16

Before starting the infiltrations with PRGF, the patient had been asked to rate the pain level on a visual analog scale (VAS) of 1 to 10, with 10 being the most intense imaginable pain. Pain score was subsequently rated and registered during every visit. An initial photograph of the lesion also was obtained to establish a starting point for further comparisons of clinical evolution of the lesions.

Prior to each infiltration, the plasma was separated into 2 fractions. The second fraction was the one that corresponded to the highest number of platelets and included the 2 mL of plasma just above the white series (or buffy coat). This fraction of plasma was the one used to infiltrate the lesions.

Plasma rich in growth factors was activated just before infiltration. The activation was done by adding 10% calcium chloride. Once activated, it was infiltrated into the active lesion using a 31-G × 1/6-in hypodermic needle and a 2-mL Luer-lock syringe. Infiltrations were performed without anesthesia. Four punctures were made for each ulcerative lesion, dividing the lesion into 4 points: upper, lower, right, and left. Plasma rich in growth factors was infiltrated until a slight blanching was observed in the surrounding tissue. At that moment, the infiltration was stopped and was carried out in the next infiltration site.

One treatment session was performed per week, with follow-up 1 week after treatment. In the control visit, the state of the lesions was re-evaluated, and it was decided whether new infiltrations were needed. The treatment was finished when complete epithelialization of the lesion was visualized or the associated symptoms disappeared. At each visit, photographs were taken, and the patient assessed the severity of pain on the VAS.

Statistical Analysis—A Shapiro-Wilk test was carried out with the obtained data to check the normal distribution of the sample. The evolution of pain during the study was compared by paired t test. The qualitative variables were described by means of a frequency analysis. Quantitative variables were described by the mean and the SD. The data were analyzed with SPSS V15.0 for Windows (SPSS Inc). P<.05 showed statistical significance.

Results

A total of 15 patients were included in the study, all with atrophic-erosive lichen planus. Two patients were male, and 13 were female. The mean age (SD) of the patients included in the study was 55.27 (14.19) years. The mean number of outbreaks per year (SD) was 3.2 (1.7), with a range of 1 to 8 outbreaks.

Healing of OLP Lesions—The number of treatment sessions to achieve complete healing varied among the patients (Figures 1 and 2). Ten patients (66.7%) required a single session, 2 patients (13.3%) required 2 sessions, and 3 patients (20%) required 3 sessions. The mean time (SD) without lesions for the patients who required a single session was 10.9 (5.2) months (range, 6–24 months).

Pain Assessment—The mean (SD) score obtained on the VAS before treatment with PRGF was 8.27 (1.16); this score dropped to 1.27 (1.53) after the first treatment session and was a statistically significant difference (P=.006).

For those patients requiring more than 1 session, the mean (SD) pain scores decreased by 0.75 (0.97) points and 0 points after the first and second sessions of treatment, respectively. The mean (SD) amount of PRGF infiltrated in each patient in the first session was 2.60 (0.63) mL. In the second session, the mean (SD) amount was 1.2 (0.33) mL; these differences were statistically significant (P=.008). In the last session, the mean (SD) amount was 1.1 (0.22) mL.

Follow-up and Adverse Effects—The mean (SD) follow-up time was 47.16 (15.78) months. The patients were free of symptoms, and there were no adverse effects derived from the treatment during follow-up.

Comment

The primary goal of OLP treatment is to stop the outbreaks.^1,9,13 The lack of potency of corticosteroids in some patients with OLP could be due in part to the inadequate selection of the vehicle (ointment/oral rinse) for the extension and characteristics of the lesion or because of an inappropriate prescription dose, time, and/or frequency, as described by González-Moles.¹⁷ However, even when using an appropriate protocol, some lesions are resistant to topical treatment and require other therapeutic modalities.^1,9,13 Previously proposed topical treatments include different immunosuppressants, such as the mammalian target of rapamycin, tacrolimus ointment 0.1%, pimecrolimus cream 1%, or cyclosporine A (50–100 mg/mL) formulations.¹⁸ Nevertheless, these drugs seem to have a greater number of side effects than topical steroids, and tacrolimus has been associated with cases of oral malignancy after continuing treatment.¹⁵

Severe and/or recalcitrant lesions and extraoral involvement have been successfully treated with systemic prednisone (40–80 mg/d).^1,9,13 Nevertheless, systemic corticosteroid toxicity requires that these treatments should be used only when necessary at the lowest possible dose and for the shortest possible duration.¹⁹ Other nonpharmacologic options for treatment are photodynamic, UV, and low-level laser therapy.^20,21 They have been accepted as supplementary modalities in different inflammatory skin conditions but present important technical requirements. Their effectiveness in corticosteroid-resistant cases have not been definitively assessed. Interestingly, promising results recently have been reported by Bennardo et al²² when comparing the efficacy of autologous platelet concentrates with triamcinolone injection.

In our study, the use of PRGF stopped the lesions’ evolution since the first treatment session, reducing them by 6.5-fold. The positive effects observed may have been promoted by the activity of different proteins present in PRGF (eg, platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor, epidermal growth factor, fibroblast growth factor, fibronectin). These molecules contribute to collagen synthesis; angiogenesis; endothelial cell migration and proliferation; or keratinocyte cell migration, proliferation, differentiation, growth, and migration—phenomena that are essential for healing and re-epithelialization.^23-25

Different studies also have supported an anti-inflammatory effect of PRGF mediated by an inhibition of the transcription of nuclear factor–κB and the expression of cyclooxygenase-2 and chemokine receptor type 4 produced by its high content of hepatocyte growth factor or the reduction of inflammatory marker expression, such as intercellular adhesion molecule 1. The development of an efficient 3-dimensional fibrin scaffold formation that occurs after PRGF administration also could facilitate healing, helping some cell populations to guide their position and function.^23-25

Limitations of our study include the small number of patients and the absence of a control group. The higher number of female patients in the study did not seem to affect the results, as differences related to gender have not been reported when treating patients with OLP with autologous platelet concentrates or other modalities of treatment.

Conclusion

Results from our study indicate that the use of PRGF could be a new treatment option for OLP cases refractory to conventional therapy. No complications were observed during the treatment procedure or during the complete follow-up period. Nonetheless, new prospective studies with a greater number of patients and longer follow-up periods are needed to confirm these preliminary results.

Lichen planus is a chronic inflammatory mucocutaneous disease that usually affects the skin and/or the genital and oral mucosae.^1,2 This disease classically presents with clinical relapses or outbreaks that alternate with periods of remission or latency. Oral lichen planus (OLP) can present with or without extraoral manifestation. It sometimes is difficult to differentiate OLP from oral lichenoid reactions, which can be related to dental materials, some drugs, and systemic conditions or can be idiopathic.^1,2

Oral lichen planus is one of the most common noninfectious diseases of the oral cavity, with a reported prevalence of 1% worldwide and marked geographical differences. In Europe, the prevalence of OLP ranges from 1% to 2%.^3,4 It is more frequent in women (1.5:1 to 2:1) and usually appears in the fourth and fifth decades of life.^1-4

The causes of OLP have not been entirely elucidated, but it is broadly accepted that there is a deregulation on different T lymphocytes that in turn causes effects on CD8 lymphocytes in response to an external noxa. This unknown “trigger” or starting factor also produces an impact on basal keratinocytes. Therefore, the pathogenesis of lichen planus is influenced by a series of cellular events mediated by different cytokines.^2,5,6 Among these, tumor necrosis factor α and IL-1 are known to have important roles in the disease. More recently, other cytokines, such as IL-4, secreted by type 2 helper T cells, also have been related to the development and progression of the oral lesions.^5,6 In addition to the factors that generate the onset of the disease, there are others that may precipitate clinical outbreaks. Different factors have been related to the progression of the disease, influencing the initiation, perpetuation, and/or worsening of OLP lesions.^1,2 Exactly how these factors affect disease progression is another challenging question. The list of possible or potential factors related to disease progression is long; nonetheless, in the vast majority, a clear explanation at a molecular level has not been clearly demonstrated.^2,5

Conventionally, 6 clinical presentations of OLP lesions divided into 2 main groups have been described in the oral cavity: white forms (reticular, papular, and plaquelike) and red forms (erythematous, atrophic-erosive, and bullous).^1,7-9

Oral lichen planus mainly is treated with topically or systemically administered steroids based on the presence of symptoms such as pain and inability to perform daily activities (eg, eating, talking).^5,10 The treatment of choice often is based on the professional’s experience, as there are no broadly accepted national or international clinical practice guidelines on steroid type, administration route, dose, vehicle for administration, or maintenance.¹¹ Despite this lack of unified criteria, different topical and systemic steroid administration protocols allow a reduction in the symptoms or even the disappearance of the red lesions to be achieved in many cases. Unfortunately, there are many patients with lesions refractory to standard treatments for OLP.¹² Several alternatives for these patients have been described in the literature, though on many occasions these alternatives present substantial side effects for the patient.¹³ The search for an effective treatment without side effects is still challenging. One of the treatments tested under this premise has been the application of plasma rich in growth factors (PRGF) by means of infiltration or topical application, in both cases obtaining good results without side effects.¹⁴

We sought to analyze the information from a case series of patients treated at the Eduardo Anitua Clinic (Vitoria-Gasteiz, Spain) and describe the results and follow-up of patients with erosive OLP refractory to standard therapy who have been successfully treated by local infiltration of PRGF as the only treatment.

Material and Methods

Patients—We included data from the database of the clinical center with de-identified information of patients with erosive OLP diagnosed clinically and histopathologically who did not respond to conventional treatment (ie, topical and/or systemic corticosteroids [depending on the case]) as well as patients who presented with extensive erosive OLP with systemic involvement and whose systemic treatment was not effective in resolving oral manifestations.

Therapies Administered and Evaluations—Lesions refractory to conventional corticosteroid protocols had been previously treated for 30 days with 0.5% triamcinolone acetonide mouth rinse followed by a cycle of 1% triamcinolone acetonide mouth rinse. Subsequently, a cycle of oral corticosteroids (prednisone for 30 days: 1 mg/kg/d in a single morning dose with staged reduction after the first week) had been administered. One dayafter the corticosteroid treatment was suspended, the patients were treated by PRGF-Endoret (BTI Biotechnology Institute) infiltration following the protocol described by Anitua et al.^15,16

Before starting the infiltrations with PRGF, the patient had been asked to rate the pain level on a visual analog scale (VAS) of 1 to 10, with 10 being the most intense imaginable pain. Pain score was subsequently rated and registered during every visit. An initial photograph of the lesion also was obtained to establish a starting point for further comparisons of clinical evolution of the lesions.

Prior to each infiltration, the plasma was separated into 2 fractions. The second fraction was the one that corresponded to the highest number of platelets and included the 2 mL of plasma just above the white series (or buffy coat). This fraction of plasma was the one used to infiltrate the lesions.

Plasma rich in growth factors was activated just before infiltration. The activation was done by adding 10% calcium chloride. Once activated, it was infiltrated into the active lesion using a 31-G × 1/6-in hypodermic needle and a 2-mL Luer-lock syringe. Infiltrations were performed without anesthesia. Four punctures were made for each ulcerative lesion, dividing the lesion into 4 points: upper, lower, right, and left. Plasma rich in growth factors was infiltrated until a slight blanching was observed in the surrounding tissue. At that moment, the infiltration was stopped and was carried out in the next infiltration site.

One treatment session was performed per week, with follow-up 1 week after treatment. In the control visit, the state of the lesions was re-evaluated, and it was decided whether new infiltrations were needed. The treatment was finished when complete epithelialization of the lesion was visualized or the associated symptoms disappeared. At each visit, photographs were taken, and the patient assessed the severity of pain on the VAS.

Statistical Analysis—A Shapiro-Wilk test was carried out with the obtained data to check the normal distribution of the sample. The evolution of pain during the study was compared by paired t test. The qualitative variables were described by means of a frequency analysis. Quantitative variables were described by the mean and the SD. The data were analyzed with SPSS V15.0 for Windows (SPSS Inc). P<.05 showed statistical significance.

Results

A total of 15 patients were included in the study, all with atrophic-erosive lichen planus. Two patients were male, and 13 were female. The mean age (SD) of the patients included in the study was 55.27 (14.19) years. The mean number of outbreaks per year (SD) was 3.2 (1.7), with a range of 1 to 8 outbreaks.

Healing of OLP Lesions—The number of treatment sessions to achieve complete healing varied among the patients (Figures 1 and 2). Ten patients (66.7%) required a single session, 2 patients (13.3%) required 2 sessions, and 3 patients (20%) required 3 sessions. The mean time (SD) without lesions for the patients who required a single session was 10.9 (5.2) months (range, 6–24 months).

Pain Assessment—The mean (SD) score obtained on the VAS before treatment with PRGF was 8.27 (1.16); this score dropped to 1.27 (1.53) after the first treatment session and was a statistically significant difference (P=.006).

For those patients requiring more than 1 session, the mean (SD) pain scores decreased by 0.75 (0.97) points and 0 points after the first and second sessions of treatment, respectively. The mean (SD) amount of PRGF infiltrated in each patient in the first session was 2.60 (0.63) mL. In the second session, the mean (SD) amount was 1.2 (0.33) mL; these differences were statistically significant (P=.008). In the last session, the mean (SD) amount was 1.1 (0.22) mL.

Follow-up and Adverse Effects—The mean (SD) follow-up time was 47.16 (15.78) months. The patients were free of symptoms, and there were no adverse effects derived from the treatment during follow-up.

Comment

The primary goal of OLP treatment is to stop the outbreaks.^1,9,13 The lack of potency of corticosteroids in some patients with OLP could be due in part to the inadequate selection of the vehicle (ointment/oral rinse) for the extension and characteristics of the lesion or because of an inappropriate prescription dose, time, and/or frequency, as described by González-Moles.¹⁷ However, even when using an appropriate protocol, some lesions are resistant to topical treatment and require other therapeutic modalities.^1,9,13 Previously proposed topical treatments include different immunosuppressants, such as the mammalian target of rapamycin, tacrolimus ointment 0.1%, pimecrolimus cream 1%, or cyclosporine A (50–100 mg/mL) formulations.¹⁸ Nevertheless, these drugs seem to have a greater number of side effects than topical steroids, and tacrolimus has been associated with cases of oral malignancy after continuing treatment.¹⁵

Severe and/or recalcitrant lesions and extraoral involvement have been successfully treated with systemic prednisone (40–80 mg/d).^1,9,13 Nevertheless, systemic corticosteroid toxicity requires that these treatments should be used only when necessary at the lowest possible dose and for the shortest possible duration.¹⁹ Other nonpharmacologic options for treatment are photodynamic, UV, and low-level laser therapy.^20,21 They have been accepted as supplementary modalities in different inflammatory skin conditions but present important technical requirements. Their effectiveness in corticosteroid-resistant cases have not been definitively assessed. Interestingly, promising results recently have been reported by Bennardo et al²² when comparing the efficacy of autologous platelet concentrates with triamcinolone injection.

In our study, the use of PRGF stopped the lesions’ evolution since the first treatment session, reducing them by 6.5-fold. The positive effects observed may have been promoted by the activity of different proteins present in PRGF (eg, platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor, epidermal growth factor, fibroblast growth factor, fibronectin). These molecules contribute to collagen synthesis; angiogenesis; endothelial cell migration and proliferation; or keratinocyte cell migration, proliferation, differentiation, growth, and migration—phenomena that are essential for healing and re-epithelialization.^23-25

Different studies also have supported an anti-inflammatory effect of PRGF mediated by an inhibition of the transcription of nuclear factor–κB and the expression of cyclooxygenase-2 and chemokine receptor type 4 produced by its high content of hepatocyte growth factor or the reduction of inflammatory marker expression, such as intercellular adhesion molecule 1. The development of an efficient 3-dimensional fibrin scaffold formation that occurs after PRGF administration also could facilitate healing, helping some cell populations to guide their position and function.^23-25

Limitations of our study include the small number of patients and the absence of a control group. The higher number of female patients in the study did not seem to affect the results, as differences related to gender have not been reported when treating patients with OLP with autologous platelet concentrates or other modalities of treatment.

Conclusion

Results from our study indicate that the use of PRGF could be a new treatment option for OLP cases refractory to conventional therapy. No complications were observed during the treatment procedure or during the complete follow-up period. Nonetheless, new prospective studies with a greater number of patients and longer follow-up periods are needed to confirm these preliminary results.

Lichen planus is a chronic inflammatory mucocutaneous disease that usually affects the skin and/or the genital and oral mucosae.^1,2 This disease classically presents with clinical relapses or outbreaks that alternate with periods of remission or latency. Oral lichen planus (OLP) can present with or without extraoral manifestation. It sometimes is difficult to differentiate OLP from oral lichenoid reactions, which can be related to dental materials, some drugs, and systemic conditions or can be idiopathic.^1,2

Oral lichen planus is one of the most common noninfectious diseases of the oral cavity, with a reported prevalence of 1% worldwide and marked geographical differences. In Europe, the prevalence of OLP ranges from 1% to 2%.^3,4 It is more frequent in women (1.5:1 to 2:1) and usually appears in the fourth and fifth decades of life.^1-4

The causes of OLP have not been entirely elucidated, but it is broadly accepted that there is a deregulation on different T lymphocytes that in turn causes effects on CD8 lymphocytes in response to an external noxa. This unknown “trigger” or starting factor also produces an impact on basal keratinocytes. Therefore, the pathogenesis of lichen planus is influenced by a series of cellular events mediated by different cytokines.^2,5,6 Among these, tumor necrosis factor α and IL-1 are known to have important roles in the disease. More recently, other cytokines, such as IL-4, secreted by type 2 helper T cells, also have been related to the development and progression of the oral lesions.^5,6 In addition to the factors that generate the onset of the disease, there are others that may precipitate clinical outbreaks. Different factors have been related to the progression of the disease, influencing the initiation, perpetuation, and/or worsening of OLP lesions.^1,2 Exactly how these factors affect disease progression is another challenging question. The list of possible or potential factors related to disease progression is long; nonetheless, in the vast majority, a clear explanation at a molecular level has not been clearly demonstrated.^2,5

Conventionally, 6 clinical presentations of OLP lesions divided into 2 main groups have been described in the oral cavity: white forms (reticular, papular, and plaquelike) and red forms (erythematous, atrophic-erosive, and bullous).^1,7-9

Oral lichen planus mainly is treated with topically or systemically administered steroids based on the presence of symptoms such as pain and inability to perform daily activities (eg, eating, talking).^5,10 The treatment of choice often is based on the professional’s experience, as there are no broadly accepted national or international clinical practice guidelines on steroid type, administration route, dose, vehicle for administration, or maintenance.¹¹ Despite this lack of unified criteria, different topical and systemic steroid administration protocols allow a reduction in the symptoms or even the disappearance of the red lesions to be achieved in many cases. Unfortunately, there are many patients with lesions refractory to standard treatments for OLP.¹² Several alternatives for these patients have been described in the literature, though on many occasions these alternatives present substantial side effects for the patient.¹³ The search for an effective treatment without side effects is still challenging. One of the treatments tested under this premise has been the application of plasma rich in growth factors (PRGF) by means of infiltration or topical application, in both cases obtaining good results without side effects.¹⁴

We sought to analyze the information from a case series of patients treated at the Eduardo Anitua Clinic (Vitoria-Gasteiz, Spain) and describe the results and follow-up of patients with erosive OLP refractory to standard therapy who have been successfully treated by local infiltration of PRGF as the only treatment.

Material and Methods

Patients—We included data from the database of the clinical center with de-identified information of patients with erosive OLP diagnosed clinically and histopathologically who did not respond to conventional treatment (ie, topical and/or systemic corticosteroids [depending on the case]) as well as patients who presented with extensive erosive OLP with systemic involvement and whose systemic treatment was not effective in resolving oral manifestations.

Therapies Administered and Evaluations—Lesions refractory to conventional corticosteroid protocols had been previously treated for 30 days with 0.5% triamcinolone acetonide mouth rinse followed by a cycle of 1% triamcinolone acetonide mouth rinse. Subsequently, a cycle of oral corticosteroids (prednisone for 30 days: 1 mg/kg/d in a single morning dose with staged reduction after the first week) had been administered. One dayafter the corticosteroid treatment was suspended, the patients were treated by PRGF-Endoret (BTI Biotechnology Institute) infiltration following the protocol described by Anitua et al.^15,16

Before starting the infiltrations with PRGF, the patient had been asked to rate the pain level on a visual analog scale (VAS) of 1 to 10, with 10 being the most intense imaginable pain. Pain score was subsequently rated and registered during every visit. An initial photograph of the lesion also was obtained to establish a starting point for further comparisons of clinical evolution of the lesions.

Prior to each infiltration, the plasma was separated into 2 fractions. The second fraction was the one that corresponded to the highest number of platelets and included the 2 mL of plasma just above the white series (or buffy coat). This fraction of plasma was the one used to infiltrate the lesions.

Plasma rich in growth factors was activated just before infiltration. The activation was done by adding 10% calcium chloride. Once activated, it was infiltrated into the active lesion using a 31-G × 1/6-in hypodermic needle and a 2-mL Luer-lock syringe. Infiltrations were performed without anesthesia. Four punctures were made for each ulcerative lesion, dividing the lesion into 4 points: upper, lower, right, and left. Plasma rich in growth factors was infiltrated until a slight blanching was observed in the surrounding tissue. At that moment, the infiltration was stopped and was carried out in the next infiltration site.

One treatment session was performed per week, with follow-up 1 week after treatment. In the control visit, the state of the lesions was re-evaluated, and it was decided whether new infiltrations were needed. The treatment was finished when complete epithelialization of the lesion was visualized or the associated symptoms disappeared. At each visit, photographs were taken, and the patient assessed the severity of pain on the VAS.

Statistical Analysis—A Shapiro-Wilk test was carried out with the obtained data to check the normal distribution of the sample. The evolution of pain during the study was compared by paired t test. The qualitative variables were described by means of a frequency analysis. Quantitative variables were described by the mean and the SD. The data were analyzed with SPSS V15.0 for Windows (SPSS Inc). P<.05 showed statistical significance.

Results

A total of 15 patients were included in the study, all with atrophic-erosive lichen planus. Two patients were male, and 13 were female. The mean age (SD) of the patients included in the study was 55.27 (14.19) years. The mean number of outbreaks per year (SD) was 3.2 (1.7), with a range of 1 to 8 outbreaks.

Healing of OLP Lesions—The number of treatment sessions to achieve complete healing varied among the patients (Figures 1 and 2). Ten patients (66.7%) required a single session, 2 patients (13.3%) required 2 sessions, and 3 patients (20%) required 3 sessions. The mean time (SD) without lesions for the patients who required a single session was 10.9 (5.2) months (range, 6–24 months).

Pain Assessment—The mean (SD) score obtained on the VAS before treatment with PRGF was 8.27 (1.16); this score dropped to 1.27 (1.53) after the first treatment session and was a statistically significant difference (P=.006).

For those patients requiring more than 1 session, the mean (SD) pain scores decreased by 0.75 (0.97) points and 0 points after the first and second sessions of treatment, respectively. The mean (SD) amount of PRGF infiltrated in each patient in the first session was 2.60 (0.63) mL. In the second session, the mean (SD) amount was 1.2 (0.33) mL; these differences were statistically significant (P=.008). In the last session, the mean (SD) amount was 1.1 (0.22) mL.

Follow-up and Adverse Effects—The mean (SD) follow-up time was 47.16 (15.78) months. The patients were free of symptoms, and there were no adverse effects derived from the treatment during follow-up.

Comment

The primary goal of OLP treatment is to stop the outbreaks.^1,9,13 The lack of potency of corticosteroids in some patients with OLP could be due in part to the inadequate selection of the vehicle (ointment/oral rinse) for the extension and characteristics of the lesion or because of an inappropriate prescription dose, time, and/or frequency, as described by González-Moles.¹⁷ However, even when using an appropriate protocol, some lesions are resistant to topical treatment and require other therapeutic modalities.^1,9,13 Previously proposed topical treatments include different immunosuppressants, such as the mammalian target of rapamycin, tacrolimus ointment 0.1%, pimecrolimus cream 1%, or cyclosporine A (50–100 mg/mL) formulations.¹⁸ Nevertheless, these drugs seem to have a greater number of side effects than topical steroids, and tacrolimus has been associated with cases of oral malignancy after continuing treatment.¹⁵

Severe and/or recalcitrant lesions and extraoral involvement have been successfully treated with systemic prednisone (40–80 mg/d).^1,9,13 Nevertheless, systemic corticosteroid toxicity requires that these treatments should be used only when necessary at the lowest possible dose and for the shortest possible duration.¹⁹ Other nonpharmacologic options for treatment are photodynamic, UV, and low-level laser therapy.^20,21 They have been accepted as supplementary modalities in different inflammatory skin conditions but present important technical requirements. Their effectiveness in corticosteroid-resistant cases have not been definitively assessed. Interestingly, promising results recently have been reported by Bennardo et al²² when comparing the efficacy of autologous platelet concentrates with triamcinolone injection.

In our study, the use of PRGF stopped the lesions’ evolution since the first treatment session, reducing them by 6.5-fold. The positive effects observed may have been promoted by the activity of different proteins present in PRGF (eg, platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor, epidermal growth factor, fibroblast growth factor, fibronectin). These molecules contribute to collagen synthesis; angiogenesis; endothelial cell migration and proliferation; or keratinocyte cell migration, proliferation, differentiation, growth, and migration—phenomena that are essential for healing and re-epithelialization.^23-25

Different studies also have supported an anti-inflammatory effect of PRGF mediated by an inhibition of the transcription of nuclear factor–κB and the expression of cyclooxygenase-2 and chemokine receptor type 4 produced by its high content of hepatocyte growth factor or the reduction of inflammatory marker expression, such as intercellular adhesion molecule 1. The development of an efficient 3-dimensional fibrin scaffold formation that occurs after PRGF administration also could facilitate healing, helping some cell populations to guide their position and function.^23-25

Limitations of our study include the small number of patients and the absence of a control group. The higher number of female patients in the study did not seem to affect the results, as differences related to gender have not been reported when treating patients with OLP with autologous platelet concentrates or other modalities of treatment.

Conclusion

Results from our study indicate that the use of PRGF could be a new treatment option for OLP cases refractory to conventional therapy. No complications were observed during the treatment procedure or during the complete follow-up period. Nonetheless, new prospective studies with a greater number of patients and longer follow-up periods are needed to confirm these preliminary results.

The number of monoclonal antibodies developed for therapeutic use has rapidly expanded over the last decade due to their generally favorable adverse effect (AE) profiles and efficacy.¹ Tumor necrosis factor α inhibitors and general integrin antagonists are well-known examples of such monoclonal antibodies. Common conditions utilizing immunotherapy include inflammatory bowel diseases (IBDs), such as Crohn disease and ulcerative colitis (UC).²

The monoclonal antibody vedolizumab, approved in 2014 for moderate to severe UC and Crohn disease, selectively antagonizes α4β7 integrin to target a specific population of gastrointestinal T lymphocytes, preventing their mobilization to areas of inflammation.³ Adverse effects in patients treated with vedolizumab occur at a rate comparable to placebo and largely are considered nonserious^4,5; the most commonly reported AE is disease exacerbation (13%–17% of patients).^5,6 Published reports of cutaneous AEs at administration of vedolizumab include urticaria during infusion, appearance of cutaneous manifestations characteristic of IBD, psoriasis, Henoch-Schönlein purpura, and Sweet syndrome.^7-10

We present the case of a 61-year-old woman with UC who developed reactive granulomatous dermatitis (RGD), interstitial granulomatous dermatitis (IGD) type secondary to vedolizumab. This adverse reaction has not, to our knowledge, been previously reported.

Case Report

A 61-year-old woman with a medical history of UC treated with vedolizumab and myelodysplastic syndrome treated with intravenous immunoglobulin (due to hypogammaglobulinemia following allogeneic stem cell transplantation 14 months prior) presented with a concern of a rash. The patient had been in a baseline state of health until 1 week after receiving her second dose of vedolizumab, at which time she developed a mildly pruritic maculopapular rash on the back and chest. Triamcinolone ointment and hydroxyzine were recommended during an initial telehealth consultation with an oncologist with minimal improvement. The rash continued to spread distally with worsening pruritus.

The patient returned to her oncologist for a routine follow-up appointment 5 days after initial teleconsultation. She reported poor oral intake due to oropharyngeal pain and a worsening rash; her husband added a report of recent onset of somnolence. She was admitted to the hospital, and intravenous fluids were administered.

At admission, the patient was hypotensive; vital signs were otherwise normal. Physical examination revealed the oropharynx was erythematous. Pink lichenoid papules coalescing into plaques were present diffusely across the trunk, arms, and legs; the hands, feet, and face were spared (Figure 1).

Photograph courtesy of William Beuerlein, DO (Jacksonville, Florida).

A complete blood cell count and comprehensive metabolic panel were unremarkable. A lumbar puncture, chest radiograph, blood cultures, urinalysis, and urine cultures did not identify a clear infectious cause for the rash, though the workup for infection did raise concern about active cytomegalovirus (CMV) infection with colitis and pneumonitis. Computed tomography of the head showed no acute hemorrhage.

Dermatology was consulted and determined that the appearance of the rash was most consistent with a lichenoid drug eruption, likely secondary to vedolizumab that was administered 1 week before the rash onset. Analysis of a skin biopsy revealed a dense dermal histiocytic and lymphocytic infiltrate in close approximation to blood vessels, confirmed by immunohistochemical staining for CD45, CD43, CD68, CD34, c-KIT, and myeloperoxidase (Figures 2A and 2B). Colloidal iron staining of the specimen revealed no mucin (Figure 2C).

Photographs courtesy of William Beuerlein, DO (Jacksonville, Florida) and Angela Niehaus, MD (WinstonSalem, North Carolina).

Taken together, the clinical presentation and histopathologic findings were determined to be most consistent with RGD, IGD type, with secondary vasculitis due to vedolizumab. The patient was treated with triamcinolone ointment and low-dose prednisone. Vedolizumab was discontinued. The rash resolved several weeks after cessation of vedolizumab.

Comment

This case describes the development of RGD, IGD type, as an AE of vedolizumab for the treatment of IBD. Reactive granulomatous dermatitis encompasses a spectrum of cutaneous reactions that includes the diagnosis formerly distinctly identified as IGD.¹¹ This variety of RGD is characterized by histologic findings of heavy histiocytic inflammation in the reticular layer of the dermis with interstitial and perivascular neutrophils, lymphocytes, and histiocytes, as well as the absence of mucin. Interstitial granulomatous dermatitis–type reactions commonly are associated with autoimmune conditions and medications, with accumulating examples occurring in the setting of other biologic therapies, including the IL-6 receptor inhibitor tocilizumab; the programmed death receptor-1 inhibitor nivolumab; and the tumor necrosis factor α inhibitors infliximab, etanercept, and adalimumab.^12-15

Although our patient represents CMV infection while being treated with vedolizumab, the relationship between the two is unclear. Development of CMV infection while receiving vedolizumab has been reported in the literature in a patient who was concurrently immunosuppressed with azathioprine.¹⁶ In contrast, vedolizumab administration has been utilized as a treatment of CMV infection in IBD patients, either alone or in combination with antiviral agents, with successful resolution of infection.^17,18 Additional observations of the interaction between CMV infection and vedolizumab would be required to determine if the onset of CMV infection in this patient represents an additional risk of the medication.

Identifying a relationship between a monoclonal antibody therapy, such as vedolizumab, and RGD, IGD type, might be difficult in clinical practice, particularly if this type of reaction has not been previously associated with the culprit medication. In our patient, onset of cutaneous findings in relation to dosing of vedolizumab and exclusion of other possible causes of the rash supported the decision to stop vedolizumab. However, this decision often is challenging in patients with multiple concurrent medical conditions and those whose therapeutic options are limited.

Conclusion

Ulcerative colitis is not an uncommon condition; utilization of targeted monoclonal antibodies as a treatment strategy is expanding.^2,19 As implementation of vedolizumab as a targeted biologic therapy for this disease increases, additional cases of IGD might emerge with greater frequency. Because IBD and autoimmune conditions have a tendency to coincide, awareness of the reaction presented here might be particularly important for dermatologists managing cutaneous manifestations of autoimmune conditions, as patients might present with a clinical picture complicated by preexisting skin findings.²⁰ Furthermore, as reports of RGD, IGD type, in response to several monoclonal antibodies accumulate, it is prudent for all physicians to be aware of this potential complication of this class of medication so that they can make educated decisions about continuing monoclonal antibody therapy.

The number of monoclonal antibodies developed for therapeutic use has rapidly expanded over the last decade due to their generally favorable adverse effect (AE) profiles and efficacy.¹ Tumor necrosis factor α inhibitors and general integrin antagonists are well-known examples of such monoclonal antibodies. Common conditions utilizing immunotherapy include inflammatory bowel diseases (IBDs), such as Crohn disease and ulcerative colitis (UC).²

The monoclonal antibody vedolizumab, approved in 2014 for moderate to severe UC and Crohn disease, selectively antagonizes α4β7 integrin to target a specific population of gastrointestinal T lymphocytes, preventing their mobilization to areas of inflammation.³ Adverse effects in patients treated with vedolizumab occur at a rate comparable to placebo and largely are considered nonserious^4,5; the most commonly reported AE is disease exacerbation (13%–17% of patients).^5,6 Published reports of cutaneous AEs at administration of vedolizumab include urticaria during infusion, appearance of cutaneous manifestations characteristic of IBD, psoriasis, Henoch-Schönlein purpura, and Sweet syndrome.^7-10

We present the case of a 61-year-old woman with UC who developed reactive granulomatous dermatitis (RGD), interstitial granulomatous dermatitis (IGD) type secondary to vedolizumab. This adverse reaction has not, to our knowledge, been previously reported.

Case Report

A 61-year-old woman with a medical history of UC treated with vedolizumab and myelodysplastic syndrome treated with intravenous immunoglobulin (due to hypogammaglobulinemia following allogeneic stem cell transplantation 14 months prior) presented with a concern of a rash. The patient had been in a baseline state of health until 1 week after receiving her second dose of vedolizumab, at which time she developed a mildly pruritic maculopapular rash on the back and chest. Triamcinolone ointment and hydroxyzine were recommended during an initial telehealth consultation with an oncologist with minimal improvement. The rash continued to spread distally with worsening pruritus.

The patient returned to her oncologist for a routine follow-up appointment 5 days after initial teleconsultation. She reported poor oral intake due to oropharyngeal pain and a worsening rash; her husband added a report of recent onset of somnolence. She was admitted to the hospital, and intravenous fluids were administered.

At admission, the patient was hypotensive; vital signs were otherwise normal. Physical examination revealed the oropharynx was erythematous. Pink lichenoid papules coalescing into plaques were present diffusely across the trunk, arms, and legs; the hands, feet, and face were spared (Figure 1).

Photograph courtesy of William Beuerlein, DO (Jacksonville, Florida).

A complete blood cell count and comprehensive metabolic panel were unremarkable. A lumbar puncture, chest radiograph, blood cultures, urinalysis, and urine cultures did not identify a clear infectious cause for the rash, though the workup for infection did raise concern about active cytomegalovirus (CMV) infection with colitis and pneumonitis. Computed tomography of the head showed no acute hemorrhage.

Dermatology was consulted and determined that the appearance of the rash was most consistent with a lichenoid drug eruption, likely secondary to vedolizumab that was administered 1 week before the rash onset. Analysis of a skin biopsy revealed a dense dermal histiocytic and lymphocytic infiltrate in close approximation to blood vessels, confirmed by immunohistochemical staining for CD45, CD43, CD68, CD34, c-KIT, and myeloperoxidase (Figures 2A and 2B). Colloidal iron staining of the specimen revealed no mucin (Figure 2C).

Photographs courtesy of William Beuerlein, DO (Jacksonville, Florida) and Angela Niehaus, MD (WinstonSalem, North Carolina).

Taken together, the clinical presentation and histopathologic findings were determined to be most consistent with RGD, IGD type, with secondary vasculitis due to vedolizumab. The patient was treated with triamcinolone ointment and low-dose prednisone. Vedolizumab was discontinued. The rash resolved several weeks after cessation of vedolizumab.

Comment

This case describes the development of RGD, IGD type, as an AE of vedolizumab for the treatment of IBD. Reactive granulomatous dermatitis encompasses a spectrum of cutaneous reactions that includes the diagnosis formerly distinctly identified as IGD.¹¹ This variety of RGD is characterized by histologic findings of heavy histiocytic inflammation in the reticular layer of the dermis with interstitial and perivascular neutrophils, lymphocytes, and histiocytes, as well as the absence of mucin. Interstitial granulomatous dermatitis–type reactions commonly are associated with autoimmune conditions and medications, with accumulating examples occurring in the setting of other biologic therapies, including the IL-6 receptor inhibitor tocilizumab; the programmed death receptor-1 inhibitor nivolumab; and the tumor necrosis factor α inhibitors infliximab, etanercept, and adalimumab.^12-15

Although our patient represents CMV infection while being treated with vedolizumab, the relationship between the two is unclear. Development of CMV infection while receiving vedolizumab has been reported in the literature in a patient who was concurrently immunosuppressed with azathioprine.¹⁶ In contrast, vedolizumab administration has been utilized as a treatment of CMV infection in IBD patients, either alone or in combination with antiviral agents, with successful resolution of infection.^17,18 Additional observations of the interaction between CMV infection and vedolizumab would be required to determine if the onset of CMV infection in this patient represents an additional risk of the medication.

Identifying a relationship between a monoclonal antibody therapy, such as vedolizumab, and RGD, IGD type, might be difficult in clinical practice, particularly if this type of reaction has not been previously associated with the culprit medication. In our patient, onset of cutaneous findings in relation to dosing of vedolizumab and exclusion of other possible causes of the rash supported the decision to stop vedolizumab. However, this decision often is challenging in patients with multiple concurrent medical conditions and those whose therapeutic options are limited.

Conclusion

Ulcerative colitis is not an uncommon condition; utilization of targeted monoclonal antibodies as a treatment strategy is expanding.^2,19 As implementation of vedolizumab as a targeted biologic therapy for this disease increases, additional cases of IGD might emerge with greater frequency. Because IBD and autoimmune conditions have a tendency to coincide, awareness of the reaction presented here might be particularly important for dermatologists managing cutaneous manifestations of autoimmune conditions, as patients might present with a clinical picture complicated by preexisting skin findings.²⁰ Furthermore, as reports of RGD, IGD type, in response to several monoclonal antibodies accumulate, it is prudent for all physicians to be aware of this potential complication of this class of medication so that they can make educated decisions about continuing monoclonal antibody therapy.

The number of monoclonal antibodies developed for therapeutic use has rapidly expanded over the last decade due to their generally favorable adverse effect (AE) profiles and efficacy.¹ Tumor necrosis factor α inhibitors and general integrin antagonists are well-known examples of such monoclonal antibodies. Common conditions utilizing immunotherapy include inflammatory bowel diseases (IBDs), such as Crohn disease and ulcerative colitis (UC).²

The monoclonal antibody vedolizumab, approved in 2014 for moderate to severe UC and Crohn disease, selectively antagonizes α4β7 integrin to target a specific population of gastrointestinal T lymphocytes, preventing their mobilization to areas of inflammation.³ Adverse effects in patients treated with vedolizumab occur at a rate comparable to placebo and largely are considered nonserious^4,5; the most commonly reported AE is disease exacerbation (13%–17% of patients).^5,6 Published reports of cutaneous AEs at administration of vedolizumab include urticaria during infusion, appearance of cutaneous manifestations characteristic of IBD, psoriasis, Henoch-Schönlein purpura, and Sweet syndrome.^7-10

We present the case of a 61-year-old woman with UC who developed reactive granulomatous dermatitis (RGD), interstitial granulomatous dermatitis (IGD) type secondary to vedolizumab. This adverse reaction has not, to our knowledge, been previously reported.

Case Report

A 61-year-old woman with a medical history of UC treated with vedolizumab and myelodysplastic syndrome treated with intravenous immunoglobulin (due to hypogammaglobulinemia following allogeneic stem cell transplantation 14 months prior) presented with a concern of a rash. The patient had been in a baseline state of health until 1 week after receiving her second dose of vedolizumab, at which time she developed a mildly pruritic maculopapular rash on the back and chest. Triamcinolone ointment and hydroxyzine were recommended during an initial telehealth consultation with an oncologist with minimal improvement. The rash continued to spread distally with worsening pruritus.

The patient returned to her oncologist for a routine follow-up appointment 5 days after initial teleconsultation. She reported poor oral intake due to oropharyngeal pain and a worsening rash; her husband added a report of recent onset of somnolence. She was admitted to the hospital, and intravenous fluids were administered.

At admission, the patient was hypotensive; vital signs were otherwise normal. Physical examination revealed the oropharynx was erythematous. Pink lichenoid papules coalescing into plaques were present diffusely across the trunk, arms, and legs; the hands, feet, and face were spared (Figure 1).

Photograph courtesy of William Beuerlein, DO (Jacksonville, Florida).

A complete blood cell count and comprehensive metabolic panel were unremarkable. A lumbar puncture, chest radiograph, blood cultures, urinalysis, and urine cultures did not identify a clear infectious cause for the rash, though the workup for infection did raise concern about active cytomegalovirus (CMV) infection with colitis and pneumonitis. Computed tomography of the head showed no acute hemorrhage.

Dermatology was consulted and determined that the appearance of the rash was most consistent with a lichenoid drug eruption, likely secondary to vedolizumab that was administered 1 week before the rash onset. Analysis of a skin biopsy revealed a dense dermal histiocytic and lymphocytic infiltrate in close approximation to blood vessels, confirmed by immunohistochemical staining for CD45, CD43, CD68, CD34, c-KIT, and myeloperoxidase (Figures 2A and 2B). Colloidal iron staining of the specimen revealed no mucin (Figure 2C).

Photographs courtesy of William Beuerlein, DO (Jacksonville, Florida) and Angela Niehaus, MD (WinstonSalem, North Carolina).

Taken together, the clinical presentation and histopathologic findings were determined to be most consistent with RGD, IGD type, with secondary vasculitis due to vedolizumab. The patient was treated with triamcinolone ointment and low-dose prednisone. Vedolizumab was discontinued. The rash resolved several weeks after cessation of vedolizumab.

Comment

This case describes the development of RGD, IGD type, as an AE of vedolizumab for the treatment of IBD. Reactive granulomatous dermatitis encompasses a spectrum of cutaneous reactions that includes the diagnosis formerly distinctly identified as IGD.¹¹ This variety of RGD is characterized by histologic findings of heavy histiocytic inflammation in the reticular layer of the dermis with interstitial and perivascular neutrophils, lymphocytes, and histiocytes, as well as the absence of mucin. Interstitial granulomatous dermatitis–type reactions commonly are associated with autoimmune conditions and medications, with accumulating examples occurring in the setting of other biologic therapies, including the IL-6 receptor inhibitor tocilizumab; the programmed death receptor-1 inhibitor nivolumab; and the tumor necrosis factor α inhibitors infliximab, etanercept, and adalimumab.^12-15

Although our patient represents CMV infection while being treated with vedolizumab, the relationship between the two is unclear. Development of CMV infection while receiving vedolizumab has been reported in the literature in a patient who was concurrently immunosuppressed with azathioprine.¹⁶ In contrast, vedolizumab administration has been utilized as a treatment of CMV infection in IBD patients, either alone or in combination with antiviral agents, with successful resolution of infection.^17,18 Additional observations of the interaction between CMV infection and vedolizumab would be required to determine if the onset of CMV infection in this patient represents an additional risk of the medication.

Identifying a relationship between a monoclonal antibody therapy, such as vedolizumab, and RGD, IGD type, might be difficult in clinical practice, particularly if this type of reaction has not been previously associated with the culprit medication. In our patient, onset of cutaneous findings in relation to dosing of vedolizumab and exclusion of other possible causes of the rash supported the decision to stop vedolizumab. However, this decision often is challenging in patients with multiple concurrent medical conditions and those whose therapeutic options are limited.

Conclusion

Ulcerative colitis is not an uncommon condition; utilization of targeted monoclonal antibodies as a treatment strategy is expanding.^2,19 As implementation of vedolizumab as a targeted biologic therapy for this disease increases, additional cases of IGD might emerge with greater frequency. Because IBD and autoimmune conditions have a tendency to coincide, awareness of the reaction presented here might be particularly important for dermatologists managing cutaneous manifestations of autoimmune conditions, as patients might present with a clinical picture complicated by preexisting skin findings.²⁰ Furthermore, as reports of RGD, IGD type, in response to several monoclonal antibodies accumulate, it is prudent for all physicians to be aware of this potential complication of this class of medication so that they can make educated decisions about continuing monoclonal antibody therapy.

Current selection criteria for autologous hematopoietic stem cell transplant (AHSCT) in patients with rapidly progressing systemic sclerosis were validated in a study presented at the annual meeting of the Canadian Rheumatology Association.

The study, which associated AHSCT with improvement in overall survival and an acceptable risk of adverse events, “provides valuable real-world, long-term data pertaining to key clinical outcomes to support the use of AHSCT in patients with rapidly progressing systemic sclerosis,” reported Nancy Maltez, MD, a rheumatologist and clinical investigator who is on the faculty of the University of Ottawa.

Fnaq / Wikimedia Commons / CC BY-SA 4.0

The prospective study enrolled 85 patients in Canada and 41 patients in France with rapidly progressing systemic sclerosis. The patients in both countries were enrolled with the same eligibility criteria for AHSCT, but patients in France underwent AHSCT while the patients in Canada were treated with conventional therapies, such as cyclophosphamide.

On the primary outcome of overall survival, the Kaplan-Meier curve split almost immediately in favor of AHSCT. At 4 years, more than 25% of patients in the conventional therapy group had died versus less than 5% of those who underwent AHSCT. Although the mortality curve did slope downwards in the AHSCT group over the subsequent 6 years of follow-up, it largely paralleled and remained superior to convention therapy.
 

About 50% survival advantage seen for AHSCT

In this nonrandomized study, the statistical survival advantage of AHSCT was not provided, but the survival graph showed about 75% survival at 8 years of follow-up in the AHSCT group, compared with about 50% survival in the conventional-therapy group.

Many of the secondary outcomes, including those evaluating skin involvement, preservation of lung function, and absence of renal complications also favored AHSCT, according to Dr. Maltez.

On the modified Rodnan skin score, a significant difference (P < .001) observed at 12 months was sustained at 36 months, when the score was 4.48 points lower among patients treated with AHSCT. The difference in forced vital capacity (FVC) was about 10% higher (P < .0001) in the AHSCT group.

Over long-term follow-up, the incidence of scleroderma renal crisis per 100 person-years was 6.02 cases in the conventional therapy group versus 0.58 cases (P < .001) in the AHSCT group. There was no significant difference in the proportion of patients in the two groups receiving a pacemaker over the course of follow-up, but the rate of new malignancies per 100 person-years was 3.71 in the conventional care group versus 0.58 (P < .001) in the AHSCT group.

Significant complications attributed to AHSCT were uncommon. This is important, because AHSCT was not uniformly well tolerated in the initial trials. The first of three randomized trials with AHSCT in progressive systemic sclerosis was published more than 10 years ago after a series of promising early phase trials. Each associated AHSCT with benefit, but patient selection appeared to be important.

In the ASSIST trial of 2011, AHSCT was associated with significant reductions in skin involvement and improvements in pulmonary function relative to cyclophosphamide, but enrollment was stopped after only 19 patients, and follow-up extended to only 2 years.

Substantial AHSCT-related mortality in ASTIS

In the second trial, called ASTIS, AHSCT was associated with a higher rate of mortality than cyclophosphamide after 1 year of follow-up, although there was a significantly greater long-term event-free survival for AHSCT when patients were followed out to 4 years. This study reinforced the need for cardiac screening because of because of concern that severe cardiac compromise contributed to the increased risk of AHSCT-related mortality.

The SCOT trial employed a high-intensity myeloablative conditioning regimen and total body irradiation prior to AHSCT. It is not clear that these contributed to improved survival, particularly because of the risk for irradiation to exacerbate complications in the lung and kidney, but AHSCT-related mortality was only 3% at 54 months. Patient enrollment criteria in this trial were also suspected of having played a role in the favorable results.

In the Canadian-French collaborative study, patients were considered eligible for AHSCT if they met the enrollment criteria used in the ASTIS trial, according to Dr. Maltez. She attributed the low rates of early mortality and relative absence of transplant-related death to the lessons learned in the published trials.

Overall, the data support the routine but selective use of AHSCT in rapidly progressing systemic sclerosis, Dr. Maltez concluded.

Maria Carolina Oliveira, MD, of the department of internal medicine at the University of São Paulo, generally agreed. A coauthor of a recent review of AHSCT for systemic sclerosis, Dr. Oliveira emphasized that patient selection is critical.

“AHSCT for systemic sclerosis has very specific inclusion criteria. Indeed, it is indicated for patients with severe and progressive disease but under two specific conditions: severe and progressive diffuse skin involvement and/or progressive interstitial lung disease,” she said in an interview.

Because of the thin line between benefit and risk according to disease subtypes and comorbidities, she said that it is important to be aware of relative contraindications and to recognize the risks of AHSCT.

At this time, and in the absence of better biomarkers to identify those most likely to benefit, “patients with other forms of severe scleroderma, such as those with pulmonary hypertension, scleroderma renal crisis, or severe cardiac involvement, for example, are not eligible,” she said.

Dr. Maltez and Dr. Oliveira reported having no potential conflicts of interest.

Current selection criteria for autologous hematopoietic stem cell transplant (AHSCT) in patients with rapidly progressing systemic sclerosis were validated in a study presented at the annual meeting of the Canadian Rheumatology Association.

The study, which associated AHSCT with improvement in overall survival and an acceptable risk of adverse events, “provides valuable real-world, long-term data pertaining to key clinical outcomes to support the use of AHSCT in patients with rapidly progressing systemic sclerosis,” reported Nancy Maltez, MD, a rheumatologist and clinical investigator who is on the faculty of the University of Ottawa.

Fnaq / Wikimedia Commons / CC BY-SA 4.0

The prospective study enrolled 85 patients in Canada and 41 patients in France with rapidly progressing systemic sclerosis. The patients in both countries were enrolled with the same eligibility criteria for AHSCT, but patients in France underwent AHSCT while the patients in Canada were treated with conventional therapies, such as cyclophosphamide.

On the primary outcome of overall survival, the Kaplan-Meier curve split almost immediately in favor of AHSCT. At 4 years, more than 25% of patients in the conventional therapy group had died versus less than 5% of those who underwent AHSCT. Although the mortality curve did slope downwards in the AHSCT group over the subsequent 6 years of follow-up, it largely paralleled and remained superior to convention therapy.
 

About 50% survival advantage seen for AHSCT

In this nonrandomized study, the statistical survival advantage of AHSCT was not provided, but the survival graph showed about 75% survival at 8 years of follow-up in the AHSCT group, compared with about 50% survival in the conventional-therapy group.

Many of the secondary outcomes, including those evaluating skin involvement, preservation of lung function, and absence of renal complications also favored AHSCT, according to Dr. Maltez.

On the modified Rodnan skin score, a significant difference (P < .001) observed at 12 months was sustained at 36 months, when the score was 4.48 points lower among patients treated with AHSCT. The difference in forced vital capacity (FVC) was about 10% higher (P < .0001) in the AHSCT group.

Over long-term follow-up, the incidence of scleroderma renal crisis per 100 person-years was 6.02 cases in the conventional therapy group versus 0.58 cases (P < .001) in the AHSCT group. There was no significant difference in the proportion of patients in the two groups receiving a pacemaker over the course of follow-up, but the rate of new malignancies per 100 person-years was 3.71 in the conventional care group versus 0.58 (P < .001) in the AHSCT group.

Significant complications attributed to AHSCT were uncommon. This is important, because AHSCT was not uniformly well tolerated in the initial trials. The first of three randomized trials with AHSCT in progressive systemic sclerosis was published more than 10 years ago after a series of promising early phase trials. Each associated AHSCT with benefit, but patient selection appeared to be important.

In the ASSIST trial of 2011, AHSCT was associated with significant reductions in skin involvement and improvements in pulmonary function relative to cyclophosphamide, but enrollment was stopped after only 19 patients, and follow-up extended to only 2 years.

Substantial AHSCT-related mortality in ASTIS

In the second trial, called ASTIS, AHSCT was associated with a higher rate of mortality than cyclophosphamide after 1 year of follow-up, although there was a significantly greater long-term event-free survival for AHSCT when patients were followed out to 4 years. This study reinforced the need for cardiac screening because of because of concern that severe cardiac compromise contributed to the increased risk of AHSCT-related mortality.

The SCOT trial employed a high-intensity myeloablative conditioning regimen and total body irradiation prior to AHSCT. It is not clear that these contributed to improved survival, particularly because of the risk for irradiation to exacerbate complications in the lung and kidney, but AHSCT-related mortality was only 3% at 54 months. Patient enrollment criteria in this trial were also suspected of having played a role in the favorable results.

In the Canadian-French collaborative study, patients were considered eligible for AHSCT if they met the enrollment criteria used in the ASTIS trial, according to Dr. Maltez. She attributed the low rates of early mortality and relative absence of transplant-related death to the lessons learned in the published trials.

Overall, the data support the routine but selective use of AHSCT in rapidly progressing systemic sclerosis, Dr. Maltez concluded.

Maria Carolina Oliveira, MD, of the department of internal medicine at the University of São Paulo, generally agreed. A coauthor of a recent review of AHSCT for systemic sclerosis, Dr. Oliveira emphasized that patient selection is critical.

“AHSCT for systemic sclerosis has very specific inclusion criteria. Indeed, it is indicated for patients with severe and progressive disease but under two specific conditions: severe and progressive diffuse skin involvement and/or progressive interstitial lung disease,” she said in an interview.

Because of the thin line between benefit and risk according to disease subtypes and comorbidities, she said that it is important to be aware of relative contraindications and to recognize the risks of AHSCT.

At this time, and in the absence of better biomarkers to identify those most likely to benefit, “patients with other forms of severe scleroderma, such as those with pulmonary hypertension, scleroderma renal crisis, or severe cardiac involvement, for example, are not eligible,” she said.

Dr. Maltez and Dr. Oliveira reported having no potential conflicts of interest.

Current selection criteria for autologous hematopoietic stem cell transplant (AHSCT) in patients with rapidly progressing systemic sclerosis were validated in a study presented at the annual meeting of the Canadian Rheumatology Association.

The study, which associated AHSCT with improvement in overall survival and an acceptable risk of adverse events, “provides valuable real-world, long-term data pertaining to key clinical outcomes to support the use of AHSCT in patients with rapidly progressing systemic sclerosis,” reported Nancy Maltez, MD, a rheumatologist and clinical investigator who is on the faculty of the University of Ottawa.

Fnaq / Wikimedia Commons / CC BY-SA 4.0

The prospective study enrolled 85 patients in Canada and 41 patients in France with rapidly progressing systemic sclerosis. The patients in both countries were enrolled with the same eligibility criteria for AHSCT, but patients in France underwent AHSCT while the patients in Canada were treated with conventional therapies, such as cyclophosphamide.

On the primary outcome of overall survival, the Kaplan-Meier curve split almost immediately in favor of AHSCT. At 4 years, more than 25% of patients in the conventional therapy group had died versus less than 5% of those who underwent AHSCT. Although the mortality curve did slope downwards in the AHSCT group over the subsequent 6 years of follow-up, it largely paralleled and remained superior to convention therapy.
 

About 50% survival advantage seen for AHSCT

In this nonrandomized study, the statistical survival advantage of AHSCT was not provided, but the survival graph showed about 75% survival at 8 years of follow-up in the AHSCT group, compared with about 50% survival in the conventional-therapy group.

Many of the secondary outcomes, including those evaluating skin involvement, preservation of lung function, and absence of renal complications also favored AHSCT, according to Dr. Maltez.

On the modified Rodnan skin score, a significant difference (P < .001) observed at 12 months was sustained at 36 months, when the score was 4.48 points lower among patients treated with AHSCT. The difference in forced vital capacity (FVC) was about 10% higher (P < .0001) in the AHSCT group.

Over long-term follow-up, the incidence of scleroderma renal crisis per 100 person-years was 6.02 cases in the conventional therapy group versus 0.58 cases (P < .001) in the AHSCT group. There was no significant difference in the proportion of patients in the two groups receiving a pacemaker over the course of follow-up, but the rate of new malignancies per 100 person-years was 3.71 in the conventional care group versus 0.58 (P < .001) in the AHSCT group.

Significant complications attributed to AHSCT were uncommon. This is important, because AHSCT was not uniformly well tolerated in the initial trials. The first of three randomized trials with AHSCT in progressive systemic sclerosis was published more than 10 years ago after a series of promising early phase trials. Each associated AHSCT with benefit, but patient selection appeared to be important.

In the ASSIST trial of 2011, AHSCT was associated with significant reductions in skin involvement and improvements in pulmonary function relative to cyclophosphamide, but enrollment was stopped after only 19 patients, and follow-up extended to only 2 years.

Substantial AHSCT-related mortality in ASTIS

In the second trial, called ASTIS, AHSCT was associated with a higher rate of mortality than cyclophosphamide after 1 year of follow-up, although there was a significantly greater long-term event-free survival for AHSCT when patients were followed out to 4 years. This study reinforced the need for cardiac screening because of because of concern that severe cardiac compromise contributed to the increased risk of AHSCT-related mortality.

The SCOT trial employed a high-intensity myeloablative conditioning regimen and total body irradiation prior to AHSCT. It is not clear that these contributed to improved survival, particularly because of the risk for irradiation to exacerbate complications in the lung and kidney, but AHSCT-related mortality was only 3% at 54 months. Patient enrollment criteria in this trial were also suspected of having played a role in the favorable results.

In the Canadian-French collaborative study, patients were considered eligible for AHSCT if they met the enrollment criteria used in the ASTIS trial, according to Dr. Maltez. She attributed the low rates of early mortality and relative absence of transplant-related death to the lessons learned in the published trials.

Overall, the data support the routine but selective use of AHSCT in rapidly progressing systemic sclerosis, Dr. Maltez concluded.

Maria Carolina Oliveira, MD, of the department of internal medicine at the University of São Paulo, generally agreed. A coauthor of a recent review of AHSCT for systemic sclerosis, Dr. Oliveira emphasized that patient selection is critical.

“AHSCT for systemic sclerosis has very specific inclusion criteria. Indeed, it is indicated for patients with severe and progressive disease but under two specific conditions: severe and progressive diffuse skin involvement and/or progressive interstitial lung disease,” she said in an interview.

Because of the thin line between benefit and risk according to disease subtypes and comorbidities, she said that it is important to be aware of relative contraindications and to recognize the risks of AHSCT.

At this time, and in the absence of better biomarkers to identify those most likely to benefit, “patients with other forms of severe scleroderma, such as those with pulmonary hypertension, scleroderma renal crisis, or severe cardiac involvement, for example, are not eligible,” she said.

Dr. Maltez and Dr. Oliveira reported having no potential conflicts of interest.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

The Diagnosis: Pemphigoid Gestationis

A lesional biopsy showed a subepidermal split with eosinophils and neutrophils. Perilesional biopsy for direct immunofluorescence (DIF) showed linear deposition of 3+ C3 along the basement membrane zone. The clinical, histopathologic, and immunofluorescent findings were consistent with pemphigoid gestationis (PG). Prednisone 1 mg/kg daily was initiated. Her condition continued to worsen, and cyclosporine 250 mg daily was added while prednisone was tapered, with remission of disease.

Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy, with an incidence of 1 in 50,000 to 60,000 pregnancies.¹ In terms of pathogenesis, aberrant expression of major histocompatibility complex class II molecules on placental tissues causes the loss of immune tolerance of the placenta, which leads to the production of antibodies against the placental protein bullous pemphigoid 180.² Bullous pemphigoid 180 also is a hemidesmosomal protein found in the skin of the mother; therefore, the presence of the circulating antibodies leads to separation at the dermoepidermal junction and vesiculation.

Pemphigoid gestationis is characterized by the sudden eruption of intensely pruritic urticarial papules and plaques, classically with periumbilical involvement. Tense vesicles and bullae can develop. Women with PG have an increased risk for development of Graves disease. Histopathology shows subepidermal vesiculation with a predominance of eosinophils. Direct immunofluorescence classically shows linear deposition of C3 along the basement membrane zone. Fetal complications include prematurity and small size for gestational age. Additionally, blisters can be seen in 5% to 10% of neonates due to placental transmission of autoantibodies.³

Frequently PG flares shortly postpartum. Pemphigoid gestationis resolves within 6 months postdelivery but frequently reoccurs in subsequent pregnancies. Mild disease can be treated with mid- to high-potency topical corticosteroids. Severe disease is managed with oral corticosteroids, most commonly prednisone. Refractory disease is managed with azathioprine, cyclosporine, intravenous immunoglobulin, or plasmapheresis.

The differential diagnosis of PG includes other pregnancy-associated dermatoses such as atopic eruption of pregnancy, impetigo herpetiformis, intrahepatic cholestasis of pregnancy, and polymorphous eruption of pregnancy. Atopic eruption of pregnancy is the most common dermatosis of pregnancy and is characterized by an eczematous eruption in patients with an atopic history, typically in the first trimester. Blisters are not seen, and DIF is negative. Impetigo herpetiformis, or pustular psoriasis of pregnancy, is a variant of generalized pustular psoriasis that occurs during pregnancy. Diffuse erythematous patches studded with pustules, rather than vesicles, are seen; DIF is negative. Intrahepatic cholestasis of pregnancy presents without primary skin findings and severe pruritus predominantly on the palms and soles, often with secondary excoriations. Polymorphous eruption of pregnancy presents as a polymorphous eruption of urticarial to erythematous papules and plaques commonly originating in striae. In contrast to PG, there is periumbilical sparing, vesiculation is rare, and DIF is negative.

The Diagnosis: Pemphigoid Gestationis

A lesional biopsy showed a subepidermal split with eosinophils and neutrophils. Perilesional biopsy for direct immunofluorescence (DIF) showed linear deposition of 3+ C3 along the basement membrane zone. The clinical, histopathologic, and immunofluorescent findings were consistent with pemphigoid gestationis (PG). Prednisone 1 mg/kg daily was initiated. Her condition continued to worsen, and cyclosporine 250 mg daily was added while prednisone was tapered, with remission of disease.

Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy, with an incidence of 1 in 50,000 to 60,000 pregnancies.¹ In terms of pathogenesis, aberrant expression of major histocompatibility complex class II molecules on placental tissues causes the loss of immune tolerance of the placenta, which leads to the production of antibodies against the placental protein bullous pemphigoid 180.² Bullous pemphigoid 180 also is a hemidesmosomal protein found in the skin of the mother; therefore, the presence of the circulating antibodies leads to separation at the dermoepidermal junction and vesiculation.

Pemphigoid gestationis is characterized by the sudden eruption of intensely pruritic urticarial papules and plaques, classically with periumbilical involvement. Tense vesicles and bullae can develop. Women with PG have an increased risk for development of Graves disease. Histopathology shows subepidermal vesiculation with a predominance of eosinophils. Direct immunofluorescence classically shows linear deposition of C3 along the basement membrane zone. Fetal complications include prematurity and small size for gestational age. Additionally, blisters can be seen in 5% to 10% of neonates due to placental transmission of autoantibodies.³

Frequently PG flares shortly postpartum. Pemphigoid gestationis resolves within 6 months postdelivery but frequently reoccurs in subsequent pregnancies. Mild disease can be treated with mid- to high-potency topical corticosteroids. Severe disease is managed with oral corticosteroids, most commonly prednisone. Refractory disease is managed with azathioprine, cyclosporine, intravenous immunoglobulin, or plasmapheresis.

The differential diagnosis of PG includes other pregnancy-associated dermatoses such as atopic eruption of pregnancy, impetigo herpetiformis, intrahepatic cholestasis of pregnancy, and polymorphous eruption of pregnancy. Atopic eruption of pregnancy is the most common dermatosis of pregnancy and is characterized by an eczematous eruption in patients with an atopic history, typically in the first trimester. Blisters are not seen, and DIF is negative. Impetigo herpetiformis, or pustular psoriasis of pregnancy, is a variant of generalized pustular psoriasis that occurs during pregnancy. Diffuse erythematous patches studded with pustules, rather than vesicles, are seen; DIF is negative. Intrahepatic cholestasis of pregnancy presents without primary skin findings and severe pruritus predominantly on the palms and soles, often with secondary excoriations. Polymorphous eruption of pregnancy presents as a polymorphous eruption of urticarial to erythematous papules and plaques commonly originating in striae. In contrast to PG, there is periumbilical sparing, vesiculation is rare, and DIF is negative.

The Diagnosis: Pemphigoid Gestationis

A lesional biopsy showed a subepidermal split with eosinophils and neutrophils. Perilesional biopsy for direct immunofluorescence (DIF) showed linear deposition of 3+ C3 along the basement membrane zone. The clinical, histopathologic, and immunofluorescent findings were consistent with pemphigoid gestationis (PG). Prednisone 1 mg/kg daily was initiated. Her condition continued to worsen, and cyclosporine 250 mg daily was added while prednisone was tapered, with remission of disease.

Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy, with an incidence of 1 in 50,000 to 60,000 pregnancies.¹ In terms of pathogenesis, aberrant expression of major histocompatibility complex class II molecules on placental tissues causes the loss of immune tolerance of the placenta, which leads to the production of antibodies against the placental protein bullous pemphigoid 180.² Bullous pemphigoid 180 also is a hemidesmosomal protein found in the skin of the mother; therefore, the presence of the circulating antibodies leads to separation at the dermoepidermal junction and vesiculation.

Pemphigoid gestationis is characterized by the sudden eruption of intensely pruritic urticarial papules and plaques, classically with periumbilical involvement. Tense vesicles and bullae can develop. Women with PG have an increased risk for development of Graves disease. Histopathology shows subepidermal vesiculation with a predominance of eosinophils. Direct immunofluorescence classically shows linear deposition of C3 along the basement membrane zone. Fetal complications include prematurity and small size for gestational age. Additionally, blisters can be seen in 5% to 10% of neonates due to placental transmission of autoantibodies.³

Frequently PG flares shortly postpartum. Pemphigoid gestationis resolves within 6 months postdelivery but frequently reoccurs in subsequent pregnancies. Mild disease can be treated with mid- to high-potency topical corticosteroids. Severe disease is managed with oral corticosteroids, most commonly prednisone. Refractory disease is managed with azathioprine, cyclosporine, intravenous immunoglobulin, or plasmapheresis.

The differential diagnosis of PG includes other pregnancy-associated dermatoses such as atopic eruption of pregnancy, impetigo herpetiformis, intrahepatic cholestasis of pregnancy, and polymorphous eruption of pregnancy. Atopic eruption of pregnancy is the most common dermatosis of pregnancy and is characterized by an eczematous eruption in patients with an atopic history, typically in the first trimester. Blisters are not seen, and DIF is negative. Impetigo herpetiformis, or pustular psoriasis of pregnancy, is a variant of generalized pustular psoriasis that occurs during pregnancy. Diffuse erythematous patches studded with pustules, rather than vesicles, are seen; DIF is negative. Intrahepatic cholestasis of pregnancy presents without primary skin findings and severe pruritus predominantly on the palms and soles, often with secondary excoriations. Polymorphous eruption of pregnancy presents as a polymorphous eruption of urticarial to erythematous papules and plaques commonly originating in striae. In contrast to PG, there is periumbilical sparing, vesiculation is rare, and DIF is negative.