Autoimmune Diseases

Eli Lilly has decided to stop development of baricitinib (Olumiant) for adults with active systemic lupus erythematosus (SLE) because of efficacy results from two pivotal phase 3 trials, SLE-BRAVE-I and II, the company announced Jan. 28.

Lilly said that the primary endpoint of the SLE-BRAVE-I trial, the proportion of adults with active SLE who met criteria for response on the SLE Responder Index-4 at week 52, was significantly greater among patients treated with 4 mg baricitinib daily than with placebo. However, this endpoint was not met in SLE-BRAVE-II, and no key secondary endpoints were met in either trial. In the announcement, Lilly noted that safety was not a reason for discontinuation because data from these trials were consistent with those previously seen with baricitinib.

The company statement said that it will work with investigators on concluding the combined long-term extension study of the trials.

Baricitinib, a Janus kinase (JAK) inhibitor, had previously shown promising results in a phase 2 trial in patients with SLE. It is approved by the U.S. Food and Drug Administration for treating adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor blockers at a dose of 2 mg once daily and has an emergency use authorization for the treatment of hospitalized patients with COVID-19.

The decision to stop baricitinib’s development for SLE will not affect other research efforts with the drug, the company said.

Development for atopic dermatitis

Lilly also noted that it is in discussion with the FDA about the status of a supplemental new drug application of baricitinib for the treatment of adults with moderate to severe atopic dermatitis (AD). In its press release, Lilly said, “At this point, the company does not have alignment with the FDA on the indicated population. Given the agency’s position, there is a possibility that this could lead to a Complete Response Letter (CRL). The efficacy and safety profile of Olumiant was evaluated in eight atopic dermatitis clinical trials (six double-blind, randomized, placebo-controlled studies and two long-term extension studies) inclusive of patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The safety profile in these trials was consistent with previously published Olumiant data.”

Baricitinib was the first JAK inhibitor approved to treat patients with moderate to severe AD who have an inadequate response to topical treatments in the European Union and Japan.

The Lilly announcement was made with Incyte, the company that discovered baricitinib.

Eli Lilly has decided to stop development of baricitinib (Olumiant) for adults with active systemic lupus erythematosus (SLE) because of efficacy results from two pivotal phase 3 trials, SLE-BRAVE-I and II, the company announced Jan. 28.

Lilly said that the primary endpoint of the SLE-BRAVE-I trial, the proportion of adults with active SLE who met criteria for response on the SLE Responder Index-4 at week 52, was significantly greater among patients treated with 4 mg baricitinib daily than with placebo. However, this endpoint was not met in SLE-BRAVE-II, and no key secondary endpoints were met in either trial. In the announcement, Lilly noted that safety was not a reason for discontinuation because data from these trials were consistent with those previously seen with baricitinib.

The company statement said that it will work with investigators on concluding the combined long-term extension study of the trials.

Baricitinib, a Janus kinase (JAK) inhibitor, had previously shown promising results in a phase 2 trial in patients with SLE. It is approved by the U.S. Food and Drug Administration for treating adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor blockers at a dose of 2 mg once daily and has an emergency use authorization for the treatment of hospitalized patients with COVID-19.

The decision to stop baricitinib’s development for SLE will not affect other research efforts with the drug, the company said.

Development for atopic dermatitis

Lilly also noted that it is in discussion with the FDA about the status of a supplemental new drug application of baricitinib for the treatment of adults with moderate to severe atopic dermatitis (AD). In its press release, Lilly said, “At this point, the company does not have alignment with the FDA on the indicated population. Given the agency’s position, there is a possibility that this could lead to a Complete Response Letter (CRL). The efficacy and safety profile of Olumiant was evaluated in eight atopic dermatitis clinical trials (six double-blind, randomized, placebo-controlled studies and two long-term extension studies) inclusive of patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The safety profile in these trials was consistent with previously published Olumiant data.”

Baricitinib was the first JAK inhibitor approved to treat patients with moderate to severe AD who have an inadequate response to topical treatments in the European Union and Japan.

The Lilly announcement was made with Incyte, the company that discovered baricitinib.

Eli Lilly has decided to stop development of baricitinib (Olumiant) for adults with active systemic lupus erythematosus (SLE) because of efficacy results from two pivotal phase 3 trials, SLE-BRAVE-I and II, the company announced Jan. 28.

Lilly said that the primary endpoint of the SLE-BRAVE-I trial, the proportion of adults with active SLE who met criteria for response on the SLE Responder Index-4 at week 52, was significantly greater among patients treated with 4 mg baricitinib daily than with placebo. However, this endpoint was not met in SLE-BRAVE-II, and no key secondary endpoints were met in either trial. In the announcement, Lilly noted that safety was not a reason for discontinuation because data from these trials were consistent with those previously seen with baricitinib.

The company statement said that it will work with investigators on concluding the combined long-term extension study of the trials.

Baricitinib, a Janus kinase (JAK) inhibitor, had previously shown promising results in a phase 2 trial in patients with SLE. It is approved by the U.S. Food and Drug Administration for treating adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor blockers at a dose of 2 mg once daily and has an emergency use authorization for the treatment of hospitalized patients with COVID-19.

The decision to stop baricitinib’s development for SLE will not affect other research efforts with the drug, the company said.

Development for atopic dermatitis

Lilly also noted that it is in discussion with the FDA about the status of a supplemental new drug application of baricitinib for the treatment of adults with moderate to severe atopic dermatitis (AD). In its press release, Lilly said, “At this point, the company does not have alignment with the FDA on the indicated population. Given the agency’s position, there is a possibility that this could lead to a Complete Response Letter (CRL). The efficacy and safety profile of Olumiant was evaluated in eight atopic dermatitis clinical trials (six double-blind, randomized, placebo-controlled studies and two long-term extension studies) inclusive of patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The safety profile in these trials was consistent with previously published Olumiant data.”

Baricitinib was the first JAK inhibitor approved to treat patients with moderate to severe AD who have an inadequate response to topical treatments in the European Union and Japan.

The Lilly announcement was made with Incyte, the company that discovered baricitinib.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

Chilblain lupus erythematosus, described by Jonathan Hutchinson, is an uncommon form of cutaneous lupus that affects women more frequently than men. Clinically, distal extremities such as toes, fingertips and heels, as well as the rims of the ears or nose develop erythematous to purple plaques. Lesions may be painful or pruritic. Over time, lesions may develop atrophy and resemble those of discoid lupus. While the pathogenesis is unknown, exposure to cold or wet environments can precipitate lesions.

Histopathology reveals a deep and superficial lymphocytic infiltrate with perieccrine involvement and fibrin deposition in vessels. Dermal edema is often present. Direct immunofluorescence shows an interface dermatitis positive for IgM, IgA, and C3.

The Mayo Clinic developed diagnostic criteria for diagnosing chilblains lupus. Two major criteria are acral skin lesions induced by cold exposure and evidence of lupus erythematosus in skin lesions (histopathologically or by direct immunofluorescence). Three minor criteria are the coexistence of systemic lupus erythematosus or discoid lupus erythematosus, response to antilupus treatment, and negative cryoglobulin and cold agglutinin studies.

Chilblains, or perniosis, has a similar clinical presentation to chilblain lupus erythematosus. However, serologic evidence of lupus, such as a positive antinuclear antibody (ANA), will be absent. Lupus pernio (Besnier-Tenneson syndrome) is a form of sarcoidosis that tends to favor the nose. These lesions are not precipitated by cold. It can be differentiated on histology. “COVID toes” is an entity described during the coronavirus pandemic, during which dermatologists noted pernio-like lesions in patients testing positive for coronavirus.

The patient’s labs revealed a positive ANA at 1:320 in a nucleolar speckled pattern, elevated double-stranded DNA, low C3 and C4 levels, elevated cardiolipin IgM Ab, and elevated sedimentation rate. COVID-19 antigen testing and COVID-19 antibodies were negative. A serum protein electrophoresis was negative. Cryoglobulins were negative.

Treatment includes protection from cold. Smoking cessation should be discussed. Topical steroids and topical calcineurin inhibitors are first-line treatments for mild disease. Antimalarials, such as hydroxychloroquine can be helpful. Systemic calcium channel blockers, systemic steroids, mycophenolate mofetil, and tacrolimus have all been reported as treatments. This patient responded well to hydroxychloroquine and topical steroids with full resolution of lesions.

This case was submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

Su WP et al. Cutis. 1994 Dec;54(6):395-9.

Werth V and Newman S. Chilblain lupus (SLE pernio). Dermatology Advisor. 2017.

Chilblain lupus erythematosus, described by Jonathan Hutchinson, is an uncommon form of cutaneous lupus that affects women more frequently than men. Clinically, distal extremities such as toes, fingertips and heels, as well as the rims of the ears or nose develop erythematous to purple plaques. Lesions may be painful or pruritic. Over time, lesions may develop atrophy and resemble those of discoid lupus. While the pathogenesis is unknown, exposure to cold or wet environments can precipitate lesions.

Histopathology reveals a deep and superficial lymphocytic infiltrate with perieccrine involvement and fibrin deposition in vessels. Dermal edema is often present. Direct immunofluorescence shows an interface dermatitis positive for IgM, IgA, and C3.

The Mayo Clinic developed diagnostic criteria for diagnosing chilblains lupus. Two major criteria are acral skin lesions induced by cold exposure and evidence of lupus erythematosus in skin lesions (histopathologically or by direct immunofluorescence). Three minor criteria are the coexistence of systemic lupus erythematosus or discoid lupus erythematosus, response to antilupus treatment, and negative cryoglobulin and cold agglutinin studies.

Chilblains, or perniosis, has a similar clinical presentation to chilblain lupus erythematosus. However, serologic evidence of lupus, such as a positive antinuclear antibody (ANA), will be absent. Lupus pernio (Besnier-Tenneson syndrome) is a form of sarcoidosis that tends to favor the nose. These lesions are not precipitated by cold. It can be differentiated on histology. “COVID toes” is an entity described during the coronavirus pandemic, during which dermatologists noted pernio-like lesions in patients testing positive for coronavirus.

The patient’s labs revealed a positive ANA at 1:320 in a nucleolar speckled pattern, elevated double-stranded DNA, low C3 and C4 levels, elevated cardiolipin IgM Ab, and elevated sedimentation rate. COVID-19 antigen testing and COVID-19 antibodies were negative. A serum protein electrophoresis was negative. Cryoglobulins were negative.

Treatment includes protection from cold. Smoking cessation should be discussed. Topical steroids and topical calcineurin inhibitors are first-line treatments for mild disease. Antimalarials, such as hydroxychloroquine can be helpful. Systemic calcium channel blockers, systemic steroids, mycophenolate mofetil, and tacrolimus have all been reported as treatments. This patient responded well to hydroxychloroquine and topical steroids with full resolution of lesions.

This case was submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

Su WP et al. Cutis. 1994 Dec;54(6):395-9.

Werth V and Newman S. Chilblain lupus (SLE pernio). Dermatology Advisor. 2017.

Chilblain lupus erythematosus, described by Jonathan Hutchinson, is an uncommon form of cutaneous lupus that affects women more frequently than men. Clinically, distal extremities such as toes, fingertips and heels, as well as the rims of the ears or nose develop erythematous to purple plaques. Lesions may be painful or pruritic. Over time, lesions may develop atrophy and resemble those of discoid lupus. While the pathogenesis is unknown, exposure to cold or wet environments can precipitate lesions.

Histopathology reveals a deep and superficial lymphocytic infiltrate with perieccrine involvement and fibrin deposition in vessels. Dermal edema is often present. Direct immunofluorescence shows an interface dermatitis positive for IgM, IgA, and C3.

The Mayo Clinic developed diagnostic criteria for diagnosing chilblains lupus. Two major criteria are acral skin lesions induced by cold exposure and evidence of lupus erythematosus in skin lesions (histopathologically or by direct immunofluorescence). Three minor criteria are the coexistence of systemic lupus erythematosus or discoid lupus erythematosus, response to antilupus treatment, and negative cryoglobulin and cold agglutinin studies.

Chilblains, or perniosis, has a similar clinical presentation to chilblain lupus erythematosus. However, serologic evidence of lupus, such as a positive antinuclear antibody (ANA), will be absent. Lupus pernio (Besnier-Tenneson syndrome) is a form of sarcoidosis that tends to favor the nose. These lesions are not precipitated by cold. It can be differentiated on histology. “COVID toes” is an entity described during the coronavirus pandemic, during which dermatologists noted pernio-like lesions in patients testing positive for coronavirus.

The patient’s labs revealed a positive ANA at 1:320 in a nucleolar speckled pattern, elevated double-stranded DNA, low C3 and C4 levels, elevated cardiolipin IgM Ab, and elevated sedimentation rate. COVID-19 antigen testing and COVID-19 antibodies were negative. A serum protein electrophoresis was negative. Cryoglobulins were negative.

Treatment includes protection from cold. Smoking cessation should be discussed. Topical steroids and topical calcineurin inhibitors are first-line treatments for mild disease. Antimalarials, such as hydroxychloroquine can be helpful. Systemic calcium channel blockers, systemic steroids, mycophenolate mofetil, and tacrolimus have all been reported as treatments. This patient responded well to hydroxychloroquine and topical steroids with full resolution of lesions.

This case was submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

Su WP et al. Cutis. 1994 Dec;54(6):395-9.

Werth V and Newman S. Chilblain lupus (SLE pernio). Dermatology Advisor. 2017.

Clinical assessment for pulmonary disease and malignancy in patients with dermatomyositis should not be replaced with serologic tests at this time, according to Jeffrey P. Callen, MD.

That’s because the validity and reproducibility of testing in commercial laboratories remain questionable, Dr. Callen, professor of medicine and chief of the division of dermatology at the University of Louisville, Ky., said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “The testing in research laboratories is not widely available and the results are often delayed by weeks to months,” he said.

In addition, while the associations between antibody results and risks of malignancy or pulmonary disease are “statistically valid,” he said, “there are patients with disease in whom antibodies are not present and those without associated disease in whom the testing was positive.” For example, there are patients positive for anti–transition initiation factor (TIF)-1gamma but don’t have a malignancy, “and the ones with anti-MDA-5 tend to have pulmonary disease, but there are patients with anti-MDA-5 who don’t have pulmonary disease.”

Compared with patients with systemic lupus erythematosus, patients with dermatomyositis tend to have more itching and they tend of have fewer serologic abnormalities, such as anti-Ro/SS-A antibody, “but there is overlap,” Dr. Callen said. “The reason to differentiate cutaneous lupus erythematosus from dermatomyositis is because we think that patients who have amyopathic dermatomyositis still have an increased risk of having or developing an internal malignancy,” he added. Another differentiating point that is substantive is the presence of Gottron papules.

In a recent development related to antibody testing, researchers demonstrated that the IgG2 isotype of anti-TIF-1gamma antibodies is a biomarker of cancer and mortality in adult dermatomyositis.

According to population-based studies, about 20%-25% of dermatomyositis patients have had, have, or will develop a cancer (Lancet 2001;357: 96-100). Amyopathic dermatomyositis patients may also have cancer. Polymyositis patients generally have lower rates and their risk of subsequent malignancy is much closer to that of the general population, suggesting that the presence of the association is due to a “diagnostic suspicion bias,” Dr. Callen said.

A large-scale multicenter cohort study that set out to identify the risk factors and prognosis of patients with cancer-associated myositis found that ovarian cancer seems to be overrepresented. The only serologic abnormality that was statistically significant was anti-TIF-1gamma antibody (P less than .001). Patients with cancer-associated myositis also have less overall survival compared with those with non–cancer-associated myositis (P = .004), with malignancy being the primary cause of death (P less than .001).

In what is believed to be the largest study of its kind, Dr. Callen and colleagues retrospectively examined the prevalence of malignancy and screening practices in 400 dermatomyositis patients. Of the 400 patients, 48 (12%) had malignancies, and 21 cancers (40%) were diagnosed within 1 year of the dermatomyositis diagnosis. Both classic dermatomyositis and amyopathic dermatomyositis were associated with cancer, and 27 patients (6.8%) had a cancer at the time of diagnosis. Of those, 59% were asymptomatic; their cancers were discovered with CT scans, suggesting that “blind” screening is effective in identifying cancers in DM patients.

Dr. Callen’s malignancy evaluation includes chest x-ray, CT of the chest and abdomen, stool Hematest in all dermatomyositis patients; a mammogram, pelvic ultrasound and/or CT of the pelvis in women; and age, race or ethnicity-related testing. “I generally reevaluate patients annually for 3 years, because data from epidemiologic studies suggest that after 3 years [from the initial diagnosis], the rates of malignancy return toward normal,” he said. “I also evaluate any new symptom that might be suggestive of malignancy. The remaining issue is how to handle a patient in remission for several years, but who develops a relapse. What I do is perform another malignancy assessment.”

According to results from a meta-analysis of risk factors and systematic review of screening approaches, factors that increase malignancy risk include dermatomyositis subtype (risk ratio, 2.21), older age (weighted mean difference 11.19), male gender (RR, 1.53), dysphagia (RR, 2.09), cutaneous necrosis (RR, 2.73), and positive anti-TIF-1gamma (RR, 4.41).

Factors associated with a decreased risk of malignancy include polymyositis (RR, 0.49), clinically amyopathic dermatomyositis subtypes (RR, 0.44), Raynaud’s phenomenon (RR, 0.61), interstitial lung disease (RR, 0.49), very high serum creatine kinase (WMD –1189.96) or lactate dehydrogenase levels (WMD –336.53), and anti-Jo1 (RR, 0.45) or anti-EJ (RR, 0.17) positivity.

The analysis also found that CT scanning of the thorax, abdomen and pelvis appeared to yield a high proportion of underlying asymptomatic cancers. Limited evidence relating to the utility of tumor markers and 18F-FDG PET/CT was available.

As for treatment, the use of tofacitinib for cutaneous lesions of dermatomyositis has been suggested in various studies. In a recent open-label study of 10 patients with dermatomyositis who took extended release the JAK inhibitor tofacitinib 11 mg daily for 12 weeks, half experienced moderate improvement in disease activity, and the other half experienced minimal improvement. JAK inhibitors have been used in patients with juvenile dermatomyositis.

Dr. Callen’s treatment approach with dermatomyositis patients includes recommendations for sunscreens and protective clothing, plus assessment of vitamin D levels. “I will use topical emollients, corticosteroids, and calcineurin inhibitors,” he said. “Antimalarials might be used. I generally reach for methotrexate or mycophenolate mofetil relatively early. IVIG has also been studied.” Off-label therapies that have been used include dapsone, thalidomide, leflunomide, sirolimus, chlorambucil, etanercept, infliximab, rituximab, apremilast, tofacitinib, lenabasum, and low-dose naltrexone.

Dr. Callen disclosed that he is a consultant to Genentech and is a member of the safety monitoring committee for Principia Biopharma. He holds equity in Celgene, Pfizer, 3M, Johnson & Johnson, Merck, Abbott Laboratories, AbbVie, Procter & Gamble, Gilead, Allergen, and Amgen.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Clinical assessment for pulmonary disease and malignancy in patients with dermatomyositis should not be replaced with serologic tests at this time, according to Jeffrey P. Callen, MD.

That’s because the validity and reproducibility of testing in commercial laboratories remain questionable, Dr. Callen, professor of medicine and chief of the division of dermatology at the University of Louisville, Ky., said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “The testing in research laboratories is not widely available and the results are often delayed by weeks to months,” he said.

In addition, while the associations between antibody results and risks of malignancy or pulmonary disease are “statistically valid,” he said, “there are patients with disease in whom antibodies are not present and those without associated disease in whom the testing was positive.” For example, there are patients positive for anti–transition initiation factor (TIF)-1gamma but don’t have a malignancy, “and the ones with anti-MDA-5 tend to have pulmonary disease, but there are patients with anti-MDA-5 who don’t have pulmonary disease.”

Compared with patients with systemic lupus erythematosus, patients with dermatomyositis tend to have more itching and they tend of have fewer serologic abnormalities, such as anti-Ro/SS-A antibody, “but there is overlap,” Dr. Callen said. “The reason to differentiate cutaneous lupus erythematosus from dermatomyositis is because we think that patients who have amyopathic dermatomyositis still have an increased risk of having or developing an internal malignancy,” he added. Another differentiating point that is substantive is the presence of Gottron papules.

In a recent development related to antibody testing, researchers demonstrated that the IgG2 isotype of anti-TIF-1gamma antibodies is a biomarker of cancer and mortality in adult dermatomyositis.

According to population-based studies, about 20%-25% of dermatomyositis patients have had, have, or will develop a cancer (Lancet 2001;357: 96-100). Amyopathic dermatomyositis patients may also have cancer. Polymyositis patients generally have lower rates and their risk of subsequent malignancy is much closer to that of the general population, suggesting that the presence of the association is due to a “diagnostic suspicion bias,” Dr. Callen said.

A large-scale multicenter cohort study that set out to identify the risk factors and prognosis of patients with cancer-associated myositis found that ovarian cancer seems to be overrepresented. The only serologic abnormality that was statistically significant was anti-TIF-1gamma antibody (P less than .001). Patients with cancer-associated myositis also have less overall survival compared with those with non–cancer-associated myositis (P = .004), with malignancy being the primary cause of death (P less than .001).

In what is believed to be the largest study of its kind, Dr. Callen and colleagues retrospectively examined the prevalence of malignancy and screening practices in 400 dermatomyositis patients. Of the 400 patients, 48 (12%) had malignancies, and 21 cancers (40%) were diagnosed within 1 year of the dermatomyositis diagnosis. Both classic dermatomyositis and amyopathic dermatomyositis were associated with cancer, and 27 patients (6.8%) had a cancer at the time of diagnosis. Of those, 59% were asymptomatic; their cancers were discovered with CT scans, suggesting that “blind” screening is effective in identifying cancers in DM patients.

Dr. Callen’s malignancy evaluation includes chest x-ray, CT of the chest and abdomen, stool Hematest in all dermatomyositis patients; a mammogram, pelvic ultrasound and/or CT of the pelvis in women; and age, race or ethnicity-related testing. “I generally reevaluate patients annually for 3 years, because data from epidemiologic studies suggest that after 3 years [from the initial diagnosis], the rates of malignancy return toward normal,” he said. “I also evaluate any new symptom that might be suggestive of malignancy. The remaining issue is how to handle a patient in remission for several years, but who develops a relapse. What I do is perform another malignancy assessment.”

According to results from a meta-analysis of risk factors and systematic review of screening approaches, factors that increase malignancy risk include dermatomyositis subtype (risk ratio, 2.21), older age (weighted mean difference 11.19), male gender (RR, 1.53), dysphagia (RR, 2.09), cutaneous necrosis (RR, 2.73), and positive anti-TIF-1gamma (RR, 4.41).

Factors associated with a decreased risk of malignancy include polymyositis (RR, 0.49), clinically amyopathic dermatomyositis subtypes (RR, 0.44), Raynaud’s phenomenon (RR, 0.61), interstitial lung disease (RR, 0.49), very high serum creatine kinase (WMD –1189.96) or lactate dehydrogenase levels (WMD –336.53), and anti-Jo1 (RR, 0.45) or anti-EJ (RR, 0.17) positivity.

The analysis also found that CT scanning of the thorax, abdomen and pelvis appeared to yield a high proportion of underlying asymptomatic cancers. Limited evidence relating to the utility of tumor markers and 18F-FDG PET/CT was available.

As for treatment, the use of tofacitinib for cutaneous lesions of dermatomyositis has been suggested in various studies. In a recent open-label study of 10 patients with dermatomyositis who took extended release the JAK inhibitor tofacitinib 11 mg daily for 12 weeks, half experienced moderate improvement in disease activity, and the other half experienced minimal improvement. JAK inhibitors have been used in patients with juvenile dermatomyositis.

Dr. Callen’s treatment approach with dermatomyositis patients includes recommendations for sunscreens and protective clothing, plus assessment of vitamin D levels. “I will use topical emollients, corticosteroids, and calcineurin inhibitors,” he said. “Antimalarials might be used. I generally reach for methotrexate or mycophenolate mofetil relatively early. IVIG has also been studied.” Off-label therapies that have been used include dapsone, thalidomide, leflunomide, sirolimus, chlorambucil, etanercept, infliximab, rituximab, apremilast, tofacitinib, lenabasum, and low-dose naltrexone.

Dr. Callen disclosed that he is a consultant to Genentech and is a member of the safety monitoring committee for Principia Biopharma. He holds equity in Celgene, Pfizer, 3M, Johnson & Johnson, Merck, Abbott Laboratories, AbbVie, Procter & Gamble, Gilead, Allergen, and Amgen.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Clinical assessment for pulmonary disease and malignancy in patients with dermatomyositis should not be replaced with serologic tests at this time, according to Jeffrey P. Callen, MD.

That’s because the validity and reproducibility of testing in commercial laboratories remain questionable, Dr. Callen, professor of medicine and chief of the division of dermatology at the University of Louisville, Ky., said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “The testing in research laboratories is not widely available and the results are often delayed by weeks to months,” he said.

In addition, while the associations between antibody results and risks of malignancy or pulmonary disease are “statistically valid,” he said, “there are patients with disease in whom antibodies are not present and those without associated disease in whom the testing was positive.” For example, there are patients positive for anti–transition initiation factor (TIF)-1gamma but don’t have a malignancy, “and the ones with anti-MDA-5 tend to have pulmonary disease, but there are patients with anti-MDA-5 who don’t have pulmonary disease.”

Compared with patients with systemic lupus erythematosus, patients with dermatomyositis tend to have more itching and they tend of have fewer serologic abnormalities, such as anti-Ro/SS-A antibody, “but there is overlap,” Dr. Callen said. “The reason to differentiate cutaneous lupus erythematosus from dermatomyositis is because we think that patients who have amyopathic dermatomyositis still have an increased risk of having or developing an internal malignancy,” he added. Another differentiating point that is substantive is the presence of Gottron papules.

In a recent development related to antibody testing, researchers demonstrated that the IgG2 isotype of anti-TIF-1gamma antibodies is a biomarker of cancer and mortality in adult dermatomyositis.

According to population-based studies, about 20%-25% of dermatomyositis patients have had, have, or will develop a cancer (Lancet 2001;357: 96-100). Amyopathic dermatomyositis patients may also have cancer. Polymyositis patients generally have lower rates and their risk of subsequent malignancy is much closer to that of the general population, suggesting that the presence of the association is due to a “diagnostic suspicion bias,” Dr. Callen said.

A large-scale multicenter cohort study that set out to identify the risk factors and prognosis of patients with cancer-associated myositis found that ovarian cancer seems to be overrepresented. The only serologic abnormality that was statistically significant was anti-TIF-1gamma antibody (P less than .001). Patients with cancer-associated myositis also have less overall survival compared with those with non–cancer-associated myositis (P = .004), with malignancy being the primary cause of death (P less than .001).

In what is believed to be the largest study of its kind, Dr. Callen and colleagues retrospectively examined the prevalence of malignancy and screening practices in 400 dermatomyositis patients. Of the 400 patients, 48 (12%) had malignancies, and 21 cancers (40%) were diagnosed within 1 year of the dermatomyositis diagnosis. Both classic dermatomyositis and amyopathic dermatomyositis were associated with cancer, and 27 patients (6.8%) had a cancer at the time of diagnosis. Of those, 59% were asymptomatic; their cancers were discovered with CT scans, suggesting that “blind” screening is effective in identifying cancers in DM patients.

Dr. Callen’s malignancy evaluation includes chest x-ray, CT of the chest and abdomen, stool Hematest in all dermatomyositis patients; a mammogram, pelvic ultrasound and/or CT of the pelvis in women; and age, race or ethnicity-related testing. “I generally reevaluate patients annually for 3 years, because data from epidemiologic studies suggest that after 3 years [from the initial diagnosis], the rates of malignancy return toward normal,” he said. “I also evaluate any new symptom that might be suggestive of malignancy. The remaining issue is how to handle a patient in remission for several years, but who develops a relapse. What I do is perform another malignancy assessment.”

According to results from a meta-analysis of risk factors and systematic review of screening approaches, factors that increase malignancy risk include dermatomyositis subtype (risk ratio, 2.21), older age (weighted mean difference 11.19), male gender (RR, 1.53), dysphagia (RR, 2.09), cutaneous necrosis (RR, 2.73), and positive anti-TIF-1gamma (RR, 4.41).

Factors associated with a decreased risk of malignancy include polymyositis (RR, 0.49), clinically amyopathic dermatomyositis subtypes (RR, 0.44), Raynaud’s phenomenon (RR, 0.61), interstitial lung disease (RR, 0.49), very high serum creatine kinase (WMD –1189.96) or lactate dehydrogenase levels (WMD –336.53), and anti-Jo1 (RR, 0.45) or anti-EJ (RR, 0.17) positivity.

The analysis also found that CT scanning of the thorax, abdomen and pelvis appeared to yield a high proportion of underlying asymptomatic cancers. Limited evidence relating to the utility of tumor markers and 18F-FDG PET/CT was available.

As for treatment, the use of tofacitinib for cutaneous lesions of dermatomyositis has been suggested in various studies. In a recent open-label study of 10 patients with dermatomyositis who took extended release the JAK inhibitor tofacitinib 11 mg daily for 12 weeks, half experienced moderate improvement in disease activity, and the other half experienced minimal improvement. JAK inhibitors have been used in patients with juvenile dermatomyositis.

Dr. Callen’s treatment approach with dermatomyositis patients includes recommendations for sunscreens and protective clothing, plus assessment of vitamin D levels. “I will use topical emollients, corticosteroids, and calcineurin inhibitors,” he said. “Antimalarials might be used. I generally reach for methotrexate or mycophenolate mofetil relatively early. IVIG has also been studied.” Off-label therapies that have been used include dapsone, thalidomide, leflunomide, sirolimus, chlorambucil, etanercept, infliximab, rituximab, apremilast, tofacitinib, lenabasum, and low-dose naltrexone.

Dr. Callen disclosed that he is a consultant to Genentech and is a member of the safety monitoring committee for Principia Biopharma. He holds equity in Celgene, Pfizer, 3M, Johnson & Johnson, Merck, Abbott Laboratories, AbbVie, Procter & Gamble, Gilead, Allergen, and Amgen.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

A new survey-based estimate puts the prevalence of vitiligo somewhere between 0.76% and 1.11% in the United States and suggests that 40% of adults with the autoimmune disorder may be undiagnosed.

“The remarkably high number of participants with undiagnosed vitiligo” indicates a need for “the development and validation of teledermatology apps that allow for potential diagnosis,” Kavita Gandhi, MS, of the patient and health impact group at Pfizer in Collegeville, Pa., and associates said in JAMA Dermatology.

The estimated range of 0.76%-1.11% prevalence represents 1.9 million to 2.8 million adults with vitiligo in the general population, based on responses from 40,888 participants surveyed between Dec. 30, 2019, and March 11, 2020, and further physician evaluation of photos uploaded by 113 respondents, they explained. The investigators used a representative sample of the U.S. population, of people ages 18-85 years.

A prior vitiligo diagnosis was reported by 314 participants, and another 249 screened positive through the survey, for a self-reported overall prevalence of 1.38% in the adult population and a previously undiagnosed prevalence of 0.61%. The physician adjudication brought the overall prevalence down to 0.76% and the undiagnosed prevalence to 0.29%. “These findings suggest that up to 40% of adults with vitiligo in the U.S. may be undiagnosed,” the investigators wrote.

Survey questions covering the laterality of lesions broke the 1.38% overall prevalence down to 0.77% nonsegmental vitiligo (self-reported as bilateral) and 0.61% segmental (unilateral). The 0.76% overall prevalence provided by the three dermatologist reviewers worked out to 0.58% classified as nonsegmental and 0.18% as segmental, Ms. Gandhi and associates said.

“The distinction between segmental and nonsegmental vitiligo is of prime importance [since] patients are usually concerned by the spreading of the disease and its unpredictable course, which is the hallmark of nonsegmental vitiligo,” the researchers noted.

The analysis was the first, to the authors’ knowledge, to identify several trends among the undiagnosed population. The proportion of nonwhite adults was higher in the undiagnosed group (40.2%) than among those with a diagnosis (31.5%), as was Hispanic, Latino, or Spanish origin (21.3% vs. 15.3%). Unilateral presentation was seen in 54.2% of the undiagnosed adults and 37.3% of those with diagnosed vitiligo, they reported.

The study was sponsored by Pfizer, which employs several of the investigators. Two of the investigators disclosed multiple conflicts of interest involving other companies.

[email protected]

A new survey-based estimate puts the prevalence of vitiligo somewhere between 0.76% and 1.11% in the United States and suggests that 40% of adults with the autoimmune disorder may be undiagnosed.

“The remarkably high number of participants with undiagnosed vitiligo” indicates a need for “the development and validation of teledermatology apps that allow for potential diagnosis,” Kavita Gandhi, MS, of the patient and health impact group at Pfizer in Collegeville, Pa., and associates said in JAMA Dermatology.

The estimated range of 0.76%-1.11% prevalence represents 1.9 million to 2.8 million adults with vitiligo in the general population, based on responses from 40,888 participants surveyed between Dec. 30, 2019, and March 11, 2020, and further physician evaluation of photos uploaded by 113 respondents, they explained. The investigators used a representative sample of the U.S. population, of people ages 18-85 years.

A prior vitiligo diagnosis was reported by 314 participants, and another 249 screened positive through the survey, for a self-reported overall prevalence of 1.38% in the adult population and a previously undiagnosed prevalence of 0.61%. The physician adjudication brought the overall prevalence down to 0.76% and the undiagnosed prevalence to 0.29%. “These findings suggest that up to 40% of adults with vitiligo in the U.S. may be undiagnosed,” the investigators wrote.

Survey questions covering the laterality of lesions broke the 1.38% overall prevalence down to 0.77% nonsegmental vitiligo (self-reported as bilateral) and 0.61% segmental (unilateral). The 0.76% overall prevalence provided by the three dermatologist reviewers worked out to 0.58% classified as nonsegmental and 0.18% as segmental, Ms. Gandhi and associates said.

“The distinction between segmental and nonsegmental vitiligo is of prime importance [since] patients are usually concerned by the spreading of the disease and its unpredictable course, which is the hallmark of nonsegmental vitiligo,” the researchers noted.

The analysis was the first, to the authors’ knowledge, to identify several trends among the undiagnosed population. The proportion of nonwhite adults was higher in the undiagnosed group (40.2%) than among those with a diagnosis (31.5%), as was Hispanic, Latino, or Spanish origin (21.3% vs. 15.3%). Unilateral presentation was seen in 54.2% of the undiagnosed adults and 37.3% of those with diagnosed vitiligo, they reported.

The study was sponsored by Pfizer, which employs several of the investigators. Two of the investigators disclosed multiple conflicts of interest involving other companies.

[email protected]

A new survey-based estimate puts the prevalence of vitiligo somewhere between 0.76% and 1.11% in the United States and suggests that 40% of adults with the autoimmune disorder may be undiagnosed.

“The remarkably high number of participants with undiagnosed vitiligo” indicates a need for “the development and validation of teledermatology apps that allow for potential diagnosis,” Kavita Gandhi, MS, of the patient and health impact group at Pfizer in Collegeville, Pa., and associates said in JAMA Dermatology.

The estimated range of 0.76%-1.11% prevalence represents 1.9 million to 2.8 million adults with vitiligo in the general population, based on responses from 40,888 participants surveyed between Dec. 30, 2019, and March 11, 2020, and further physician evaluation of photos uploaded by 113 respondents, they explained. The investigators used a representative sample of the U.S. population, of people ages 18-85 years.

A prior vitiligo diagnosis was reported by 314 participants, and another 249 screened positive through the survey, for a self-reported overall prevalence of 1.38% in the adult population and a previously undiagnosed prevalence of 0.61%. The physician adjudication brought the overall prevalence down to 0.76% and the undiagnosed prevalence to 0.29%. “These findings suggest that up to 40% of adults with vitiligo in the U.S. may be undiagnosed,” the investigators wrote.

Survey questions covering the laterality of lesions broke the 1.38% overall prevalence down to 0.77% nonsegmental vitiligo (self-reported as bilateral) and 0.61% segmental (unilateral). The 0.76% overall prevalence provided by the three dermatologist reviewers worked out to 0.58% classified as nonsegmental and 0.18% as segmental, Ms. Gandhi and associates said.

“The distinction between segmental and nonsegmental vitiligo is of prime importance [since] patients are usually concerned by the spreading of the disease and its unpredictable course, which is the hallmark of nonsegmental vitiligo,” the researchers noted.

The analysis was the first, to the authors’ knowledge, to identify several trends among the undiagnosed population. The proportion of nonwhite adults was higher in the undiagnosed group (40.2%) than among those with a diagnosis (31.5%), as was Hispanic, Latino, or Spanish origin (21.3% vs. 15.3%). Unilateral presentation was seen in 54.2% of the undiagnosed adults and 37.3% of those with diagnosed vitiligo, they reported.

The study was sponsored by Pfizer, which employs several of the investigators. Two of the investigators disclosed multiple conflicts of interest involving other companies.

[email protected]

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Continuation of hydroxychloroquine (HCQ) when a patient’s systemic lupus erythematosus (SLE) is in remission or has very low disease activity is linked to a lower risk of flares than is reducing or stopping the antimalarial drug, according to new research presented at the virtual annual meeting of the American College of Rheumatology.

Marc Bruxelle/Getty Images

“Though HCQ is a cornerstone SLE drug, physicians and patients often consider lowering or stopping the drug during remission or low disease activity in order to limit long-term toxicity,” Sasha Bernatsky, MD, PhD, a professor of rheumatology at McGill University in Montreal, told attendees. Her group’s findings revealed a 20% increased risk of flares in those who reduced their HCQ dose and a 56% greater risk of flares in those who discontinued HCQ, compared with those who continued on a maintenance dose.

“I’m going to be using these results in discussions with my patients regarding what the potential implications are of lowering or stopping hydroxychloroquine,” Dr. Bernatsky told attendees. “I think, in the end, this information should be in their hands so that they can be the ones to make these decisions with us, and, of course, given the significant flare rates even in remission, we need to keep on working on optimizing lupus treatments.”
 

Study details

The researchers analyzed prospective data from 1,460 patients enrolled in the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) cohort, which includes 33 sites across Europe, Asia, and North America. Patients in this cohort undergo annual follow-ups after enrollment within 15 months of their diagnosis. The study population was 89% female and 52% white. All participants either had low disease activity, defined as a score of 4 or lower on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and/or as a prednisone dose no greater than 7.5 mg/day, or were in complete remission, defined as a 0 on SLEDAI-2K while receiving no therapy, including no prednisone or immunosuppressives in the past year.

In addition to adjusting for sex, race/ethnicity, age, education, and geographic residence, the researchers took into account baseline SLE duration, renal damage, body mass index, smoking status, and use of prednisone, immunosuppressives, and biologics. For the outcome of time to first flare, the researchers analyzed those who discontinued HCQ separately from those who reduced the dose, comparing each to those who continued HCQ maintenance therapy. The researchers defined first flare as either hospitalization because of SLE, increased disease activity (at least 4 points on the SLEDAI-2K), or therapy augmentation with steroids, immunosuppressives, antimalarials, or biologics.

Within each cohort, patients who reduced or stopped HCQ therapy were matched to patients who continued HCQ maintenance therapy based on duration of HCQ since time zero, the point at which participants were considered at risk for SLE flares. In the reduction cohort, time zero was the date of a participant’s first HCQ reduction; in the discontinuation cohort, time zero was the date a participant stopped the therapy. Because of the study’s design and reliance on person-years of exposure, it was possible for a single participant to contribute data to more than one cohort.
 

Results

The overall cohort examining reduction of HCQ dose included 564 patients who reduced their dose, contributing 1,063 person-years of data, and 778 matched patients who started HCQ at the same time but continued HCQ maintenance therapy without a dose reduction, contributing 1,242 person-years. The average duration of HCQ use since time zero in this cohort was 3.4 years.

Before stratifying for disease activity, the group who reduced their therapy experienced 40 first flares per 100 person-years, compared with 31.9 first flares per 100 person-years on maintenance therapy. Those who reduced HCQ had a 20% greater risk of flares than did those who continued it (adjusted hazard ratio, 1.2). However, when those in remission were compared with those not in remission – independent of disease activity level – patients in remission were twice as likely to experience a flare if they reduced their HCQ dose (aHR, 2.14).

In the discontinuation cohort, 389 patients who stopped HCQ therapy contributed 657 person-years, and 577 matched patients who continued HCQ maintenance therapy contributed 924 person-years. The average duration of HCQ use since time zero in this cohort was 4.2 years. Before stratifying for disease activity, the average number of first flares per 100 person-years was 41.3 in the HCQ discontinuation group and 30 in the HCQ maintenance group, resulting in a 56% higher risk of flares for those who stopped HCQ, compared with patients who continued HCQ (aHR, 1.56). Looking only at those in remission, patients were nearly three times more likely to experience a flare if they stopped HCQ than were patients not in remission who continued a maintenance dose (aHR, 2.77).
 

Patient age is an important consideration

Overall, these findings are not surprising, said Jill P. Buyon, MD, director of the division of rheumatology and of the Lupus Center at NYU-Langone Health in New York. Dr. Buyon is not involved in the current study but is studying discontinuation of HCQ in older adults with lupus.

“It has been already shown that when lupus patients discontinue HCQ, flares are more likely, but does this apply to all age groups?” Dr. Buyon asked in an interview. “Data are essential to more accurately weigh the balance between accumulating ocular exposure, the explosion of new tools to assess retinal injury, and the risk of disease flare in a population that may have more stable/quiescent disease than younger patients.”

Although HCQ’s track record with infection risk is consistently better than that of more immunosuppressive drugs and is very safe during pregnancy, Dr. Buyon said her “ophthalmology colleagues persistently emphasize the risk of retinal accumulation of drug and ocular toxicity over time.” She referenced a recent case-control study in which overall prevalence of HCQ retinopathy was 7.5%, and greater for patients taking more than 5 mg/kg of HCQ or who used HCQ for more than 10 years.

”Risk escalates with continued use, and evaluation by sensitive approaches such as multifocal electroretinography suggests nearly a third of patients accrue retinal damage,” Dr. Buyon said. “As the longevity of patients improves and comorbidities such as renal insufficiency (which affects HCQ clearance) may increase, the ratio of efficacy to toxicity would be expected to decrease.” Further, the fact that disease activity may wane as people age means that rheumatologists treating older adults need to address a critical question, she said: “Can HCQ be safely withdrawn? This question is important in the context of an even broader concern regarding management of SLE in the elderly population, a topic which has received minimal attention.”

The study is limited by its observational design and the fact that the intervention was not randomly allocated, although the researchers attempted to adjust for confounders. Dr. Bernatsky also noted that mild flares might have been missed, and the researchers did not evaluate HCQ levels or adherence, nor did the data set include physicians’ or patients’ explicitly stated reasons for HCQ reduction or discontinuation.

”We estimated that 5% of patients may have reduced HCQ therapy as result of the AAO [American Academy of Ophthalmology] guidelines, 55% because of low disease activity state, and the remainder (40%) for other reasons, possibly intolerance or patient preference,” the researchers noted in their abstract. “Among those who discontinued HCQ, 4% had retinal changes of concern, 15% were in clinical remission, and the remainder stopped for unknown reasons, possibly intolerance or patient preference.”

Dr. Buyon also pointed out that the cohort was initially intended for studying cardiovascular risk and not designed to capture all visits during each year of follow-up.

“Thus, while hospitalizations would be well captured, not all flares, particularly those not severe, would be captured, and thus we may not have the complete picture,” she said, reiterating Dr. Bernatsky’s point that mild flares may have been missed.

”Clearly, this is a very important topic for the management of our patients, particularly those who are elderly and may have already reaped the benefits of hydroxychloroquine,” Dr. Buyon said. “Of course, we have to be mindful of the potential benefit with regard to blood clotting and lipid lowering. Nevertheless, accumulated ocular toxicity and cardiac issues such as cardiomyopathy may emerge to tip the balance after years of accumulated drug exposure.”

The research was funded by the Canadian Institute of Health Research, the Singer Family Fund for Lupus Research, and the SLICC Group. Dr. Bernatsky had no disclosures. Dr. Buyon noted that she has an R34 NIH planning grant to study the safety of withdrawal of hydroxychloroquine in elderly lupus patients that is relevant to this study.

Continuation of hydroxychloroquine (HCQ) when a patient’s systemic lupus erythematosus (SLE) is in remission or has very low disease activity is linked to a lower risk of flares than is reducing or stopping the antimalarial drug, according to new research presented at the virtual annual meeting of the American College of Rheumatology.

Marc Bruxelle/Getty Images

“Though HCQ is a cornerstone SLE drug, physicians and patients often consider lowering or stopping the drug during remission or low disease activity in order to limit long-term toxicity,” Sasha Bernatsky, MD, PhD, a professor of rheumatology at McGill University in Montreal, told attendees. Her group’s findings revealed a 20% increased risk of flares in those who reduced their HCQ dose and a 56% greater risk of flares in those who discontinued HCQ, compared with those who continued on a maintenance dose.

“I’m going to be using these results in discussions with my patients regarding what the potential implications are of lowering or stopping hydroxychloroquine,” Dr. Bernatsky told attendees. “I think, in the end, this information should be in their hands so that they can be the ones to make these decisions with us, and, of course, given the significant flare rates even in remission, we need to keep on working on optimizing lupus treatments.”
 

Study details

The researchers analyzed prospective data from 1,460 patients enrolled in the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) cohort, which includes 33 sites across Europe, Asia, and North America. Patients in this cohort undergo annual follow-ups after enrollment within 15 months of their diagnosis. The study population was 89% female and 52% white. All participants either had low disease activity, defined as a score of 4 or lower on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and/or as a prednisone dose no greater than 7.5 mg/day, or were in complete remission, defined as a 0 on SLEDAI-2K while receiving no therapy, including no prednisone or immunosuppressives in the past year.

In addition to adjusting for sex, race/ethnicity, age, education, and geographic residence, the researchers took into account baseline SLE duration, renal damage, body mass index, smoking status, and use of prednisone, immunosuppressives, and biologics. For the outcome of time to first flare, the researchers analyzed those who discontinued HCQ separately from those who reduced the dose, comparing each to those who continued HCQ maintenance therapy. The researchers defined first flare as either hospitalization because of SLE, increased disease activity (at least 4 points on the SLEDAI-2K), or therapy augmentation with steroids, immunosuppressives, antimalarials, or biologics.

Within each cohort, patients who reduced or stopped HCQ therapy were matched to patients who continued HCQ maintenance therapy based on duration of HCQ since time zero, the point at which participants were considered at risk for SLE flares. In the reduction cohort, time zero was the date of a participant’s first HCQ reduction; in the discontinuation cohort, time zero was the date a participant stopped the therapy. Because of the study’s design and reliance on person-years of exposure, it was possible for a single participant to contribute data to more than one cohort.
 

Results

The overall cohort examining reduction of HCQ dose included 564 patients who reduced their dose, contributing 1,063 person-years of data, and 778 matched patients who started HCQ at the same time but continued HCQ maintenance therapy without a dose reduction, contributing 1,242 person-years. The average duration of HCQ use since time zero in this cohort was 3.4 years.

Before stratifying for disease activity, the group who reduced their therapy experienced 40 first flares per 100 person-years, compared with 31.9 first flares per 100 person-years on maintenance therapy. Those who reduced HCQ had a 20% greater risk of flares than did those who continued it (adjusted hazard ratio, 1.2). However, when those in remission were compared with those not in remission – independent of disease activity level – patients in remission were twice as likely to experience a flare if they reduced their HCQ dose (aHR, 2.14).

In the discontinuation cohort, 389 patients who stopped HCQ therapy contributed 657 person-years, and 577 matched patients who continued HCQ maintenance therapy contributed 924 person-years. The average duration of HCQ use since time zero in this cohort was 4.2 years. Before stratifying for disease activity, the average number of first flares per 100 person-years was 41.3 in the HCQ discontinuation group and 30 in the HCQ maintenance group, resulting in a 56% higher risk of flares for those who stopped HCQ, compared with patients who continued HCQ (aHR, 1.56). Looking only at those in remission, patients were nearly three times more likely to experience a flare if they stopped HCQ than were patients not in remission who continued a maintenance dose (aHR, 2.77).
 

Patient age is an important consideration

Overall, these findings are not surprising, said Jill P. Buyon, MD, director of the division of rheumatology and of the Lupus Center at NYU-Langone Health in New York. Dr. Buyon is not involved in the current study but is studying discontinuation of HCQ in older adults with lupus.

“It has been already shown that when lupus patients discontinue HCQ, flares are more likely, but does this apply to all age groups?” Dr. Buyon asked in an interview. “Data are essential to more accurately weigh the balance between accumulating ocular exposure, the explosion of new tools to assess retinal injury, and the risk of disease flare in a population that may have more stable/quiescent disease than younger patients.”

Although HCQ’s track record with infection risk is consistently better than that of more immunosuppressive drugs and is very safe during pregnancy, Dr. Buyon said her “ophthalmology colleagues persistently emphasize the risk of retinal accumulation of drug and ocular toxicity over time.” She referenced a recent case-control study in which overall prevalence of HCQ retinopathy was 7.5%, and greater for patients taking more than 5 mg/kg of HCQ or who used HCQ for more than 10 years.

”Risk escalates with continued use, and evaluation by sensitive approaches such as multifocal electroretinography suggests nearly a third of patients accrue retinal damage,” Dr. Buyon said. “As the longevity of patients improves and comorbidities such as renal insufficiency (which affects HCQ clearance) may increase, the ratio of efficacy to toxicity would be expected to decrease.” Further, the fact that disease activity may wane as people age means that rheumatologists treating older adults need to address a critical question, she said: “Can HCQ be safely withdrawn? This question is important in the context of an even broader concern regarding management of SLE in the elderly population, a topic which has received minimal attention.”

The study is limited by its observational design and the fact that the intervention was not randomly allocated, although the researchers attempted to adjust for confounders. Dr. Bernatsky also noted that mild flares might have been missed, and the researchers did not evaluate HCQ levels or adherence, nor did the data set include physicians’ or patients’ explicitly stated reasons for HCQ reduction or discontinuation.

”We estimated that 5% of patients may have reduced HCQ therapy as result of the AAO [American Academy of Ophthalmology] guidelines, 55% because of low disease activity state, and the remainder (40%) for other reasons, possibly intolerance or patient preference,” the researchers noted in their abstract. “Among those who discontinued HCQ, 4% had retinal changes of concern, 15% were in clinical remission, and the remainder stopped for unknown reasons, possibly intolerance or patient preference.”

Dr. Buyon also pointed out that the cohort was initially intended for studying cardiovascular risk and not designed to capture all visits during each year of follow-up.

“Thus, while hospitalizations would be well captured, not all flares, particularly those not severe, would be captured, and thus we may not have the complete picture,” she said, reiterating Dr. Bernatsky’s point that mild flares may have been missed.

”Clearly, this is a very important topic for the management of our patients, particularly those who are elderly and may have already reaped the benefits of hydroxychloroquine,” Dr. Buyon said. “Of course, we have to be mindful of the potential benefit with regard to blood clotting and lipid lowering. Nevertheless, accumulated ocular toxicity and cardiac issues such as cardiomyopathy may emerge to tip the balance after years of accumulated drug exposure.”

The research was funded by the Canadian Institute of Health Research, the Singer Family Fund for Lupus Research, and the SLICC Group. Dr. Bernatsky had no disclosures. Dr. Buyon noted that she has an R34 NIH planning grant to study the safety of withdrawal of hydroxychloroquine in elderly lupus patients that is relevant to this study.

Continuation of hydroxychloroquine (HCQ) when a patient’s systemic lupus erythematosus (SLE) is in remission or has very low disease activity is linked to a lower risk of flares than is reducing or stopping the antimalarial drug, according to new research presented at the virtual annual meeting of the American College of Rheumatology.

Marc Bruxelle/Getty Images

“Though HCQ is a cornerstone SLE drug, physicians and patients often consider lowering or stopping the drug during remission or low disease activity in order to limit long-term toxicity,” Sasha Bernatsky, MD, PhD, a professor of rheumatology at McGill University in Montreal, told attendees. Her group’s findings revealed a 20% increased risk of flares in those who reduced their HCQ dose and a 56% greater risk of flares in those who discontinued HCQ, compared with those who continued on a maintenance dose.

“I’m going to be using these results in discussions with my patients regarding what the potential implications are of lowering or stopping hydroxychloroquine,” Dr. Bernatsky told attendees. “I think, in the end, this information should be in their hands so that they can be the ones to make these decisions with us, and, of course, given the significant flare rates even in remission, we need to keep on working on optimizing lupus treatments.”
 

Study details

The researchers analyzed prospective data from 1,460 patients enrolled in the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) cohort, which includes 33 sites across Europe, Asia, and North America. Patients in this cohort undergo annual follow-ups after enrollment within 15 months of their diagnosis. The study population was 89% female and 52% white. All participants either had low disease activity, defined as a score of 4 or lower on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and/or as a prednisone dose no greater than 7.5 mg/day, or were in complete remission, defined as a 0 on SLEDAI-2K while receiving no therapy, including no prednisone or immunosuppressives in the past year.

In addition to adjusting for sex, race/ethnicity, age, education, and geographic residence, the researchers took into account baseline SLE duration, renal damage, body mass index, smoking status, and use of prednisone, immunosuppressives, and biologics. For the outcome of time to first flare, the researchers analyzed those who discontinued HCQ separately from those who reduced the dose, comparing each to those who continued HCQ maintenance therapy. The researchers defined first flare as either hospitalization because of SLE, increased disease activity (at least 4 points on the SLEDAI-2K), or therapy augmentation with steroids, immunosuppressives, antimalarials, or biologics.

Within each cohort, patients who reduced or stopped HCQ therapy were matched to patients who continued HCQ maintenance therapy based on duration of HCQ since time zero, the point at which participants were considered at risk for SLE flares. In the reduction cohort, time zero was the date of a participant’s first HCQ reduction; in the discontinuation cohort, time zero was the date a participant stopped the therapy. Because of the study’s design and reliance on person-years of exposure, it was possible for a single participant to contribute data to more than one cohort.
 

Results

The overall cohort examining reduction of HCQ dose included 564 patients who reduced their dose, contributing 1,063 person-years of data, and 778 matched patients who started HCQ at the same time but continued HCQ maintenance therapy without a dose reduction, contributing 1,242 person-years. The average duration of HCQ use since time zero in this cohort was 3.4 years.

Before stratifying for disease activity, the group who reduced their therapy experienced 40 first flares per 100 person-years, compared with 31.9 first flares per 100 person-years on maintenance therapy. Those who reduced HCQ had a 20% greater risk of flares than did those who continued it (adjusted hazard ratio, 1.2). However, when those in remission were compared with those not in remission – independent of disease activity level – patients in remission were twice as likely to experience a flare if they reduced their HCQ dose (aHR, 2.14).

In the discontinuation cohort, 389 patients who stopped HCQ therapy contributed 657 person-years, and 577 matched patients who continued HCQ maintenance therapy contributed 924 person-years. The average duration of HCQ use since time zero in this cohort was 4.2 years. Before stratifying for disease activity, the average number of first flares per 100 person-years was 41.3 in the HCQ discontinuation group and 30 in the HCQ maintenance group, resulting in a 56% higher risk of flares for those who stopped HCQ, compared with patients who continued HCQ (aHR, 1.56). Looking only at those in remission, patients were nearly three times more likely to experience a flare if they stopped HCQ than were patients not in remission who continued a maintenance dose (aHR, 2.77).
 

Patient age is an important consideration

Overall, these findings are not surprising, said Jill P. Buyon, MD, director of the division of rheumatology and of the Lupus Center at NYU-Langone Health in New York. Dr. Buyon is not involved in the current study but is studying discontinuation of HCQ in older adults with lupus.

“It has been already shown that when lupus patients discontinue HCQ, flares are more likely, but does this apply to all age groups?” Dr. Buyon asked in an interview. “Data are essential to more accurately weigh the balance between accumulating ocular exposure, the explosion of new tools to assess retinal injury, and the risk of disease flare in a population that may have more stable/quiescent disease than younger patients.”

Although HCQ’s track record with infection risk is consistently better than that of more immunosuppressive drugs and is very safe during pregnancy, Dr. Buyon said her “ophthalmology colleagues persistently emphasize the risk of retinal accumulation of drug and ocular toxicity over time.” She referenced a recent case-control study in which overall prevalence of HCQ retinopathy was 7.5%, and greater for patients taking more than 5 mg/kg of HCQ or who used HCQ for more than 10 years.

”Risk escalates with continued use, and evaluation by sensitive approaches such as multifocal electroretinography suggests nearly a third of patients accrue retinal damage,” Dr. Buyon said. “As the longevity of patients improves and comorbidities such as renal insufficiency (which affects HCQ clearance) may increase, the ratio of efficacy to toxicity would be expected to decrease.” Further, the fact that disease activity may wane as people age means that rheumatologists treating older adults need to address a critical question, she said: “Can HCQ be safely withdrawn? This question is important in the context of an even broader concern regarding management of SLE in the elderly population, a topic which has received minimal attention.”

The study is limited by its observational design and the fact that the intervention was not randomly allocated, although the researchers attempted to adjust for confounders. Dr. Bernatsky also noted that mild flares might have been missed, and the researchers did not evaluate HCQ levels or adherence, nor did the data set include physicians’ or patients’ explicitly stated reasons for HCQ reduction or discontinuation.

”We estimated that 5% of patients may have reduced HCQ therapy as result of the AAO [American Academy of Ophthalmology] guidelines, 55% because of low disease activity state, and the remainder (40%) for other reasons, possibly intolerance or patient preference,” the researchers noted in their abstract. “Among those who discontinued HCQ, 4% had retinal changes of concern, 15% were in clinical remission, and the remainder stopped for unknown reasons, possibly intolerance or patient preference.”

Dr. Buyon also pointed out that the cohort was initially intended for studying cardiovascular risk and not designed to capture all visits during each year of follow-up.

“Thus, while hospitalizations would be well captured, not all flares, particularly those not severe, would be captured, and thus we may not have the complete picture,” she said, reiterating Dr. Bernatsky’s point that mild flares may have been missed.

”Clearly, this is a very important topic for the management of our patients, particularly those who are elderly and may have already reaped the benefits of hydroxychloroquine,” Dr. Buyon said. “Of course, we have to be mindful of the potential benefit with regard to blood clotting and lipid lowering. Nevertheless, accumulated ocular toxicity and cardiac issues such as cardiomyopathy may emerge to tip the balance after years of accumulated drug exposure.”

The research was funded by the Canadian Institute of Health Research, the Singer Family Fund for Lupus Research, and the SLICC Group. Dr. Bernatsky had no disclosures. Dr. Buyon noted that she has an R34 NIH planning grant to study the safety of withdrawal of hydroxychloroquine in elderly lupus patients that is relevant to this study.

Rituximab effectively reduced skin sclerosis and appeared to have a beneficial effect on interstitial lung disease (ILD) for patients with systemic sclerosis (SSc) in a randomized, clinical trial.

Courtesy Charlotte E. LaSenna and Dr. Andrea Maderal, University of Miami

At 24 weeks’ follow-up, there was significant improvement in total skin thickness scores among patients who received four once-weekly rituximab infusions, compared with patients who received placebo infusions. Among patients who received rituximab, there were also small but significant improvements in percentage of forced vital capacity (FVC). Among patients who received placebo, FVC worsened, reported Ayumi Yoshizaki, MD, of the University of Tokyo and colleagues.

“Systemic sclerosis is considered to have high unmet medical needs because of its poor prognosis and the lack of satisfactory and effective treatments,” he said at the virtual annual meeting of the American College of Rheumatology.

“Several clinical studies have suggested that B-cell depletion therapy with rituximab anti-CD20 antibody is effective in treating skin and lung fibrosis of SSc. However, no randomized, placebo-controlled trial has been able to confirm the efficacy of rituximab in SSc,” Dr. Yoshizaki said.

A rheumatologist who is currently conducting an investigator-initiated trial in which patients with SSC are undergoing treatment with rituximab followed by belimumab (Benlysta) said in an interview that he found the data to be “super interesting.”

“There are a lot of reasons to think that B cells might be important in systemic sclerosis, and actually that’s why our group had previously done an investigator-initiated trial with belimumab years ago,” said Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York.

Randomized trial

Dr. Yoshizaki and colleagues conducted the randomized, placebo-controlled DESIRES trial in four hospitals in Japan to evaluate the safety and efficacy of rituximab for the treatment of SSc.

In the investigator-initiated trial, patients aged 20-79 years who fulfilled ACR and European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis and who had a modified Rodnan Skin Score (mRSS) of 10 or more and a life expectancy of at least 6 months were randomly assigned to receive infusions with either rituximab 375 mg/m² or placebo once weekly for 4 weeks. Patients and clinicians were masked to treatment allocation.

The trial included 56 patients (51 women, 5 men). Of all patients enrolled, 27 of 28 who were allocated to receive rituximab and 22 of 28 who were allocated to receive placebo underwent at least one infusion and completed 24 weeks of follow-up.

The absolute change in mRSS at 24 weeks after the start of therapy, the primary endpoint, was –6.30 in the rituximab group, compared with +2.14 in the placebo group, a difference of –8.44 (P < .0001).

In a subgroup analysis, rituximab was superior to placebo regardless of disease duration, disease type (diffuse cutaneous or limited cutaneous SSc), prior receipt of systemic corticosteroids or immunosuppressants, or having C-reactive protein levels less than 0.3 mg/dL or at least 0.3 mg/dL.

However, there was no significant benefit with rituximab for patients with baseline mRSS of at least 20 or for those without ILD at baseline.

There was also evidence that rituximab reduced lung fibrosis. For patients assigned to the active drug, the absolute change in FVC at 24 weeks was +0.09% of the predicted value, compared with –3.56% for patients who received placebo (P = .044).

The researchers also observed radiographic evidence of lung improvement. The absolute change in the percentage of lung field occupied with interstitial shadows was –0.32% in the rituximab arm versus +2.39% in the placebo arm (P = .034). There was no significant between-group difference in the absolute change in diffusing capacity of lung for carbon monoxide, however.

Adverse events that occurred more frequently with rituximab included oral mucositis, diarrhea, and decreased neutrophil and white blood cell counts.

Convincing results

“What I thought the Japanese study did was to give a much more convincing proof of concept than has been out there,” Dr. Spiera said in an interview.

“There have been some preliminary experiences that have been encouraging with rituximab in scleroderma, most of which has been open label,” he said.

He also referred to a retrospective study by EUSTAR, the European Scleroderma Trials and Research group, which indicated that patients who had previously received rituximab seemed to have had better outcomes than patients who had been treated with other therapies.

Dr. Spiera added that, although he was glad to see the data from a randomized, placebo-controlled trial in this population, he was uncomfortable with the idea of leaving patients untreated for 6 months.

“From the standpoint of somebody wanting to know what strategies might be promising, this is great for us, but I would not have designed the trial that way,” he said.

The study results were previously published in the Lancet Rheumatology.

The study was supported by grants from the Japan Agency for Medical Research and Development and Zenyaku Kogyo. Dr. Yoshizaki disclosed no relevant financial relationships. Dr. Spiera has received grant/research support from and has consulted for Roche/Genentech, maker of rituximab, and has received compensation from other companies.

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

Rituximab effectively reduced skin sclerosis and appeared to have a beneficial effect on interstitial lung disease (ILD) for patients with systemic sclerosis (SSc) in a randomized, clinical trial.

Courtesy Charlotte E. LaSenna and Dr. Andrea Maderal, University of Miami

At 24 weeks’ follow-up, there was significant improvement in total skin thickness scores among patients who received four once-weekly rituximab infusions, compared with patients who received placebo infusions. Among patients who received rituximab, there were also small but significant improvements in percentage of forced vital capacity (FVC). Among patients who received placebo, FVC worsened, reported Ayumi Yoshizaki, MD, of the University of Tokyo and colleagues.

“Systemic sclerosis is considered to have high unmet medical needs because of its poor prognosis and the lack of satisfactory and effective treatments,” he said at the virtual annual meeting of the American College of Rheumatology.

“Several clinical studies have suggested that B-cell depletion therapy with rituximab anti-CD20 antibody is effective in treating skin and lung fibrosis of SSc. However, no randomized, placebo-controlled trial has been able to confirm the efficacy of rituximab in SSc,” Dr. Yoshizaki said.

A rheumatologist who is currently conducting an investigator-initiated trial in which patients with SSC are undergoing treatment with rituximab followed by belimumab (Benlysta) said in an interview that he found the data to be “super interesting.”

“There are a lot of reasons to think that B cells might be important in systemic sclerosis, and actually that’s why our group had previously done an investigator-initiated trial with belimumab years ago,” said Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York.

Randomized trial

Dr. Yoshizaki and colleagues conducted the randomized, placebo-controlled DESIRES trial in four hospitals in Japan to evaluate the safety and efficacy of rituximab for the treatment of SSc.

In the investigator-initiated trial, patients aged 20-79 years who fulfilled ACR and European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis and who had a modified Rodnan Skin Score (mRSS) of 10 or more and a life expectancy of at least 6 months were randomly assigned to receive infusions with either rituximab 375 mg/m² or placebo once weekly for 4 weeks. Patients and clinicians were masked to treatment allocation.

The trial included 56 patients (51 women, 5 men). Of all patients enrolled, 27 of 28 who were allocated to receive rituximab and 22 of 28 who were allocated to receive placebo underwent at least one infusion and completed 24 weeks of follow-up.

The absolute change in mRSS at 24 weeks after the start of therapy, the primary endpoint, was –6.30 in the rituximab group, compared with +2.14 in the placebo group, a difference of –8.44 (P < .0001).

In a subgroup analysis, rituximab was superior to placebo regardless of disease duration, disease type (diffuse cutaneous or limited cutaneous SSc), prior receipt of systemic corticosteroids or immunosuppressants, or having C-reactive protein levels less than 0.3 mg/dL or at least 0.3 mg/dL.

However, there was no significant benefit with rituximab for patients with baseline mRSS of at least 20 or for those without ILD at baseline.

There was also evidence that rituximab reduced lung fibrosis. For patients assigned to the active drug, the absolute change in FVC at 24 weeks was +0.09% of the predicted value, compared with –3.56% for patients who received placebo (P = .044).

The researchers also observed radiographic evidence of lung improvement. The absolute change in the percentage of lung field occupied with interstitial shadows was –0.32% in the rituximab arm versus +2.39% in the placebo arm (P = .034). There was no significant between-group difference in the absolute change in diffusing capacity of lung for carbon monoxide, however.

Adverse events that occurred more frequently with rituximab included oral mucositis, diarrhea, and decreased neutrophil and white blood cell counts.

Convincing results

“What I thought the Japanese study did was to give a much more convincing proof of concept than has been out there,” Dr. Spiera said in an interview.

“There have been some preliminary experiences that have been encouraging with rituximab in scleroderma, most of which has been open label,” he said.

He also referred to a retrospective study by EUSTAR, the European Scleroderma Trials and Research group, which indicated that patients who had previously received rituximab seemed to have had better outcomes than patients who had been treated with other therapies.

Dr. Spiera added that, although he was glad to see the data from a randomized, placebo-controlled trial in this population, he was uncomfortable with the idea of leaving patients untreated for 6 months.

“From the standpoint of somebody wanting to know what strategies might be promising, this is great for us, but I would not have designed the trial that way,” he said.

The study results were previously published in the Lancet Rheumatology.

The study was supported by grants from the Japan Agency for Medical Research and Development and Zenyaku Kogyo. Dr. Yoshizaki disclosed no relevant financial relationships. Dr. Spiera has received grant/research support from and has consulted for Roche/Genentech, maker of rituximab, and has received compensation from other companies.

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

Rituximab effectively reduced skin sclerosis and appeared to have a beneficial effect on interstitial lung disease (ILD) for patients with systemic sclerosis (SSc) in a randomized, clinical trial.

Courtesy Charlotte E. LaSenna and Dr. Andrea Maderal, University of Miami

At 24 weeks’ follow-up, there was significant improvement in total skin thickness scores among patients who received four once-weekly rituximab infusions, compared with patients who received placebo infusions. Among patients who received rituximab, there were also small but significant improvements in percentage of forced vital capacity (FVC). Among patients who received placebo, FVC worsened, reported Ayumi Yoshizaki, MD, of the University of Tokyo and colleagues.

“Systemic sclerosis is considered to have high unmet medical needs because of its poor prognosis and the lack of satisfactory and effective treatments,” he said at the virtual annual meeting of the American College of Rheumatology.

“Several clinical studies have suggested that B-cell depletion therapy with rituximab anti-CD20 antibody is effective in treating skin and lung fibrosis of SSc. However, no randomized, placebo-controlled trial has been able to confirm the efficacy of rituximab in SSc,” Dr. Yoshizaki said.

A rheumatologist who is currently conducting an investigator-initiated trial in which patients with SSC are undergoing treatment with rituximab followed by belimumab (Benlysta) said in an interview that he found the data to be “super interesting.”

“There are a lot of reasons to think that B cells might be important in systemic sclerosis, and actually that’s why our group had previously done an investigator-initiated trial with belimumab years ago,” said Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York.

Randomized trial

Dr. Yoshizaki and colleagues conducted the randomized, placebo-controlled DESIRES trial in four hospitals in Japan to evaluate the safety and efficacy of rituximab for the treatment of SSc.

In the investigator-initiated trial, patients aged 20-79 years who fulfilled ACR and European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis and who had a modified Rodnan Skin Score (mRSS) of 10 or more and a life expectancy of at least 6 months were randomly assigned to receive infusions with either rituximab 375 mg/m² or placebo once weekly for 4 weeks. Patients and clinicians were masked to treatment allocation.

The trial included 56 patients (51 women, 5 men). Of all patients enrolled, 27 of 28 who were allocated to receive rituximab and 22 of 28 who were allocated to receive placebo underwent at least one infusion and completed 24 weeks of follow-up.

The absolute change in mRSS at 24 weeks after the start of therapy, the primary endpoint, was –6.30 in the rituximab group, compared with +2.14 in the placebo group, a difference of –8.44 (P < .0001).

In a subgroup analysis, rituximab was superior to placebo regardless of disease duration, disease type (diffuse cutaneous or limited cutaneous SSc), prior receipt of systemic corticosteroids or immunosuppressants, or having C-reactive protein levels less than 0.3 mg/dL or at least 0.3 mg/dL.

However, there was no significant benefit with rituximab for patients with baseline mRSS of at least 20 or for those without ILD at baseline.

There was also evidence that rituximab reduced lung fibrosis. For patients assigned to the active drug, the absolute change in FVC at 24 weeks was +0.09% of the predicted value, compared with –3.56% for patients who received placebo (P = .044).

The researchers also observed radiographic evidence of lung improvement. The absolute change in the percentage of lung field occupied with interstitial shadows was –0.32% in the rituximab arm versus +2.39% in the placebo arm (P = .034). There was no significant between-group difference in the absolute change in diffusing capacity of lung for carbon monoxide, however.

Adverse events that occurred more frequently with rituximab included oral mucositis, diarrhea, and decreased neutrophil and white blood cell counts.

Convincing results

“What I thought the Japanese study did was to give a much more convincing proof of concept than has been out there,” Dr. Spiera said in an interview.

“There have been some preliminary experiences that have been encouraging with rituximab in scleroderma, most of which has been open label,” he said.

He also referred to a retrospective study by EUSTAR, the European Scleroderma Trials and Research group, which indicated that patients who had previously received rituximab seemed to have had better outcomes than patients who had been treated with other therapies.

Dr. Spiera added that, although he was glad to see the data from a randomized, placebo-controlled trial in this population, he was uncomfortable with the idea of leaving patients untreated for 6 months.

“From the standpoint of somebody wanting to know what strategies might be promising, this is great for us, but I would not have designed the trial that way,” he said.

The study results were previously published in the Lancet Rheumatology.

The study was supported by grants from the Japan Agency for Medical Research and Development and Zenyaku Kogyo. Dr. Yoshizaki disclosed no relevant financial relationships. Dr. Spiera has received grant/research support from and has consulted for Roche/Genentech, maker of rituximab, and has received compensation from other companies.

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

Hidradenitis suppurativa (HS) is a chronic inflammatory, androgen gland disorder characterized by recurrent rupture of the hair follicles with a vigorous inflammatory response. This response results in abscess formation and development of draining sinus tracts and hypertrophic fibrous scars.^1,2 Pain, discomfort, and odorous discharge from the recalcitrant lesions have a profound impact on patient quality of life.^3,4

The morbidity and disease burden associated with HS are particularly underestimated, as patients frequently report debilitating pain that often is overlooked.^5,6 Additionally, the quality and intensity of perceived pain are compounded by frequently associated depression and anxiety.^7-9 Pain has been reported by patients with HS to be the highest cause of morbidity, despite the disfiguring nature of the disease and its associated psychosocial distress.^7,10 Nonetheless, HS lacks an accepted pain management algorithm similar to those that have been developed for the treatment of other acute or chronic pain disorders, such as back pain and sickle cell disease.^4,11-13

Given the lack of formal studies regarding pain management in patients with HS, clinicians are limited to general pain guidelines, expert opinion, small trials, and patient preference.³ Furthermore, effective pain management in HS necessitates the treatment of both chronic pain affecting daily function and acute pain present during disease flares, surgical interventions, and dressing changes.³ The result is a wide array of strategies used for HS-associated pain.^3,4

Epidemiology and Pathophysiology

Hidradenitis suppurativa historically has been an overlooked and underdiagnosed disease, which limits epidemiology data.⁵ Current estimates are that HS affects approximately 1% of the general population; however, prevalence rates range from 0.03% to 4.1%.^14-16

The exact etiology of HS remains unclear, but it is thought that genetic factors, immune dysregulation, and environmental/behavioral influences all contribute to its pathophysiology.^1,17 Up to 40% of patients with HS report a positive family history of the disease.^18-20 Hidradenitis suppurativa has been associated with other inflammatory disease states, such as inflammatory bowel disease, spondyloarthropathies, and pyoderma gangrenosum.^16,21,22

It is thought that HS is the result of some defect in keratin clearance that leads to follicular hyperkeratinization and occlusion.¹ Resultant rupture of pilosebaceous units and spillage of contents (including keratin and bacteria) into the surrounding dermis triggers a vigorous inflammatory response. Sinus tracts and fistulas become the targets of bacterial colonization, biofilm formation, and secondary infection. The result is suppuration and extension of the lesions as well as sustained chronic inflammation.^23,24

Although the etiology of HS is complex, several modifiable risk factors for the disease have been identified, most prominently cigarette smoking and obesity. Approximately 70% of patients with HS smoke cigarettes.^2,15,25,26 Obesity has a well-known association with HS, and it is possible that weight reduction lowers disease severity.^27-30

Clinical Presentation and Diagnosis

Establishing a diagnosis of HS necessitates recognition of disease morphology, topography, and chronicity. Hidradenitis suppurativa most commonly occurs in the axillae, inguinal and anogenital region, perineal region, and inframammary region.^5,31 A typical history involves a prolonged disease course with recurrent lesions and intermittent periods of improvement or remission. Primary lesions are deep, inflamed, painful, and sterile. Ultimately, these lesions rupture and track subcutaneously.^15,25 Intercommunicating sinus tracts form from multiple recurrent nodules in close proximity and may ultimately lead to fibrotic scarring and local architectural distortion.³² The Hurley staging system helps to guide treatment interventions based on disease severity. Approach to pain management is discussed below.

Pain Management in HS: General Principles

Pain management is complex for clinicians, as there are limited studies from which to draw treatment recommendations. Incomplete understanding of the etiology and pathophysiology of the disease contributes to the lack of established management guidelines.

A PubMed search of articles indexed for MEDLINE using the terms hidradenitis, suppurativa, pain, and management revealed 61 different results dating back to 1980, 52 of which had been published in the last 5 years. When the word acute was added to the search, there were only 6 results identified. These results clearly reflect a better understanding of HS-mediated pain as well as clinical unmet needs and evolving strategies in pain management therapeutics. However, many of these studies reflect therapies focused on the mediation or modulation of HS pathogenesis rather than potential pain management therapies.

In addition, the heterogenous nature of the pain experience in HS poses a challenge for clinicians. Patients may experience multiple pain types concurrently, including inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic, as well as pain related to arthritis.^3,33,34 Pain perception is further complicated by the observation that patients with HS have high rates of psychiatric comorbidities such as depression and anxiety, both of which profoundly alter perception of both the strength and quality of pain.^7,8,22,35 A suggested algorithm for treatment of pain in HS is described in the eTable.³⁶

Chronicity is a hallmark of HS. Patients experience a prolonged disease course involving acute painful exacerbations superimposed on chronic pain that affects all aspects of daily life. Changes in self-perception, daily living activities, mood state, physical functioning, and physical comfort frequently are reported to have a major impact on quality of life.^1,3,37

In 2018, Thorlacius et al³⁸ created a multistakeholder consensus on a core outcome set of domains detailing what to measure in clinical trials for HS. The authors hoped that the routine adoption of these core domains would promote the collection of consistent and relevant information, bolster the strength of evidence synthesis, and minimize the risk for outcome reporting bias among studies.³⁸ It is important to ascertain the patient’s description of his/her pain to distinguish between stimulus-dependent nociceptive pain vs spontaneous neuropathic pain.^3,7,10 The most common pain descriptors used by patients are “shooting,” “itchy,” “blinding,” “cutting,” and “exhausting.”¹⁰ In addition to obtaining descriptive factors, it is important for the clinician to obtain information on the timing of the pain, whether or not the pain is relieved with spontaneous or surgical drainage, and if the patient is experiencing chronic background pain secondary to scarring or skin contraction.³ With the routine utilization of a consistent set of core domains, advances in our understanding of the different elements of HS pain, and increased provider awareness of the disease, the future of pain management in patients with HS seems promising.

Acute and Perioperative Pain Management

Acute Pain Management—The pain in HS can range from mild to excruciating.^3,7 The difference between acute and chronic pain in this condition may be hard to delineate, as patients may have intense acute flares on top of a baseline level of chronic pain.^3,7,14 These factors, in combination with various pain types of differing etiologies, make the treatment of HS-associated pain a therapeutic challenge.

The first-line treatments for acute pain in HS are oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical analgesics.³ These treatment modalities are especially helpful for nociceptive pain, which often is described as having an aching or tender quality.³ Topical treatment for acute pain episodes includes diclofenac gel and liposomal lidocaine cream.³⁹ Topical lidocaine in particular has the benefit of being rapid acting, and its effect can last 1 to 2 hours. Ketamine has been anecdotally used as a topical treatment. Treatment options for neuropathic pain include topical amitriptyline, gabapentin, and pregabalin.³⁹ Dressings and ice packs may be used in cases of mild acute pain, depending on patient preference.³

First-line therapies may not provide adequate pain control in many patients.^3,40,41 Should the first-line treatments fail, oral opiates can be considered as a treatment option, especially if the patient has a history of recurrent pain unresponsive to milder methods of pain control.^3,40,41 However, prudence should be exercised, as patients with HS have a higher risk for opioid abuse, and referral to a pain specialist is advisable.⁴⁰ Generally, use of opioids should be limited to the smallest period of time possible.^40,41 Codeine can be used as a first opioid option, with hydromorphone available as an alternative.⁴¹

Pain caused by inflamed abscesses and nodules can be treated with either intralesional corticosteroids or incision and drainage. Intralesional triamcinolone has been found to cause substantial pain relief within 1 day of injection in patients with HS.^3,42

Prompt discussion about the remitting course of HS will prepare patients for flares. Although the therapies discussed here aim to reduce the clinical severity and inflammation associated with HS, achieving pain-free remission can be challenging. Barriers to developing a long-term treatment regimen include intolerable side effects or simply nonresponsive disease.^36,43

Management of Perioperative Pain—Medical treatment of HS often yields only transient or mild results. Hurley stage II or III lesions typically require surgical removal of affected tissues.^32,44-46 Surgery may dramatically reduce the primary disease burden and provide substantial pain relief.^3,4,44 Complete resection of the affected tissue by wide excision is the most common surgical procedure used.^46-48 However, various tissue-sparing techniques, such as skin-tissue-sparing excision with electrosurgical peeling, also have been utilized. Tissue-sparing surgical techniques may lead to shorter healing times and less postoperative pain.⁴⁸

There currently is little guidance available on the perioperative management of pain as it relates to surgical procedures for HS. The pain experienced from surgery varies based on the area and location of affected tissue; extent of disease; surgical technique used; and whether primary closure, closure by secondary intention, or skin grafting is utilized.^47,49 Medical treatment aimed at reducing inflammation prior to surgical intervention may improve postoperative pain and complications.

The use of general vs local anesthesia during surgery depends on the extent of the disease and the amount of tissue being removed; however, the use of local anesthesia has been associated with a higher recurrence of disease, possibly owing to less aggressive tissue removal.⁵⁰ Intraoperatively, the injection of 0.5% bupivacaine around the wound edges may lead to less postoperative pain.^3,48 Postoperative pain usually is managed with acetaminophen and NSAIDs.⁴⁸ In cases of severe postoperative pain, short- and long-acting opioid oxycodone preparations may be used. The combination of diclofenac and tramadol also has been used postoperatively.³ Patients who do not undergo extensive surgery often can leave the hospital the same day.

Effective strategies for mitigating HS-associated pain must address the chronic pain component of the disease. Long-term management involves lifestyle modifications and pharmacologic agents.

Chronic Pain Management

Although HS is not a curable disease, there are treatments available to minimize symptoms. Long-term management of HS is essential to minimize the effects of chronic pain and physical scarring associated with inflammation.³¹ In one study from the French Society of Dermatology, pain reported by patients with HS was directly associated with severity and duration of disease, emotional symptoms, and reduced functionality.⁵¹ For these reasons, many treatments for HS target reducing clinical severity and achieving remission, often defined as more than 6 months without any recurrence of lesions.⁵² In addition to lifestyle management, therapies available to manage HS include topical and systemic medications as well as procedures such as surgical excision.^36,43,52,53

Lifestyle Modifications

Regardless of the severity of HS, all patients may benefit from basic education on the pathogenesis of the disease.³⁶ The associations with smoking and obesity have been well documented, and treatment of these comorbid conditions is indicated.^36,43,52 For example, in relation to obesity, the use of metformin is very well tolerated and seems to positively impact HS symptoms.⁴³ Several studies have suggested that weight reduction lowers disease severity.^28-30 Patients should be counseled on the importance of smoking cessation and weight loss.

Finally, the emotional impact of HS is not to be discounted, both the physical and social discomfort as well as the chronicity of the disease and frustration with treatment.⁵¹ Chronic pain has been associated with increased rates of depression, and 43% of patients with HS specifically have been diagnosed with major depressive disorder.⁷ For these reasons, clinician guidance, social support, and websites can improve patient understanding of the disease, adherence to treatment, and comorbid anxiety and depression.⁵²

Topical Therapy

Topical therapy generally is limited to mild disease and is geared at decreasing inflammation or superimposed infection.^36,52 Some of the earliest therapies used were topical antibiotics.⁴³ Topical clindamycin has been shown to be as effective as oral tetracyclines in reducing the number of abscesses, but neither treatment substantially reduces pain associated with smaller nodules.⁵⁴ Intralesional corticosteroids such as triamcinolone acetonide have been shown to decrease both patient-reported pain and physician-assessed severity within 1 to 7 days.⁴² Routine injection, however, is not a feasible means of long-term treatment both because of inconvenience and the potential adverse effects of corticosteroids.^36,52 Both topical clindamycin and intralesional steroids are helpful in reducing inflammation prior to planned surgical intervention.^36,52,53

Newer topical therapies include resorcinol peels and combination antimicrobials, such as 2% triclosan and oral zinc gluconate.^52,53 Data surrounding the use of resorcinol in mild to moderate HS are promising and have shown decreased severity of both new and long-standing nodules. Fifteen-percent resorcinol peels are helpful tools that allow for self-administration by patients during exacerbations to decrease pain and flare duration.^55,56 In a 2016 clinical trial, a combination of oral zinc gluconate with topical triclosan was shown to reduce flare-ups and nodules in mild HS.⁵⁷ Oral zinc alone may have anti-inflammatory properties and generally is well tolerated.^43,53 Topical therapies have a role in reducing HS-associated pain but often are limited to milder disease.

Systemic Agents

Several therapeutic options exist for the treatment of HS; however, a detailed description of their mechanisms and efficacies is beyond the scope of this review, which is focused on pain. Briefly, these systemic agents include antibiotics, retinoids, corticosteroids, antiandrogens, and biologics.^43,52,53

Treatment with antibiotics such as tetracyclines or a combination of clindamycin plus rifampin has been shown to produce complete remission in 60% to 80% of users; however, this treatment requires more than 6 months of antibiotic therapy, which can be difficult to tolerate.^52,53,58 Relapse is common after antibiotic cessation.^2,43,52 Antibiotics have demonstrated efficacy during acute flares and in reducing inflammatory activity prior to surgery.⁵²

Retinoids have been utilized in the treatment of HS because of their action on sebaceous glands and hair follicles.^43,53 Acitretin has been shown to be the most effective oral retinoid available in the United States.⁴³ Unfortunately, many of the studies investigating the use of retinoids for treatment of HS are limited by small sample size.^36,43,52

Because HS is predominantly an inflammatory condition, immunosuppressants have been adapted to manage patients when antibiotics and topicals have failed. Systemic steroids rarely are used for long-term therapy because of the severe side effects and are preferred only for acute management.^36,52 Cyclosporine and dapsone have demonstrated efficacy in treating moderate to severe HS, whereas methotrexate and colchicine have shown little efficacy.⁵² Both cyclosporine and dapsone are difficult to tolerate, require laboratory monitoring, and lead to only conservative improvement rather than remission in most patients.⁴³

Immune dysregulation in HS involves elevated levels of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which is a key mediator of inflammation and a stimulator of other inflammatory cytokines.^59,60 The first approved biologic treatment of HS was adalimumab, a TNF-α inhibitor, which showed a 50% reduction in total abscess and inflammatory nodule count in 60% of patients with moderate to severe HS.^61-63 Of course, TNF-α inhibitor therapy is not without risks, specifically those of infection.^43,53,61,62 Maintenance therapy may be required if patients relapse.^53,61

Various interleukin inhibitors also have emerged as potential therapies for HS, such as ustekinumab and anakinra.^36,64 Both have been subject to numerous small case trials that have reported improvements in clinical severity and pain; however, both drugs were associated with a fair number of nonresponders.^36,64,65

Surgical Procedures

Although HS lesions may regress on their own in a matter of weeks, surgical drainage allows an acute alleviation of the severe burning pain associated with HS flares.^36,52,53 Because of improved understanding of the disease pathophysiology, recent therapies targeting the hair follicle have been developed and have shown promising results. These therapies include laser- and light-based procedures. Long-pulsed Nd:YAG laser therapy reduces the number of hair follicles and sebaceous glands and has been effective for Hurley stage I or II disease.^{36,43,52,53,66} Photodynamic therapy offers a less-invasive option compared to surgery and laser therapy.^52,53,66 Both Nd:YAG and CO₂ laser therapy offer low recurrence rates (<30%) due to destruction of the apocrine unit.^43,53 Photodynamic therapy for mild disease offers a less-invasive option compared to surgery and laser therapy.⁵³ There is a need for larger randomized controlled trials involving laser, light, and CO₂ therapies.⁶⁶

Conclusion

Hidradenitis suppurativa is a debilitating condition with an underestimated disease burden. Although the pathophysiology of the disease is not completely understood, it is evident that pain is a major cause of morbidity. Patients experience a multitude of acute and chronic pain types: inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic. Pain perception and quality of life are further impacted by psychiatric conditions such as depression and anxiety, both of which are common comorbidities in patients with HS. Several pharmacologic agents have been used to treat HS-associated pain with mixed results. First-line treatment of acute pain episodes includes oral acetaminophen, NSAIDs, and topical analgesics. Management of chronic pain includes utilization of topical agents, systemic agents, and biologics, as well as addressing lifestyle (eg, obesity, smoking status) and psychiatric comorbidities. Although these therapies have roles in HS pain management, the most effective pain remedies developed thus far are limited to surgery and TNF-α inhibitors. Optimization of pain control in patients with HS requires multidisciplinary collaboration among dermatologists, pain specialists, psychiatrists, and other members of the health care team. Further large-scale studies are needed to create an evidence-based treatment algorithm for the management of pain in HS.

Hidradenitis suppurativa (HS) is a chronic inflammatory, androgen gland disorder characterized by recurrent rupture of the hair follicles with a vigorous inflammatory response. This response results in abscess formation and development of draining sinus tracts and hypertrophic fibrous scars.^1,2 Pain, discomfort, and odorous discharge from the recalcitrant lesions have a profound impact on patient quality of life.^3,4

The morbidity and disease burden associated with HS are particularly underestimated, as patients frequently report debilitating pain that often is overlooked.^5,6 Additionally, the quality and intensity of perceived pain are compounded by frequently associated depression and anxiety.^7-9 Pain has been reported by patients with HS to be the highest cause of morbidity, despite the disfiguring nature of the disease and its associated psychosocial distress.^7,10 Nonetheless, HS lacks an accepted pain management algorithm similar to those that have been developed for the treatment of other acute or chronic pain disorders, such as back pain and sickle cell disease.^4,11-13

Given the lack of formal studies regarding pain management in patients with HS, clinicians are limited to general pain guidelines, expert opinion, small trials, and patient preference.³ Furthermore, effective pain management in HS necessitates the treatment of both chronic pain affecting daily function and acute pain present during disease flares, surgical interventions, and dressing changes.³ The result is a wide array of strategies used for HS-associated pain.^3,4

Epidemiology and Pathophysiology

Hidradenitis suppurativa historically has been an overlooked and underdiagnosed disease, which limits epidemiology data.⁵ Current estimates are that HS affects approximately 1% of the general population; however, prevalence rates range from 0.03% to 4.1%.^14-16

The exact etiology of HS remains unclear, but it is thought that genetic factors, immune dysregulation, and environmental/behavioral influences all contribute to its pathophysiology.^1,17 Up to 40% of patients with HS report a positive family history of the disease.^18-20 Hidradenitis suppurativa has been associated with other inflammatory disease states, such as inflammatory bowel disease, spondyloarthropathies, and pyoderma gangrenosum.^16,21,22

It is thought that HS is the result of some defect in keratin clearance that leads to follicular hyperkeratinization and occlusion.¹ Resultant rupture of pilosebaceous units and spillage of contents (including keratin and bacteria) into the surrounding dermis triggers a vigorous inflammatory response. Sinus tracts and fistulas become the targets of bacterial colonization, biofilm formation, and secondary infection. The result is suppuration and extension of the lesions as well as sustained chronic inflammation.^23,24

Although the etiology of HS is complex, several modifiable risk factors for the disease have been identified, most prominently cigarette smoking and obesity. Approximately 70% of patients with HS smoke cigarettes.^2,15,25,26 Obesity has a well-known association with HS, and it is possible that weight reduction lowers disease severity.^27-30

Clinical Presentation and Diagnosis

Establishing a diagnosis of HS necessitates recognition of disease morphology, topography, and chronicity. Hidradenitis suppurativa most commonly occurs in the axillae, inguinal and anogenital region, perineal region, and inframammary region.^5,31 A typical history involves a prolonged disease course with recurrent lesions and intermittent periods of improvement or remission. Primary lesions are deep, inflamed, painful, and sterile. Ultimately, these lesions rupture and track subcutaneously.^15,25 Intercommunicating sinus tracts form from multiple recurrent nodules in close proximity and may ultimately lead to fibrotic scarring and local architectural distortion.³² The Hurley staging system helps to guide treatment interventions based on disease severity. Approach to pain management is discussed below.

Pain Management in HS: General Principles

Pain management is complex for clinicians, as there are limited studies from which to draw treatment recommendations. Incomplete understanding of the etiology and pathophysiology of the disease contributes to the lack of established management guidelines.

A PubMed search of articles indexed for MEDLINE using the terms hidradenitis, suppurativa, pain, and management revealed 61 different results dating back to 1980, 52 of which had been published in the last 5 years. When the word acute was added to the search, there were only 6 results identified. These results clearly reflect a better understanding of HS-mediated pain as well as clinical unmet needs and evolving strategies in pain management therapeutics. However, many of these studies reflect therapies focused on the mediation or modulation of HS pathogenesis rather than potential pain management therapies.

In addition, the heterogenous nature of the pain experience in HS poses a challenge for clinicians. Patients may experience multiple pain types concurrently, including inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic, as well as pain related to arthritis.^3,33,34 Pain perception is further complicated by the observation that patients with HS have high rates of psychiatric comorbidities such as depression and anxiety, both of which profoundly alter perception of both the strength and quality of pain.^7,8,22,35 A suggested algorithm for treatment of pain in HS is described in the eTable.³⁶

Chronicity is a hallmark of HS. Patients experience a prolonged disease course involving acute painful exacerbations superimposed on chronic pain that affects all aspects of daily life. Changes in self-perception, daily living activities, mood state, physical functioning, and physical comfort frequently are reported to have a major impact on quality of life.^1,3,37

In 2018, Thorlacius et al³⁸ created a multistakeholder consensus on a core outcome set of domains detailing what to measure in clinical trials for HS. The authors hoped that the routine adoption of these core domains would promote the collection of consistent and relevant information, bolster the strength of evidence synthesis, and minimize the risk for outcome reporting bias among studies.³⁸ It is important to ascertain the patient’s description of his/her pain to distinguish between stimulus-dependent nociceptive pain vs spontaneous neuropathic pain.^3,7,10 The most common pain descriptors used by patients are “shooting,” “itchy,” “blinding,” “cutting,” and “exhausting.”¹⁰ In addition to obtaining descriptive factors, it is important for the clinician to obtain information on the timing of the pain, whether or not the pain is relieved with spontaneous or surgical drainage, and if the patient is experiencing chronic background pain secondary to scarring or skin contraction.³ With the routine utilization of a consistent set of core domains, advances in our understanding of the different elements of HS pain, and increased provider awareness of the disease, the future of pain management in patients with HS seems promising.

Acute and Perioperative Pain Management

Acute Pain Management—The pain in HS can range from mild to excruciating.^3,7 The difference between acute and chronic pain in this condition may be hard to delineate, as patients may have intense acute flares on top of a baseline level of chronic pain.^3,7,14 These factors, in combination with various pain types of differing etiologies, make the treatment of HS-associated pain a therapeutic challenge.

The first-line treatments for acute pain in HS are oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical analgesics.³ These treatment modalities are especially helpful for nociceptive pain, which often is described as having an aching or tender quality.³ Topical treatment for acute pain episodes includes diclofenac gel and liposomal lidocaine cream.³⁹ Topical lidocaine in particular has the benefit of being rapid acting, and its effect can last 1 to 2 hours. Ketamine has been anecdotally used as a topical treatment. Treatment options for neuropathic pain include topical amitriptyline, gabapentin, and pregabalin.³⁹ Dressings and ice packs may be used in cases of mild acute pain, depending on patient preference.³

First-line therapies may not provide adequate pain control in many patients.^3,40,41 Should the first-line treatments fail, oral opiates can be considered as a treatment option, especially if the patient has a history of recurrent pain unresponsive to milder methods of pain control.^3,40,41 However, prudence should be exercised, as patients with HS have a higher risk for opioid abuse, and referral to a pain specialist is advisable.⁴⁰ Generally, use of opioids should be limited to the smallest period of time possible.^40,41 Codeine can be used as a first opioid option, with hydromorphone available as an alternative.⁴¹

Pain caused by inflamed abscesses and nodules can be treated with either intralesional corticosteroids or incision and drainage. Intralesional triamcinolone has been found to cause substantial pain relief within 1 day of injection in patients with HS.^3,42

Prompt discussion about the remitting course of HS will prepare patients for flares. Although the therapies discussed here aim to reduce the clinical severity and inflammation associated with HS, achieving pain-free remission can be challenging. Barriers to developing a long-term treatment regimen include intolerable side effects or simply nonresponsive disease.^36,43

Management of Perioperative Pain—Medical treatment of HS often yields only transient or mild results. Hurley stage II or III lesions typically require surgical removal of affected tissues.^32,44-46 Surgery may dramatically reduce the primary disease burden and provide substantial pain relief.^3,4,44 Complete resection of the affected tissue by wide excision is the most common surgical procedure used.^46-48 However, various tissue-sparing techniques, such as skin-tissue-sparing excision with electrosurgical peeling, also have been utilized. Tissue-sparing surgical techniques may lead to shorter healing times and less postoperative pain.⁴⁸

There currently is little guidance available on the perioperative management of pain as it relates to surgical procedures for HS. The pain experienced from surgery varies based on the area and location of affected tissue; extent of disease; surgical technique used; and whether primary closure, closure by secondary intention, or skin grafting is utilized.^47,49 Medical treatment aimed at reducing inflammation prior to surgical intervention may improve postoperative pain and complications.

The use of general vs local anesthesia during surgery depends on the extent of the disease and the amount of tissue being removed; however, the use of local anesthesia has been associated with a higher recurrence of disease, possibly owing to less aggressive tissue removal.⁵⁰ Intraoperatively, the injection of 0.5% bupivacaine around the wound edges may lead to less postoperative pain.^3,48 Postoperative pain usually is managed with acetaminophen and NSAIDs.⁴⁸ In cases of severe postoperative pain, short- and long-acting opioid oxycodone preparations may be used. The combination of diclofenac and tramadol also has been used postoperatively.³ Patients who do not undergo extensive surgery often can leave the hospital the same day.

Effective strategies for mitigating HS-associated pain must address the chronic pain component of the disease. Long-term management involves lifestyle modifications and pharmacologic agents.

Chronic Pain Management

Although HS is not a curable disease, there are treatments available to minimize symptoms. Long-term management of HS is essential to minimize the effects of chronic pain and physical scarring associated with inflammation.³¹ In one study from the French Society of Dermatology, pain reported by patients with HS was directly associated with severity and duration of disease, emotional symptoms, and reduced functionality.⁵¹ For these reasons, many treatments for HS target reducing clinical severity and achieving remission, often defined as more than 6 months without any recurrence of lesions.⁵² In addition to lifestyle management, therapies available to manage HS include topical and systemic medications as well as procedures such as surgical excision.^36,43,52,53

Lifestyle Modifications

Regardless of the severity of HS, all patients may benefit from basic education on the pathogenesis of the disease.³⁶ The associations with smoking and obesity have been well documented, and treatment of these comorbid conditions is indicated.^36,43,52 For example, in relation to obesity, the use of metformin is very well tolerated and seems to positively impact HS symptoms.⁴³ Several studies have suggested that weight reduction lowers disease severity.^28-30 Patients should be counseled on the importance of smoking cessation and weight loss.

Finally, the emotional impact of HS is not to be discounted, both the physical and social discomfort as well as the chronicity of the disease and frustration with treatment.⁵¹ Chronic pain has been associated with increased rates of depression, and 43% of patients with HS specifically have been diagnosed with major depressive disorder.⁷ For these reasons, clinician guidance, social support, and websites can improve patient understanding of the disease, adherence to treatment, and comorbid anxiety and depression.⁵²

Topical Therapy

Topical therapy generally is limited to mild disease and is geared at decreasing inflammation or superimposed infection.^36,52 Some of the earliest therapies used were topical antibiotics.⁴³ Topical clindamycin has been shown to be as effective as oral tetracyclines in reducing the number of abscesses, but neither treatment substantially reduces pain associated with smaller nodules.⁵⁴ Intralesional corticosteroids such as triamcinolone acetonide have been shown to decrease both patient-reported pain and physician-assessed severity within 1 to 7 days.⁴² Routine injection, however, is not a feasible means of long-term treatment both because of inconvenience and the potential adverse effects of corticosteroids.^36,52 Both topical clindamycin and intralesional steroids are helpful in reducing inflammation prior to planned surgical intervention.^36,52,53

Newer topical therapies include resorcinol peels and combination antimicrobials, such as 2% triclosan and oral zinc gluconate.^52,53 Data surrounding the use of resorcinol in mild to moderate HS are promising and have shown decreased severity of both new and long-standing nodules. Fifteen-percent resorcinol peels are helpful tools that allow for self-administration by patients during exacerbations to decrease pain and flare duration.^55,56 In a 2016 clinical trial, a combination of oral zinc gluconate with topical triclosan was shown to reduce flare-ups and nodules in mild HS.⁵⁷ Oral zinc alone may have anti-inflammatory properties and generally is well tolerated.^43,53 Topical therapies have a role in reducing HS-associated pain but often are limited to milder disease.

Systemic Agents

Several therapeutic options exist for the treatment of HS; however, a detailed description of their mechanisms and efficacies is beyond the scope of this review, which is focused on pain. Briefly, these systemic agents include antibiotics, retinoids, corticosteroids, antiandrogens, and biologics.^43,52,53

Treatment with antibiotics such as tetracyclines or a combination of clindamycin plus rifampin has been shown to produce complete remission in 60% to 80% of users; however, this treatment requires more than 6 months of antibiotic therapy, which can be difficult to tolerate.^52,53,58 Relapse is common after antibiotic cessation.^2,43,52 Antibiotics have demonstrated efficacy during acute flares and in reducing inflammatory activity prior to surgery.⁵²

Retinoids have been utilized in the treatment of HS because of their action on sebaceous glands and hair follicles.^43,53 Acitretin has been shown to be the most effective oral retinoid available in the United States.⁴³ Unfortunately, many of the studies investigating the use of retinoids for treatment of HS are limited by small sample size.^36,43,52

Because HS is predominantly an inflammatory condition, immunosuppressants have been adapted to manage patients when antibiotics and topicals have failed. Systemic steroids rarely are used for long-term therapy because of the severe side effects and are preferred only for acute management.^36,52 Cyclosporine and dapsone have demonstrated efficacy in treating moderate to severe HS, whereas methotrexate and colchicine have shown little efficacy.⁵² Both cyclosporine and dapsone are difficult to tolerate, require laboratory monitoring, and lead to only conservative improvement rather than remission in most patients.⁴³

Immune dysregulation in HS involves elevated levels of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which is a key mediator of inflammation and a stimulator of other inflammatory cytokines.^59,60 The first approved biologic treatment of HS was adalimumab, a TNF-α inhibitor, which showed a 50% reduction in total abscess and inflammatory nodule count in 60% of patients with moderate to severe HS.^61-63 Of course, TNF-α inhibitor therapy is not without risks, specifically those of infection.^43,53,61,62 Maintenance therapy may be required if patients relapse.^53,61

Various interleukin inhibitors also have emerged as potential therapies for HS, such as ustekinumab and anakinra.^36,64 Both have been subject to numerous small case trials that have reported improvements in clinical severity and pain; however, both drugs were associated with a fair number of nonresponders.^36,64,65

Surgical Procedures

Although HS lesions may regress on their own in a matter of weeks, surgical drainage allows an acute alleviation of the severe burning pain associated with HS flares.^36,52,53 Because of improved understanding of the disease pathophysiology, recent therapies targeting the hair follicle have been developed and have shown promising results. These therapies include laser- and light-based procedures. Long-pulsed Nd:YAG laser therapy reduces the number of hair follicles and sebaceous glands and has been effective for Hurley stage I or II disease.^{36,43,52,53,66} Photodynamic therapy offers a less-invasive option compared to surgery and laser therapy.^52,53,66 Both Nd:YAG and CO₂ laser therapy offer low recurrence rates (<30%) due to destruction of the apocrine unit.^43,53 Photodynamic therapy for mild disease offers a less-invasive option compared to surgery and laser therapy.⁵³ There is a need for larger randomized controlled trials involving laser, light, and CO₂ therapies.⁶⁶

Conclusion

Hidradenitis suppurativa is a debilitating condition with an underestimated disease burden. Although the pathophysiology of the disease is not completely understood, it is evident that pain is a major cause of morbidity. Patients experience a multitude of acute and chronic pain types: inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic. Pain perception and quality of life are further impacted by psychiatric conditions such as depression and anxiety, both of which are common comorbidities in patients with HS. Several pharmacologic agents have been used to treat HS-associated pain with mixed results. First-line treatment of acute pain episodes includes oral acetaminophen, NSAIDs, and topical analgesics. Management of chronic pain includes utilization of topical agents, systemic agents, and biologics, as well as addressing lifestyle (eg, obesity, smoking status) and psychiatric comorbidities. Although these therapies have roles in HS pain management, the most effective pain remedies developed thus far are limited to surgery and TNF-α inhibitors. Optimization of pain control in patients with HS requires multidisciplinary collaboration among dermatologists, pain specialists, psychiatrists, and other members of the health care team. Further large-scale studies are needed to create an evidence-based treatment algorithm for the management of pain in HS.

Hidradenitis suppurativa (HS) is a chronic inflammatory, androgen gland disorder characterized by recurrent rupture of the hair follicles with a vigorous inflammatory response. This response results in abscess formation and development of draining sinus tracts and hypertrophic fibrous scars.^1,2 Pain, discomfort, and odorous discharge from the recalcitrant lesions have a profound impact on patient quality of life.^3,4

The morbidity and disease burden associated with HS are particularly underestimated, as patients frequently report debilitating pain that often is overlooked.^5,6 Additionally, the quality and intensity of perceived pain are compounded by frequently associated depression and anxiety.^7-9 Pain has been reported by patients with HS to be the highest cause of morbidity, despite the disfiguring nature of the disease and its associated psychosocial distress.^7,10 Nonetheless, HS lacks an accepted pain management algorithm similar to those that have been developed for the treatment of other acute or chronic pain disorders, such as back pain and sickle cell disease.^4,11-13

Given the lack of formal studies regarding pain management in patients with HS, clinicians are limited to general pain guidelines, expert opinion, small trials, and patient preference.³ Furthermore, effective pain management in HS necessitates the treatment of both chronic pain affecting daily function and acute pain present during disease flares, surgical interventions, and dressing changes.³ The result is a wide array of strategies used for HS-associated pain.^3,4

Epidemiology and Pathophysiology

Hidradenitis suppurativa historically has been an overlooked and underdiagnosed disease, which limits epidemiology data.⁵ Current estimates are that HS affects approximately 1% of the general population; however, prevalence rates range from 0.03% to 4.1%.^14-16

The exact etiology of HS remains unclear, but it is thought that genetic factors, immune dysregulation, and environmental/behavioral influences all contribute to its pathophysiology.^1,17 Up to 40% of patients with HS report a positive family history of the disease.^18-20 Hidradenitis suppurativa has been associated with other inflammatory disease states, such as inflammatory bowel disease, spondyloarthropathies, and pyoderma gangrenosum.^16,21,22

It is thought that HS is the result of some defect in keratin clearance that leads to follicular hyperkeratinization and occlusion.¹ Resultant rupture of pilosebaceous units and spillage of contents (including keratin and bacteria) into the surrounding dermis triggers a vigorous inflammatory response. Sinus tracts and fistulas become the targets of bacterial colonization, biofilm formation, and secondary infection. The result is suppuration and extension of the lesions as well as sustained chronic inflammation.^23,24

Although the etiology of HS is complex, several modifiable risk factors for the disease have been identified, most prominently cigarette smoking and obesity. Approximately 70% of patients with HS smoke cigarettes.^2,15,25,26 Obesity has a well-known association with HS, and it is possible that weight reduction lowers disease severity.^27-30

Clinical Presentation and Diagnosis

Establishing a diagnosis of HS necessitates recognition of disease morphology, topography, and chronicity. Hidradenitis suppurativa most commonly occurs in the axillae, inguinal and anogenital region, perineal region, and inframammary region.^5,31 A typical history involves a prolonged disease course with recurrent lesions and intermittent periods of improvement or remission. Primary lesions are deep, inflamed, painful, and sterile. Ultimately, these lesions rupture and track subcutaneously.^15,25 Intercommunicating sinus tracts form from multiple recurrent nodules in close proximity and may ultimately lead to fibrotic scarring and local architectural distortion.³² The Hurley staging system helps to guide treatment interventions based on disease severity. Approach to pain management is discussed below.

Pain Management in HS: General Principles

Pain management is complex for clinicians, as there are limited studies from which to draw treatment recommendations. Incomplete understanding of the etiology and pathophysiology of the disease contributes to the lack of established management guidelines.

A PubMed search of articles indexed for MEDLINE using the terms hidradenitis, suppurativa, pain, and management revealed 61 different results dating back to 1980, 52 of which had been published in the last 5 years. When the word acute was added to the search, there were only 6 results identified. These results clearly reflect a better understanding of HS-mediated pain as well as clinical unmet needs and evolving strategies in pain management therapeutics. However, many of these studies reflect therapies focused on the mediation or modulation of HS pathogenesis rather than potential pain management therapies.

In addition, the heterogenous nature of the pain experience in HS poses a challenge for clinicians. Patients may experience multiple pain types concurrently, including inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic, as well as pain related to arthritis.^3,33,34 Pain perception is further complicated by the observation that patients with HS have high rates of psychiatric comorbidities such as depression and anxiety, both of which profoundly alter perception of both the strength and quality of pain.^7,8,22,35 A suggested algorithm for treatment of pain in HS is described in the eTable.³⁶

Chronicity is a hallmark of HS. Patients experience a prolonged disease course involving acute painful exacerbations superimposed on chronic pain that affects all aspects of daily life. Changes in self-perception, daily living activities, mood state, physical functioning, and physical comfort frequently are reported to have a major impact on quality of life.^1,3,37

In 2018, Thorlacius et al³⁸ created a multistakeholder consensus on a core outcome set of domains detailing what to measure in clinical trials for HS. The authors hoped that the routine adoption of these core domains would promote the collection of consistent and relevant information, bolster the strength of evidence synthesis, and minimize the risk for outcome reporting bias among studies.³⁸ It is important to ascertain the patient’s description of his/her pain to distinguish between stimulus-dependent nociceptive pain vs spontaneous neuropathic pain.^3,7,10 The most common pain descriptors used by patients are “shooting,” “itchy,” “blinding,” “cutting,” and “exhausting.”¹⁰ In addition to obtaining descriptive factors, it is important for the clinician to obtain information on the timing of the pain, whether or not the pain is relieved with spontaneous or surgical drainage, and if the patient is experiencing chronic background pain secondary to scarring or skin contraction.³ With the routine utilization of a consistent set of core domains, advances in our understanding of the different elements of HS pain, and increased provider awareness of the disease, the future of pain management in patients with HS seems promising.

Acute and Perioperative Pain Management

Acute Pain Management—The pain in HS can range from mild to excruciating.^3,7 The difference between acute and chronic pain in this condition may be hard to delineate, as patients may have intense acute flares on top of a baseline level of chronic pain.^3,7,14 These factors, in combination with various pain types of differing etiologies, make the treatment of HS-associated pain a therapeutic challenge.

The first-line treatments for acute pain in HS are oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical analgesics.³ These treatment modalities are especially helpful for nociceptive pain, which often is described as having an aching or tender quality.³ Topical treatment for acute pain episodes includes diclofenac gel and liposomal lidocaine cream.³⁹ Topical lidocaine in particular has the benefit of being rapid acting, and its effect can last 1 to 2 hours. Ketamine has been anecdotally used as a topical treatment. Treatment options for neuropathic pain include topical amitriptyline, gabapentin, and pregabalin.³⁹ Dressings and ice packs may be used in cases of mild acute pain, depending on patient preference.³

First-line therapies may not provide adequate pain control in many patients.^3,40,41 Should the first-line treatments fail, oral opiates can be considered as a treatment option, especially if the patient has a history of recurrent pain unresponsive to milder methods of pain control.^3,40,41 However, prudence should be exercised, as patients with HS have a higher risk for opioid abuse, and referral to a pain specialist is advisable.⁴⁰ Generally, use of opioids should be limited to the smallest period of time possible.^40,41 Codeine can be used as a first opioid option, with hydromorphone available as an alternative.⁴¹

Pain caused by inflamed abscesses and nodules can be treated with either intralesional corticosteroids or incision and drainage. Intralesional triamcinolone has been found to cause substantial pain relief within 1 day of injection in patients with HS.^3,42

Prompt discussion about the remitting course of HS will prepare patients for flares. Although the therapies discussed here aim to reduce the clinical severity and inflammation associated with HS, achieving pain-free remission can be challenging. Barriers to developing a long-term treatment regimen include intolerable side effects or simply nonresponsive disease.^36,43

Management of Perioperative Pain—Medical treatment of HS often yields only transient or mild results. Hurley stage II or III lesions typically require surgical removal of affected tissues.^32,44-46 Surgery may dramatically reduce the primary disease burden and provide substantial pain relief.^3,4,44 Complete resection of the affected tissue by wide excision is the most common surgical procedure used.^46-48 However, various tissue-sparing techniques, such as skin-tissue-sparing excision with electrosurgical peeling, also have been utilized. Tissue-sparing surgical techniques may lead to shorter healing times and less postoperative pain.⁴⁸

There currently is little guidance available on the perioperative management of pain as it relates to surgical procedures for HS. The pain experienced from surgery varies based on the area and location of affected tissue; extent of disease; surgical technique used; and whether primary closure, closure by secondary intention, or skin grafting is utilized.^47,49 Medical treatment aimed at reducing inflammation prior to surgical intervention may improve postoperative pain and complications.

The use of general vs local anesthesia during surgery depends on the extent of the disease and the amount of tissue being removed; however, the use of local anesthesia has been associated with a higher recurrence of disease, possibly owing to less aggressive tissue removal.⁵⁰ Intraoperatively, the injection of 0.5% bupivacaine around the wound edges may lead to less postoperative pain.^3,48 Postoperative pain usually is managed with acetaminophen and NSAIDs.⁴⁸ In cases of severe postoperative pain, short- and long-acting opioid oxycodone preparations may be used. The combination of diclofenac and tramadol also has been used postoperatively.³ Patients who do not undergo extensive surgery often can leave the hospital the same day.

Effective strategies for mitigating HS-associated pain must address the chronic pain component of the disease. Long-term management involves lifestyle modifications and pharmacologic agents.

Chronic Pain Management

Although HS is not a curable disease, there are treatments available to minimize symptoms. Long-term management of HS is essential to minimize the effects of chronic pain and physical scarring associated with inflammation.³¹ In one study from the French Society of Dermatology, pain reported by patients with HS was directly associated with severity and duration of disease, emotional symptoms, and reduced functionality.⁵¹ For these reasons, many treatments for HS target reducing clinical severity and achieving remission, often defined as more than 6 months without any recurrence of lesions.⁵² In addition to lifestyle management, therapies available to manage HS include topical and systemic medications as well as procedures such as surgical excision.^36,43,52,53

Lifestyle Modifications

Regardless of the severity of HS, all patients may benefit from basic education on the pathogenesis of the disease.³⁶ The associations with smoking and obesity have been well documented, and treatment of these comorbid conditions is indicated.^36,43,52 For example, in relation to obesity, the use of metformin is very well tolerated and seems to positively impact HS symptoms.⁴³ Several studies have suggested that weight reduction lowers disease severity.^28-30 Patients should be counseled on the importance of smoking cessation and weight loss.

Finally, the emotional impact of HS is not to be discounted, both the physical and social discomfort as well as the chronicity of the disease and frustration with treatment.⁵¹ Chronic pain has been associated with increased rates of depression, and 43% of patients with HS specifically have been diagnosed with major depressive disorder.⁷ For these reasons, clinician guidance, social support, and websites can improve patient understanding of the disease, adherence to treatment, and comorbid anxiety and depression.⁵²

Topical Therapy

Topical therapy generally is limited to mild disease and is geared at decreasing inflammation or superimposed infection.^36,52 Some of the earliest therapies used were topical antibiotics.⁴³ Topical clindamycin has been shown to be as effective as oral tetracyclines in reducing the number of abscesses, but neither treatment substantially reduces pain associated with smaller nodules.⁵⁴ Intralesional corticosteroids such as triamcinolone acetonide have been shown to decrease both patient-reported pain and physician-assessed severity within 1 to 7 days.⁴² Routine injection, however, is not a feasible means of long-term treatment both because of inconvenience and the potential adverse effects of corticosteroids.^36,52 Both topical clindamycin and intralesional steroids are helpful in reducing inflammation prior to planned surgical intervention.^36,52,53

Newer topical therapies include resorcinol peels and combination antimicrobials, such as 2% triclosan and oral zinc gluconate.^52,53 Data surrounding the use of resorcinol in mild to moderate HS are promising and have shown decreased severity of both new and long-standing nodules. Fifteen-percent resorcinol peels are helpful tools that allow for self-administration by patients during exacerbations to decrease pain and flare duration.^55,56 In a 2016 clinical trial, a combination of oral zinc gluconate with topical triclosan was shown to reduce flare-ups and nodules in mild HS.⁵⁷ Oral zinc alone may have anti-inflammatory properties and generally is well tolerated.^43,53 Topical therapies have a role in reducing HS-associated pain but often are limited to milder disease.

Systemic Agents

Several therapeutic options exist for the treatment of HS; however, a detailed description of their mechanisms and efficacies is beyond the scope of this review, which is focused on pain. Briefly, these systemic agents include antibiotics, retinoids, corticosteroids, antiandrogens, and biologics.^43,52,53

Treatment with antibiotics such as tetracyclines or a combination of clindamycin plus rifampin has been shown to produce complete remission in 60% to 80% of users; however, this treatment requires more than 6 months of antibiotic therapy, which can be difficult to tolerate.^52,53,58 Relapse is common after antibiotic cessation.^2,43,52 Antibiotics have demonstrated efficacy during acute flares and in reducing inflammatory activity prior to surgery.⁵²

Retinoids have been utilized in the treatment of HS because of their action on sebaceous glands and hair follicles.^43,53 Acitretin has been shown to be the most effective oral retinoid available in the United States.⁴³ Unfortunately, many of the studies investigating the use of retinoids for treatment of HS are limited by small sample size.^36,43,52

Because HS is predominantly an inflammatory condition, immunosuppressants have been adapted to manage patients when antibiotics and topicals have failed. Systemic steroids rarely are used for long-term therapy because of the severe side effects and are preferred only for acute management.^36,52 Cyclosporine and dapsone have demonstrated efficacy in treating moderate to severe HS, whereas methotrexate and colchicine have shown little efficacy.⁵² Both cyclosporine and dapsone are difficult to tolerate, require laboratory monitoring, and lead to only conservative improvement rather than remission in most patients.⁴³

Immune dysregulation in HS involves elevated levels of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which is a key mediator of inflammation and a stimulator of other inflammatory cytokines.^59,60 The first approved biologic treatment of HS was adalimumab, a TNF-α inhibitor, which showed a 50% reduction in total abscess and inflammatory nodule count in 60% of patients with moderate to severe HS.^61-63 Of course, TNF-α inhibitor therapy is not without risks, specifically those of infection.^43,53,61,62 Maintenance therapy may be required if patients relapse.^53,61

Various interleukin inhibitors also have emerged as potential therapies for HS, such as ustekinumab and anakinra.^36,64 Both have been subject to numerous small case trials that have reported improvements in clinical severity and pain; however, both drugs were associated with a fair number of nonresponders.^36,64,65

Surgical Procedures

Although HS lesions may regress on their own in a matter of weeks, surgical drainage allows an acute alleviation of the severe burning pain associated with HS flares.^36,52,53 Because of improved understanding of the disease pathophysiology, recent therapies targeting the hair follicle have been developed and have shown promising results. These therapies include laser- and light-based procedures. Long-pulsed Nd:YAG laser therapy reduces the number of hair follicles and sebaceous glands and has been effective for Hurley stage I or II disease.^{36,43,52,53,66} Photodynamic therapy offers a less-invasive option compared to surgery and laser therapy.^52,53,66 Both Nd:YAG and CO₂ laser therapy offer low recurrence rates (<30%) due to destruction of the apocrine unit.^43,53 Photodynamic therapy for mild disease offers a less-invasive option compared to surgery and laser therapy.⁵³ There is a need for larger randomized controlled trials involving laser, light, and CO₂ therapies.⁶⁶

Conclusion

Hidradenitis suppurativa is a debilitating condition with an underestimated disease burden. Although the pathophysiology of the disease is not completely understood, it is evident that pain is a major cause of morbidity. Patients experience a multitude of acute and chronic pain types: inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic. Pain perception and quality of life are further impacted by psychiatric conditions such as depression and anxiety, both of which are common comorbidities in patients with HS. Several pharmacologic agents have been used to treat HS-associated pain with mixed results. First-line treatment of acute pain episodes includes oral acetaminophen, NSAIDs, and topical analgesics. Management of chronic pain includes utilization of topical agents, systemic agents, and biologics, as well as addressing lifestyle (eg, obesity, smoking status) and psychiatric comorbidities. Although these therapies have roles in HS pain management, the most effective pain remedies developed thus far are limited to surgery and TNF-α inhibitors. Optimization of pain control in patients with HS requires multidisciplinary collaboration among dermatologists, pain specialists, psychiatrists, and other members of the health care team. Further large-scale studies are needed to create an evidence-based treatment algorithm for the management of pain in HS.

For those of us who cannot sit in the sun and fish all day, the next best thing for preventing autoimmune diseases may be supplementation with vitamin D and fish oil-derived omega-3 fatty acids, results of a large prospective randomized trial suggest.

Ziga Plahutar

Among nearly 26,000 adults enrolled in a randomized trial designed primarily to study the effects of vitamin D and omega-3 supplementation on incident cancer and cardiovascular disease, 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of omega-3 fatty acid supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases, reported Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston.

“The clinical importance of these results is very high, given that these are nontoxic, well-tolerated supplements, and that there are no other known effective therapies to reduce the incidence of autoimmune diseases,” she said during the virtual annual meeting of the American College of Rheumatology.

“People do have to take the supplements a long time to start to see the reduction in risk, especially for vitamin D, but they make biological sense, and autoimmune diseases develop slowly over time, so taking it today isn’t going to reduce risk of developing something tomorrow,” Dr. Costenbader said in an interview.

“These supplements have other health benefits. Obviously, fish oil is anti-inflammatory, and vitamin D is good for osteoporosis prevention, especially in our patients who take glucocorticoids. People who are otherwise healthy and have a family history of autoimmune disease might also consider starting to take these supplements,” she said.

After watching her presentation, session co-moderator Gregg Silverman, MD, from the NYU Langone School of Medicine in New York, who was not involved in the study, commented “I’m going to [nutrition store] GNC to get some vitamins.”

When asked for comment, the other session moderator, Tracy Frech, MD, of Vanderbilt University, Nashville, said, “I think Dr. Costenbader’s work is very important and her presentation excellent. My current practice is replacement of vitamin D in all autoimmune disease patients with low levels and per bone health guidelines. Additionally, I discuss omega-3 supplementation with Sjögren’s [syndrome] patients as a consideration.”

Evidence base

Dr. Costenbader noted that in a 2013 observational study from France, vitamin D derived through ultraviolet (UV) light exposure was associated with a lower risk for incident Crohn’s disease but not ulcerative colitis, and in two analyses of data in 2014 from the Nurses’ Health Study, both high plasma levels of 25-OH vitamin D and geographic residence in areas of high UV exposure were associated with a decreased incidence of rheumatoid arthritis (RA).

Other observational studies have supported omega-3 fatty acids for their anti-inflammatory properties, including a 2005 Danish prospective cohort study showing a lower risk for RA in participants who reported higher levels of fatty fish intake. In a separate study conducted in 2017, healthy volunteers with higher omega-3 fatty acid/total lipid proportions in red blood cell membranes had a lower prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor and a lower incidence of progression to inflammatory arthritis, she said.

Ancillary study

Despite the evidence, however, there have been no prospective randomized trials to test the effects of either vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune disease over time.

To rectify this, Dr. Costenbader and colleagues piggybacked an ancillary study onto the Vitamin D and Omega-3 Trial (VITAL), which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older, and 13,085 women aged 55 and older.

The study had a 2 x 2 factorial design, with patients randomly assigned to vitamin D 2,000 IU/day or placebo, and then further randomized to either 1 g/day omega-3 fatty acids or placebo in both the vitamin D and placebo primary randomization arms.

At baseline 16,956 participants were assayed for 25-OH vitamin D and plasma omega 3 index, the ratio of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to total fatty acids. Participants self-reported baseline and all incident autoimmune diseases annually, with the reports confirmed by medical record review and disease criteria whenever possible.

Results

At 5 years of follow-up, confirmed incident autoimmune diseases had occurred in 123 patients in the active vitamin D group, compared with 155 in the placebo vitamin D group, translating into a hazard ratio (HR) for vitamin D of 0.78 (P = .045).

In the active omega-3 arm, 130 participants developed an autoimmune disease, compared with 148 in the placebo omega-3 arm, which translated into a nonsignificant HR of 0.85.

There was no statistical interaction between the two supplements. The investigators did observe an interaction between vitamin D and body mass index, with the effect stronger among participants with low BMI (P = .02). There also was an interaction between omega-3 fatty acids with a family history of autoimmune disease (P = .03).

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with an HR for incident autoimmune disease of 0.68 (P = .02), omega-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03).

Dr. Costenbader and colleagues acknowledged that the study was limited by the lack of a high-risk or nutritionally-deficient population, where the effects of supplementation might be larger; the restriction of the sample to older adults; and to the difficulty of confirming incident autoimmune thyroid disease from patient reports.

Cheryl Koehn, an arthritis patient advocate from Vancouver, Canada, who was not involved in the study, commented in the “chat” section of the presentation that her rheumatologist “has recommended vitamin D for years now. Says basically everyone north of Boston is vitamin D deficient. I take 1,000 IU per day. Been taking it for years.” Ms. Koehn is the founder and president of Arthritis Consumer Experts, a website that provides education to those with arthritis.

“Agreed. I tell every patient to take vitamin D supplement,” commented Fatma Dedeoglu, MD, a rheumatologist at Boston Children’s Hospital.



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

For those of us who cannot sit in the sun and fish all day, the next best thing for preventing autoimmune diseases may be supplementation with vitamin D and fish oil-derived omega-3 fatty acids, results of a large prospective randomized trial suggest.

Ziga Plahutar

Among nearly 26,000 adults enrolled in a randomized trial designed primarily to study the effects of vitamin D and omega-3 supplementation on incident cancer and cardiovascular disease, 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of omega-3 fatty acid supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases, reported Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston.

“The clinical importance of these results is very high, given that these are nontoxic, well-tolerated supplements, and that there are no other known effective therapies to reduce the incidence of autoimmune diseases,” she said during the virtual annual meeting of the American College of Rheumatology.

“People do have to take the supplements a long time to start to see the reduction in risk, especially for vitamin D, but they make biological sense, and autoimmune diseases develop slowly over time, so taking it today isn’t going to reduce risk of developing something tomorrow,” Dr. Costenbader said in an interview.

“These supplements have other health benefits. Obviously, fish oil is anti-inflammatory, and vitamin D is good for osteoporosis prevention, especially in our patients who take glucocorticoids. People who are otherwise healthy and have a family history of autoimmune disease might also consider starting to take these supplements,” she said.

After watching her presentation, session co-moderator Gregg Silverman, MD, from the NYU Langone School of Medicine in New York, who was not involved in the study, commented “I’m going to [nutrition store] GNC to get some vitamins.”

When asked for comment, the other session moderator, Tracy Frech, MD, of Vanderbilt University, Nashville, said, “I think Dr. Costenbader’s work is very important and her presentation excellent. My current practice is replacement of vitamin D in all autoimmune disease patients with low levels and per bone health guidelines. Additionally, I discuss omega-3 supplementation with Sjögren’s [syndrome] patients as a consideration.”

Evidence base

Dr. Costenbader noted that in a 2013 observational study from France, vitamin D derived through ultraviolet (UV) light exposure was associated with a lower risk for incident Crohn’s disease but not ulcerative colitis, and in two analyses of data in 2014 from the Nurses’ Health Study, both high plasma levels of 25-OH vitamin D and geographic residence in areas of high UV exposure were associated with a decreased incidence of rheumatoid arthritis (RA).

Other observational studies have supported omega-3 fatty acids for their anti-inflammatory properties, including a 2005 Danish prospective cohort study showing a lower risk for RA in participants who reported higher levels of fatty fish intake. In a separate study conducted in 2017, healthy volunteers with higher omega-3 fatty acid/total lipid proportions in red blood cell membranes had a lower prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor and a lower incidence of progression to inflammatory arthritis, she said.

Ancillary study

Despite the evidence, however, there have been no prospective randomized trials to test the effects of either vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune disease over time.

To rectify this, Dr. Costenbader and colleagues piggybacked an ancillary study onto the Vitamin D and Omega-3 Trial (VITAL), which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older, and 13,085 women aged 55 and older.

The study had a 2 x 2 factorial design, with patients randomly assigned to vitamin D 2,000 IU/day or placebo, and then further randomized to either 1 g/day omega-3 fatty acids or placebo in both the vitamin D and placebo primary randomization arms.

At baseline 16,956 participants were assayed for 25-OH vitamin D and plasma omega 3 index, the ratio of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to total fatty acids. Participants self-reported baseline and all incident autoimmune diseases annually, with the reports confirmed by medical record review and disease criteria whenever possible.

Results

At 5 years of follow-up, confirmed incident autoimmune diseases had occurred in 123 patients in the active vitamin D group, compared with 155 in the placebo vitamin D group, translating into a hazard ratio (HR) for vitamin D of 0.78 (P = .045).

In the active omega-3 arm, 130 participants developed an autoimmune disease, compared with 148 in the placebo omega-3 arm, which translated into a nonsignificant HR of 0.85.

There was no statistical interaction between the two supplements. The investigators did observe an interaction between vitamin D and body mass index, with the effect stronger among participants with low BMI (P = .02). There also was an interaction between omega-3 fatty acids with a family history of autoimmune disease (P = .03).

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with an HR for incident autoimmune disease of 0.68 (P = .02), omega-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03).

Dr. Costenbader and colleagues acknowledged that the study was limited by the lack of a high-risk or nutritionally-deficient population, where the effects of supplementation might be larger; the restriction of the sample to older adults; and to the difficulty of confirming incident autoimmune thyroid disease from patient reports.

Cheryl Koehn, an arthritis patient advocate from Vancouver, Canada, who was not involved in the study, commented in the “chat” section of the presentation that her rheumatologist “has recommended vitamin D for years now. Says basically everyone north of Boston is vitamin D deficient. I take 1,000 IU per day. Been taking it for years.” Ms. Koehn is the founder and president of Arthritis Consumer Experts, a website that provides education to those with arthritis.

“Agreed. I tell every patient to take vitamin D supplement,” commented Fatma Dedeoglu, MD, a rheumatologist at Boston Children’s Hospital.



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

For those of us who cannot sit in the sun and fish all day, the next best thing for preventing autoimmune diseases may be supplementation with vitamin D and fish oil-derived omega-3 fatty acids, results of a large prospective randomized trial suggest.

Ziga Plahutar

Among nearly 26,000 adults enrolled in a randomized trial designed primarily to study the effects of vitamin D and omega-3 supplementation on incident cancer and cardiovascular disease, 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of omega-3 fatty acid supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases, reported Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston.

“The clinical importance of these results is very high, given that these are nontoxic, well-tolerated supplements, and that there are no other known effective therapies to reduce the incidence of autoimmune diseases,” she said during the virtual annual meeting of the American College of Rheumatology.

“People do have to take the supplements a long time to start to see the reduction in risk, especially for vitamin D, but they make biological sense, and autoimmune diseases develop slowly over time, so taking it today isn’t going to reduce risk of developing something tomorrow,” Dr. Costenbader said in an interview.

“These supplements have other health benefits. Obviously, fish oil is anti-inflammatory, and vitamin D is good for osteoporosis prevention, especially in our patients who take glucocorticoids. People who are otherwise healthy and have a family history of autoimmune disease might also consider starting to take these supplements,” she said.

After watching her presentation, session co-moderator Gregg Silverman, MD, from the NYU Langone School of Medicine in New York, who was not involved in the study, commented “I’m going to [nutrition store] GNC to get some vitamins.”

When asked for comment, the other session moderator, Tracy Frech, MD, of Vanderbilt University, Nashville, said, “I think Dr. Costenbader’s work is very important and her presentation excellent. My current practice is replacement of vitamin D in all autoimmune disease patients with low levels and per bone health guidelines. Additionally, I discuss omega-3 supplementation with Sjögren’s [syndrome] patients as a consideration.”

Evidence base

Dr. Costenbader noted that in a 2013 observational study from France, vitamin D derived through ultraviolet (UV) light exposure was associated with a lower risk for incident Crohn’s disease but not ulcerative colitis, and in two analyses of data in 2014 from the Nurses’ Health Study, both high plasma levels of 25-OH vitamin D and geographic residence in areas of high UV exposure were associated with a decreased incidence of rheumatoid arthritis (RA).

Other observational studies have supported omega-3 fatty acids for their anti-inflammatory properties, including a 2005 Danish prospective cohort study showing a lower risk for RA in participants who reported higher levels of fatty fish intake. In a separate study conducted in 2017, healthy volunteers with higher omega-3 fatty acid/total lipid proportions in red blood cell membranes had a lower prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor and a lower incidence of progression to inflammatory arthritis, she said.

Ancillary study

Despite the evidence, however, there have been no prospective randomized trials to test the effects of either vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune disease over time.

To rectify this, Dr. Costenbader and colleagues piggybacked an ancillary study onto the Vitamin D and Omega-3 Trial (VITAL), which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older, and 13,085 women aged 55 and older.

The study had a 2 x 2 factorial design, with patients randomly assigned to vitamin D 2,000 IU/day or placebo, and then further randomized to either 1 g/day omega-3 fatty acids or placebo in both the vitamin D and placebo primary randomization arms.

At baseline 16,956 participants were assayed for 25-OH vitamin D and plasma omega 3 index, the ratio of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to total fatty acids. Participants self-reported baseline and all incident autoimmune diseases annually, with the reports confirmed by medical record review and disease criteria whenever possible.

Results

At 5 years of follow-up, confirmed incident autoimmune diseases had occurred in 123 patients in the active vitamin D group, compared with 155 in the placebo vitamin D group, translating into a hazard ratio (HR) for vitamin D of 0.78 (P = .045).

In the active omega-3 arm, 130 participants developed an autoimmune disease, compared with 148 in the placebo omega-3 arm, which translated into a nonsignificant HR of 0.85.

There was no statistical interaction between the two supplements. The investigators did observe an interaction between vitamin D and body mass index, with the effect stronger among participants with low BMI (P = .02). There also was an interaction between omega-3 fatty acids with a family history of autoimmune disease (P = .03).

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with an HR for incident autoimmune disease of 0.68 (P = .02), omega-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03).

Dr. Costenbader and colleagues acknowledged that the study was limited by the lack of a high-risk or nutritionally-deficient population, where the effects of supplementation might be larger; the restriction of the sample to older adults; and to the difficulty of confirming incident autoimmune thyroid disease from patient reports.

Cheryl Koehn, an arthritis patient advocate from Vancouver, Canada, who was not involved in the study, commented in the “chat” section of the presentation that her rheumatologist “has recommended vitamin D for years now. Says basically everyone north of Boston is vitamin D deficient. I take 1,000 IU per day. Been taking it for years.” Ms. Koehn is the founder and president of Arthritis Consumer Experts, a website that provides education to those with arthritis.

“Agreed. I tell every patient to take vitamin D supplement,” commented Fatma Dedeoglu, MD, a rheumatologist at Boston Children’s Hospital.



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