Lupus & Connective Tissue Diseases

People beginning treatment with the immunosuppressive drugs tocilizumab (Actemra) or tofacitinib (Xeljanz) are infrequently screened for hepatitis B virus (HBV) infection, according to a new study of patients with rheumatic diseases who are starting one of the two treatments.

“Perhaps not unexpectedly, these screening patterns conform more with recommendations from the American College of Rheumatology, which do not explicitly stipulate universal HBV screening,” wrote lead author Amir M. Mohareb, MD, of Massachusetts General Hospital in Boston. The study was published in The Journal of Rheumatology.

To determine the frequency of HBV screening among this specific population, the researchers conducted a retrospective, cross-sectional study of patients 18 years or older within the Mass General Brigham health system in the Boston area who initiated either of the two drugs before Dec. 31, 2018. Tocilizumab was approved by the Food and Drug Administration on Jan. 11, 2010, and tofacitinib was approved on Nov. 6, 2012.

The final study population included 678 patients on tocilizumab and 391 patients on tofacitinib. The mean age of the patients in each group was 61 years for tocilizumab and 60 years for tofacitinib. A large majority were female (78% of the tocilizumab group, 88% of the tofacitinib group) and 84% of patients in both groups were white. Their primary diagnosis was rheumatoid arthritis (53% of the tocilizumab group, 77% of the tofacitinib group), and most of them – 57% of patients on tocilizumab and 72% of patients on tofacitinib – had a history of being on both conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs).

HBV screening patterns were classified into three categories: complete (all three of the HBV surface antigen [HBsAg], total core antibody [anti-HBcAb], and surface antibody [HBsAb] tests); partial (any one to two tests); and none. Of the 678 patients on tocilizumab, 194 (29%) underwent complete screening, 307 (45%) underwent partial screening, and 177 (26%) had no screening. Of the 391 patients on tofacitinib, 94 (24%) underwent complete screening, 195 (50%) underwent partial screening, and 102 (26%) had none.

Inappropriate testing – defined as either HBV e-antigen (HBeAg), anti-HBcAb IgM, or HBV DNA without a positive HBsAg or total anti-HBcAb – occurred in 22% of patients on tocilizumab and 23% of patients on tofacitinib. After multivariable analysis, the authors found that Whites were less likely to undergo complete screening (odds ratio, 0.74; 95% confidence interval, 0.57-0.95) compared to non-Whites. Previous use of immunosuppressive agents such as conventional synthetic DMARDs (OR, 1.05; 95% CI, 0.72-1.55) and biologic DMARDs with or without prior csDMARDs (OR, 0.73; 95% CI, 0.48-1.12) was not associated with a likelihood of complete appropriate screening.

“These data add to the evidence indicating that clinicians are not completing pretreatment screening for latent infections prior to patients starting high-risk immunosuppressant drugs,” Gabriela Schmajuk, MD, of the University of California, San Francisco, said in an interview. “It can be dangerous, since a fraction of these patients may reactivate latent infections with HBV that can result in liver failure or death.

“On the bright side,” she added, “we have antivirals that can be given as prophylaxis against reactivation of latent HBV if patients do test positive.”

Dr. Schmajuk was previously the senior author of a similar study from the 2019 American College of Rheumatology annual meeting that found only a small percentage of patients who were new users of biologics or new synthetic DMARDs were screened for HBV or hepatitis C virus.

When asked if anything in the study stood out, she acknowledged being “somewhat surprised that patients with prior immunosuppression did not have higher rates of screening. One might expect that since those patients had more opportunities for screening – since they started new medications more times – they would have higher rates, but this did not appear to be the case.”

As a message to rheumatologists who may be starting their patients on any biologic or new synthetic DMARD, she reinforced that “we need universal HBV screening for patients starting these medications. Many clinicians are used to ordering a hepatitis B surface antigen test, but one key message is that we also need to be ordering hepatitis B core antibody tests. Patients with a positive core antibody are still at risk for reactivation.”

The authors noted their study’s limitations, including the data being retrospectively collected and some of the subjects potentially being screened in laboratories outside of the Mass General Brigham health system. In addition, they stated that their findings “may not be generalizable to nonrheumatologic settings or other immunomodulators,” although they added that studies of other patient populations have also uncovered “similarly low HBV screening frequencies.”

Several of the authors reported being supported by institutes within the National Institutes of Health. Beyond that, they declared no potential conflicts of interest.

People beginning treatment with the immunosuppressive drugs tocilizumab (Actemra) or tofacitinib (Xeljanz) are infrequently screened for hepatitis B virus (HBV) infection, according to a new study of patients with rheumatic diseases who are starting one of the two treatments.

“Perhaps not unexpectedly, these screening patterns conform more with recommendations from the American College of Rheumatology, which do not explicitly stipulate universal HBV screening,” wrote lead author Amir M. Mohareb, MD, of Massachusetts General Hospital in Boston. The study was published in The Journal of Rheumatology.

To determine the frequency of HBV screening among this specific population, the researchers conducted a retrospective, cross-sectional study of patients 18 years or older within the Mass General Brigham health system in the Boston area who initiated either of the two drugs before Dec. 31, 2018. Tocilizumab was approved by the Food and Drug Administration on Jan. 11, 2010, and tofacitinib was approved on Nov. 6, 2012.

The final study population included 678 patients on tocilizumab and 391 patients on tofacitinib. The mean age of the patients in each group was 61 years for tocilizumab and 60 years for tofacitinib. A large majority were female (78% of the tocilizumab group, 88% of the tofacitinib group) and 84% of patients in both groups were white. Their primary diagnosis was rheumatoid arthritis (53% of the tocilizumab group, 77% of the tofacitinib group), and most of them – 57% of patients on tocilizumab and 72% of patients on tofacitinib – had a history of being on both conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs).

HBV screening patterns were classified into three categories: complete (all three of the HBV surface antigen [HBsAg], total core antibody [anti-HBcAb], and surface antibody [HBsAb] tests); partial (any one to two tests); and none. Of the 678 patients on tocilizumab, 194 (29%) underwent complete screening, 307 (45%) underwent partial screening, and 177 (26%) had no screening. Of the 391 patients on tofacitinib, 94 (24%) underwent complete screening, 195 (50%) underwent partial screening, and 102 (26%) had none.

Inappropriate testing – defined as either HBV e-antigen (HBeAg), anti-HBcAb IgM, or HBV DNA without a positive HBsAg or total anti-HBcAb – occurred in 22% of patients on tocilizumab and 23% of patients on tofacitinib. After multivariable analysis, the authors found that Whites were less likely to undergo complete screening (odds ratio, 0.74; 95% confidence interval, 0.57-0.95) compared to non-Whites. Previous use of immunosuppressive agents such as conventional synthetic DMARDs (OR, 1.05; 95% CI, 0.72-1.55) and biologic DMARDs with or without prior csDMARDs (OR, 0.73; 95% CI, 0.48-1.12) was not associated with a likelihood of complete appropriate screening.

“These data add to the evidence indicating that clinicians are not completing pretreatment screening for latent infections prior to patients starting high-risk immunosuppressant drugs,” Gabriela Schmajuk, MD, of the University of California, San Francisco, said in an interview. “It can be dangerous, since a fraction of these patients may reactivate latent infections with HBV that can result in liver failure or death.

“On the bright side,” she added, “we have antivirals that can be given as prophylaxis against reactivation of latent HBV if patients do test positive.”

Dr. Schmajuk was previously the senior author of a similar study from the 2019 American College of Rheumatology annual meeting that found only a small percentage of patients who were new users of biologics or new synthetic DMARDs were screened for HBV or hepatitis C virus.

When asked if anything in the study stood out, she acknowledged being “somewhat surprised that patients with prior immunosuppression did not have higher rates of screening. One might expect that since those patients had more opportunities for screening – since they started new medications more times – they would have higher rates, but this did not appear to be the case.”

As a message to rheumatologists who may be starting their patients on any biologic or new synthetic DMARD, she reinforced that “we need universal HBV screening for patients starting these medications. Many clinicians are used to ordering a hepatitis B surface antigen test, but one key message is that we also need to be ordering hepatitis B core antibody tests. Patients with a positive core antibody are still at risk for reactivation.”

The authors noted their study’s limitations, including the data being retrospectively collected and some of the subjects potentially being screened in laboratories outside of the Mass General Brigham health system. In addition, they stated that their findings “may not be generalizable to nonrheumatologic settings or other immunomodulators,” although they added that studies of other patient populations have also uncovered “similarly low HBV screening frequencies.”

Several of the authors reported being supported by institutes within the National Institutes of Health. Beyond that, they declared no potential conflicts of interest.

People beginning treatment with the immunosuppressive drugs tocilizumab (Actemra) or tofacitinib (Xeljanz) are infrequently screened for hepatitis B virus (HBV) infection, according to a new study of patients with rheumatic diseases who are starting one of the two treatments.

“Perhaps not unexpectedly, these screening patterns conform more with recommendations from the American College of Rheumatology, which do not explicitly stipulate universal HBV screening,” wrote lead author Amir M. Mohareb, MD, of Massachusetts General Hospital in Boston. The study was published in The Journal of Rheumatology.

To determine the frequency of HBV screening among this specific population, the researchers conducted a retrospective, cross-sectional study of patients 18 years or older within the Mass General Brigham health system in the Boston area who initiated either of the two drugs before Dec. 31, 2018. Tocilizumab was approved by the Food and Drug Administration on Jan. 11, 2010, and tofacitinib was approved on Nov. 6, 2012.

The final study population included 678 patients on tocilizumab and 391 patients on tofacitinib. The mean age of the patients in each group was 61 years for tocilizumab and 60 years for tofacitinib. A large majority were female (78% of the tocilizumab group, 88% of the tofacitinib group) and 84% of patients in both groups were white. Their primary diagnosis was rheumatoid arthritis (53% of the tocilizumab group, 77% of the tofacitinib group), and most of them – 57% of patients on tocilizumab and 72% of patients on tofacitinib – had a history of being on both conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs).

HBV screening patterns were classified into three categories: complete (all three of the HBV surface antigen [HBsAg], total core antibody [anti-HBcAb], and surface antibody [HBsAb] tests); partial (any one to two tests); and none. Of the 678 patients on tocilizumab, 194 (29%) underwent complete screening, 307 (45%) underwent partial screening, and 177 (26%) had no screening. Of the 391 patients on tofacitinib, 94 (24%) underwent complete screening, 195 (50%) underwent partial screening, and 102 (26%) had none.

Inappropriate testing – defined as either HBV e-antigen (HBeAg), anti-HBcAb IgM, or HBV DNA without a positive HBsAg or total anti-HBcAb – occurred in 22% of patients on tocilizumab and 23% of patients on tofacitinib. After multivariable analysis, the authors found that Whites were less likely to undergo complete screening (odds ratio, 0.74; 95% confidence interval, 0.57-0.95) compared to non-Whites. Previous use of immunosuppressive agents such as conventional synthetic DMARDs (OR, 1.05; 95% CI, 0.72-1.55) and biologic DMARDs with or without prior csDMARDs (OR, 0.73; 95% CI, 0.48-1.12) was not associated with a likelihood of complete appropriate screening.

“These data add to the evidence indicating that clinicians are not completing pretreatment screening for latent infections prior to patients starting high-risk immunosuppressant drugs,” Gabriela Schmajuk, MD, of the University of California, San Francisco, said in an interview. “It can be dangerous, since a fraction of these patients may reactivate latent infections with HBV that can result in liver failure or death.

“On the bright side,” she added, “we have antivirals that can be given as prophylaxis against reactivation of latent HBV if patients do test positive.”

Dr. Schmajuk was previously the senior author of a similar study from the 2019 American College of Rheumatology annual meeting that found only a small percentage of patients who were new users of biologics or new synthetic DMARDs were screened for HBV or hepatitis C virus.

When asked if anything in the study stood out, she acknowledged being “somewhat surprised that patients with prior immunosuppression did not have higher rates of screening. One might expect that since those patients had more opportunities for screening – since they started new medications more times – they would have higher rates, but this did not appear to be the case.”

As a message to rheumatologists who may be starting their patients on any biologic or new synthetic DMARD, she reinforced that “we need universal HBV screening for patients starting these medications. Many clinicians are used to ordering a hepatitis B surface antigen test, but one key message is that we also need to be ordering hepatitis B core antibody tests. Patients with a positive core antibody are still at risk for reactivation.”

The authors noted their study’s limitations, including the data being retrospectively collected and some of the subjects potentially being screened in laboratories outside of the Mass General Brigham health system. In addition, they stated that their findings “may not be generalizable to nonrheumatologic settings or other immunomodulators,” although they added that studies of other patient populations have also uncovered “similarly low HBV screening frequencies.”

Several of the authors reported being supported by institutes within the National Institutes of Health. Beyond that, they declared no potential conflicts of interest.

Anifrolumab, an inhibitor of type 1 interferons, received approval from the Food and Drug Administration for the treatment of adults with moderate to severe systemic lupus erythematosus (SLE) who are receiving standard therapy, according to a statement released Aug. 2 from its manufacturer, AstraZeneca.

Courtesy AstraZeneca

Anifrolumab will be marketed as Saphnelo. It is a fully human monoclonal antibody against subunit 1 of the type 1 interferon receptor, and its approval represents the only new treatment approved for patients with SLE in a decade. The recommended dosage is 300 mg as an intravenous infusion over a 30-minute period every 4 weeks, according to its prescribing information, and it will be sold in a single-dose vial containing 300 mg/2 mL (150 mg/mL).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Increased type I interferon (IFN) signaling is associated with increased disease activity in patients with SLE, and the option of a type I IFN receptor antagonist may allow physicians to treat patients with fewer corticosteroids, according to the statement.

The approval was based on data from three trials. The TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) phase 3 research included two randomized, double-blind, placebo-controlled studies, TULIP-1 and TULIP-2. The TULIP trials each enrolled seropositive patients with moderate to severe active disease despite standard-of-care therapy (SOC), which included oral corticosteroids, antimalarials, and immunosuppressants (methotrexate, azathioprine, or mycophenolate mofetil). All patients met American College of Rheumatology criteria and had an SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, as well as British Isles Lupus Assessment Group (BILAG) index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.

TULIP-1 failed to meet its primary endpoint of SLE Responder Index (SRI) at 52 weeks, but investigators determined after the trial that some patients taking anifrolumab had been inappropriately labeled as nonresponders because the trial automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder even if they used the medication for something unrelated to SLE. When these rules were amended in a post hoc analysis, differences between the groups treated with anifrolumab and placebo widened in secondary endpoints for oral corticosteroid dose reduction, Cutaneous Lupus Erythematosus Disease Activity Severity Index response, and BILAG-Based Composite Lupus Assessment (BICLA) response.

The TULIP-2 trial included 362 patients who received a fixed dose of 300 mg anifrolumab or a placebo intravenously every 4 weeks for 48 weeks. In this study, anifrolumab patients showed significant improvement in disease activity on the BICLA scale, compared with placebo patients. The BICLA response was 47.8% in patients taking anifrolumab and 31.5% in placebo-treated patients (P = .001).

In the MUSE phase 2 trial, 305 adults with SLE were randomized to a fixed-dose intravenous infusion of 300 mg or 1,000 mg of anifrolumab or a placebo every 4 weeks, plus SOC, for 48 weeks. Patients in this study showed significant improvement on either dose, compared with placebo.

The results from the MUSE trial were published online in Arthritis & Rheumatology Nov. 7, 2016, followed by the TULIP-1 trial in The Lancet Rheumatology Nov. 11, 2019, and the TULIP-2 trial in the New England Journal of Medicine Jan. 16, 2020.

The most common treatment-related adverse events in all three studies were nasopharyngitis, upper respiratory tract infection, bronchitis, infusion-related reactions, herpes zoster, and cough. Infusion-related reactions in the trials were similar in anifrolumab and placebo patients, and included headache, nausea, vomiting, fatigue, and dizziness.

Anifrolumab has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus and is not recommended for these patients, according to the statement.

AstraZeneca said in its statement that anifrolumab is also under regulatory review in Japan and the European Union, and it continues to evaluate anifrolumab in patients with SLE in a long-term extension phase 3 trial and a phase 3 trial assessing subcutaneous delivery. The company said it “is exploring the potential of Saphnelo in a variety of diseases where type I IFN plays a key role, including lupus nephritis, cutaneous lupus erythematosus, and myositis.”

Anifrolumab, an inhibitor of type 1 interferons, received approval from the Food and Drug Administration for the treatment of adults with moderate to severe systemic lupus erythematosus (SLE) who are receiving standard therapy, according to a statement released Aug. 2 from its manufacturer, AstraZeneca.

Courtesy AstraZeneca

Anifrolumab will be marketed as Saphnelo. It is a fully human monoclonal antibody against subunit 1 of the type 1 interferon receptor, and its approval represents the only new treatment approved for patients with SLE in a decade. The recommended dosage is 300 mg as an intravenous infusion over a 30-minute period every 4 weeks, according to its prescribing information, and it will be sold in a single-dose vial containing 300 mg/2 mL (150 mg/mL).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Increased type I interferon (IFN) signaling is associated with increased disease activity in patients with SLE, and the option of a type I IFN receptor antagonist may allow physicians to treat patients with fewer corticosteroids, according to the statement.

The approval was based on data from three trials. The TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) phase 3 research included two randomized, double-blind, placebo-controlled studies, TULIP-1 and TULIP-2. The TULIP trials each enrolled seropositive patients with moderate to severe active disease despite standard-of-care therapy (SOC), which included oral corticosteroids, antimalarials, and immunosuppressants (methotrexate, azathioprine, or mycophenolate mofetil). All patients met American College of Rheumatology criteria and had an SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, as well as British Isles Lupus Assessment Group (BILAG) index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.

TULIP-1 failed to meet its primary endpoint of SLE Responder Index (SRI) at 52 weeks, but investigators determined after the trial that some patients taking anifrolumab had been inappropriately labeled as nonresponders because the trial automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder even if they used the medication for something unrelated to SLE. When these rules were amended in a post hoc analysis, differences between the groups treated with anifrolumab and placebo widened in secondary endpoints for oral corticosteroid dose reduction, Cutaneous Lupus Erythematosus Disease Activity Severity Index response, and BILAG-Based Composite Lupus Assessment (BICLA) response.

The TULIP-2 trial included 362 patients who received a fixed dose of 300 mg anifrolumab or a placebo intravenously every 4 weeks for 48 weeks. In this study, anifrolumab patients showed significant improvement in disease activity on the BICLA scale, compared with placebo patients. The BICLA response was 47.8% in patients taking anifrolumab and 31.5% in placebo-treated patients (P = .001).

In the MUSE phase 2 trial, 305 adults with SLE were randomized to a fixed-dose intravenous infusion of 300 mg or 1,000 mg of anifrolumab or a placebo every 4 weeks, plus SOC, for 48 weeks. Patients in this study showed significant improvement on either dose, compared with placebo.

The results from the MUSE trial were published online in Arthritis & Rheumatology Nov. 7, 2016, followed by the TULIP-1 trial in The Lancet Rheumatology Nov. 11, 2019, and the TULIP-2 trial in the New England Journal of Medicine Jan. 16, 2020.

The most common treatment-related adverse events in all three studies were nasopharyngitis, upper respiratory tract infection, bronchitis, infusion-related reactions, herpes zoster, and cough. Infusion-related reactions in the trials were similar in anifrolumab and placebo patients, and included headache, nausea, vomiting, fatigue, and dizziness.

Anifrolumab has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus and is not recommended for these patients, according to the statement.

AstraZeneca said in its statement that anifrolumab is also under regulatory review in Japan and the European Union, and it continues to evaluate anifrolumab in patients with SLE in a long-term extension phase 3 trial and a phase 3 trial assessing subcutaneous delivery. The company said it “is exploring the potential of Saphnelo in a variety of diseases where type I IFN plays a key role, including lupus nephritis, cutaneous lupus erythematosus, and myositis.”

Anifrolumab, an inhibitor of type 1 interferons, received approval from the Food and Drug Administration for the treatment of adults with moderate to severe systemic lupus erythematosus (SLE) who are receiving standard therapy, according to a statement released Aug. 2 from its manufacturer, AstraZeneca.

Courtesy AstraZeneca

Anifrolumab will be marketed as Saphnelo. It is a fully human monoclonal antibody against subunit 1 of the type 1 interferon receptor, and its approval represents the only new treatment approved for patients with SLE in a decade. The recommended dosage is 300 mg as an intravenous infusion over a 30-minute period every 4 weeks, according to its prescribing information, and it will be sold in a single-dose vial containing 300 mg/2 mL (150 mg/mL).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Increased type I interferon (IFN) signaling is associated with increased disease activity in patients with SLE, and the option of a type I IFN receptor antagonist may allow physicians to treat patients with fewer corticosteroids, according to the statement.

The approval was based on data from three trials. The TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) phase 3 research included two randomized, double-blind, placebo-controlled studies, TULIP-1 and TULIP-2. The TULIP trials each enrolled seropositive patients with moderate to severe active disease despite standard-of-care therapy (SOC), which included oral corticosteroids, antimalarials, and immunosuppressants (methotrexate, azathioprine, or mycophenolate mofetil). All patients met American College of Rheumatology criteria and had an SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, as well as British Isles Lupus Assessment Group (BILAG) index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.

TULIP-1 failed to meet its primary endpoint of SLE Responder Index (SRI) at 52 weeks, but investigators determined after the trial that some patients taking anifrolumab had been inappropriately labeled as nonresponders because the trial automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder even if they used the medication for something unrelated to SLE. When these rules were amended in a post hoc analysis, differences between the groups treated with anifrolumab and placebo widened in secondary endpoints for oral corticosteroid dose reduction, Cutaneous Lupus Erythematosus Disease Activity Severity Index response, and BILAG-Based Composite Lupus Assessment (BICLA) response.

The TULIP-2 trial included 362 patients who received a fixed dose of 300 mg anifrolumab or a placebo intravenously every 4 weeks for 48 weeks. In this study, anifrolumab patients showed significant improvement in disease activity on the BICLA scale, compared with placebo patients. The BICLA response was 47.8% in patients taking anifrolumab and 31.5% in placebo-treated patients (P = .001).

In the MUSE phase 2 trial, 305 adults with SLE were randomized to a fixed-dose intravenous infusion of 300 mg or 1,000 mg of anifrolumab or a placebo every 4 weeks, plus SOC, for 48 weeks. Patients in this study showed significant improvement on either dose, compared with placebo.

The results from the MUSE trial were published online in Arthritis & Rheumatology Nov. 7, 2016, followed by the TULIP-1 trial in The Lancet Rheumatology Nov. 11, 2019, and the TULIP-2 trial in the New England Journal of Medicine Jan. 16, 2020.

The most common treatment-related adverse events in all three studies were nasopharyngitis, upper respiratory tract infection, bronchitis, infusion-related reactions, herpes zoster, and cough. Infusion-related reactions in the trials were similar in anifrolumab and placebo patients, and included headache, nausea, vomiting, fatigue, and dizziness.

Anifrolumab has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus and is not recommended for these patients, according to the statement.

AstraZeneca said in its statement that anifrolumab is also under regulatory review in Japan and the European Union, and it continues to evaluate anifrolumab in patients with SLE in a long-term extension phase 3 trial and a phase 3 trial assessing subcutaneous delivery. The company said it “is exploring the potential of Saphnelo in a variety of diseases where type I IFN plays a key role, including lupus nephritis, cutaneous lupus erythematosus, and myositis.”

COVID-19 vaccinations appear to be well tolerated in patients with systemic lupus erythematosus (SLE) and come with a low risk of flare, according to the results of a global, web-based survey.

Steve Mann/Thinkstock

“Disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with SLE,” wrote lead author Renaud Felten, MD, of Strasbourg (France) University Hospital. Their results were published as a comment in Lancet Rheumatology.

To assess vaccine tolerability among lupus patients, the cross-sectional Tolerance and Consequences of Vaccination Against COVID-19 in Lupus Patients (VACOLUP) study analyzed a 43-question survey of 696 participants with a self-reported, medically confirmed diagnosis of SLE from 30 countries between March 22, 2021, and May 17, 2021. The cohort was 96% women, and their median age was 42 (interquartile range, 34-51). Nearly 36% of respondents were from Italy, 27% were from Chile, 13% were from France, and just under 9% were Americans. All participants received at least one dose of COVID-19 vaccine, and 49% received a second dose. The most common vaccines were Pfizer-BioNTech (57%), Sinovac (22%), AstraZeneca (10%), and Moderna (8%).

Only 21 participants (3%) reported a medically confirmed SLE flare after a median of 3 days (IQR, 0-29) post COVID vaccination, with most experiencing musculoskeletal symptoms (90%) and fatigue (86%). Of the 21 cases, 15 reported a subsequent change in SLE treatment and 4 were admitted to the hospital. A previous flare that occurred within a year before vaccination was associated with an increased risk of flare post vaccination (relative risk, 5.52; 95% confidence interval, 2.17-14.03; P < .0001).

Side effects – including swelling, soreness, fever, chills, fatigue, joint and muscle pain, nausea, and headache – were reported in 45% of participants (n = 316) after their first dose and in 53% of the 343 participants who received a second dose. There was no notable difference in the likelihood of side effects across gender and age or in patients who received mRNA vaccines, compared with vaccines with other modes of action. Patients who reported side effects after the first dose were more likely to also report them after the second, compared with those who reported none (109 [81%] of 135 vs. 72 [35%] of 205; RR, 2.30; 95% CI, 1.88-2.82; P < .0001).

In the majority of cases (2,232 of 2,683), the side effects were of minor or moderate intensity and did not affect the participants’ ability to perform daily tasks. The study found no significant association between side effects and a SLE flare and SLE medications or previous SLE disease manifestations.

When asked to comment on the study, Amit Saxena, MD, of the Lupus Center at New York University Langone Health, said: “What we are seeing is pretty mild to moderate in terms of follow-up side effects or lupus-related activity. Several studies have shown this amongst our autoimmune rheumatology cohort, as well as what I’ve seen clinically in my own patients. More than anything else, numbers are the most important, and this is a large study.”

He acknowledged the benefits of going directly to patients to gauge their responses and reactions, giving them the opportunity to share concerns that physicians may not think about.

“As rheumatologists, we tend to focus on certain things that might not necessarily be what the patients themselves focus on,” he said. “I think the fact that this questionnaire dealt with a lot of what people complain about – fatigue, sore arm, things that we know are part of getting the vaccine – they aren’t necessarily things we capture with tools that screen for lupus flares, for example.”

More than anything, Dr. Saxena commended the study’s timeliness. “Patients are constantly asking us about the vaccine, and there’s so much misinformation,” he said. “People say, ‘Because I have lupus, I was told not to get vaccinated.’ I don’t know where they get that information from; we are telling everyone to get it, especially our lupus patients.”

The authors recognized their study’s main limitation as the self-reported and subjective nature of the survey, which they attempted to mitigate by asking for medically confirmed flares only. They noted, however, that the short median time between vaccination and flare onset could be caused by patients confusing expected side effects for something more serious, meaning the 3% figure “could be an overestimation of the actual flare rate.”

“Vaccination is recommended for patients with rheumatic and musculoskeletal diseases according to the American College of Rheumatology,” they added, “irrespective of disease activity and severity.”

Several authors reported potential conflicts of interest, including receiving consultancy fees and grants from Pfizer, GlaxoSmithKline, AbbVie, and Janssen, all unrelated to the study.

COVID-19 vaccinations appear to be well tolerated in patients with systemic lupus erythematosus (SLE) and come with a low risk of flare, according to the results of a global, web-based survey.

Steve Mann/Thinkstock

“Disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with SLE,” wrote lead author Renaud Felten, MD, of Strasbourg (France) University Hospital. Their results were published as a comment in Lancet Rheumatology.

To assess vaccine tolerability among lupus patients, the cross-sectional Tolerance and Consequences of Vaccination Against COVID-19 in Lupus Patients (VACOLUP) study analyzed a 43-question survey of 696 participants with a self-reported, medically confirmed diagnosis of SLE from 30 countries between March 22, 2021, and May 17, 2021. The cohort was 96% women, and their median age was 42 (interquartile range, 34-51). Nearly 36% of respondents were from Italy, 27% were from Chile, 13% were from France, and just under 9% were Americans. All participants received at least one dose of COVID-19 vaccine, and 49% received a second dose. The most common vaccines were Pfizer-BioNTech (57%), Sinovac (22%), AstraZeneca (10%), and Moderna (8%).

Only 21 participants (3%) reported a medically confirmed SLE flare after a median of 3 days (IQR, 0-29) post COVID vaccination, with most experiencing musculoskeletal symptoms (90%) and fatigue (86%). Of the 21 cases, 15 reported a subsequent change in SLE treatment and 4 were admitted to the hospital. A previous flare that occurred within a year before vaccination was associated with an increased risk of flare post vaccination (relative risk, 5.52; 95% confidence interval, 2.17-14.03; P < .0001).

Side effects – including swelling, soreness, fever, chills, fatigue, joint and muscle pain, nausea, and headache – were reported in 45% of participants (n = 316) after their first dose and in 53% of the 343 participants who received a second dose. There was no notable difference in the likelihood of side effects across gender and age or in patients who received mRNA vaccines, compared with vaccines with other modes of action. Patients who reported side effects after the first dose were more likely to also report them after the second, compared with those who reported none (109 [81%] of 135 vs. 72 [35%] of 205; RR, 2.30; 95% CI, 1.88-2.82; P < .0001).

In the majority of cases (2,232 of 2,683), the side effects were of minor or moderate intensity and did not affect the participants’ ability to perform daily tasks. The study found no significant association between side effects and a SLE flare and SLE medications or previous SLE disease manifestations.

When asked to comment on the study, Amit Saxena, MD, of the Lupus Center at New York University Langone Health, said: “What we are seeing is pretty mild to moderate in terms of follow-up side effects or lupus-related activity. Several studies have shown this amongst our autoimmune rheumatology cohort, as well as what I’ve seen clinically in my own patients. More than anything else, numbers are the most important, and this is a large study.”

He acknowledged the benefits of going directly to patients to gauge their responses and reactions, giving them the opportunity to share concerns that physicians may not think about.

“As rheumatologists, we tend to focus on certain things that might not necessarily be what the patients themselves focus on,” he said. “I think the fact that this questionnaire dealt with a lot of what people complain about – fatigue, sore arm, things that we know are part of getting the vaccine – they aren’t necessarily things we capture with tools that screen for lupus flares, for example.”

More than anything, Dr. Saxena commended the study’s timeliness. “Patients are constantly asking us about the vaccine, and there’s so much misinformation,” he said. “People say, ‘Because I have lupus, I was told not to get vaccinated.’ I don’t know where they get that information from; we are telling everyone to get it, especially our lupus patients.”

The authors recognized their study’s main limitation as the self-reported and subjective nature of the survey, which they attempted to mitigate by asking for medically confirmed flares only. They noted, however, that the short median time between vaccination and flare onset could be caused by patients confusing expected side effects for something more serious, meaning the 3% figure “could be an overestimation of the actual flare rate.”

“Vaccination is recommended for patients with rheumatic and musculoskeletal diseases according to the American College of Rheumatology,” they added, “irrespective of disease activity and severity.”

Several authors reported potential conflicts of interest, including receiving consultancy fees and grants from Pfizer, GlaxoSmithKline, AbbVie, and Janssen, all unrelated to the study.

COVID-19 vaccinations appear to be well tolerated in patients with systemic lupus erythematosus (SLE) and come with a low risk of flare, according to the results of a global, web-based survey.

Steve Mann/Thinkstock

“Disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with SLE,” wrote lead author Renaud Felten, MD, of Strasbourg (France) University Hospital. Their results were published as a comment in Lancet Rheumatology.

To assess vaccine tolerability among lupus patients, the cross-sectional Tolerance and Consequences of Vaccination Against COVID-19 in Lupus Patients (VACOLUP) study analyzed a 43-question survey of 696 participants with a self-reported, medically confirmed diagnosis of SLE from 30 countries between March 22, 2021, and May 17, 2021. The cohort was 96% women, and their median age was 42 (interquartile range, 34-51). Nearly 36% of respondents were from Italy, 27% were from Chile, 13% were from France, and just under 9% were Americans. All participants received at least one dose of COVID-19 vaccine, and 49% received a second dose. The most common vaccines were Pfizer-BioNTech (57%), Sinovac (22%), AstraZeneca (10%), and Moderna (8%).

Only 21 participants (3%) reported a medically confirmed SLE flare after a median of 3 days (IQR, 0-29) post COVID vaccination, with most experiencing musculoskeletal symptoms (90%) and fatigue (86%). Of the 21 cases, 15 reported a subsequent change in SLE treatment and 4 were admitted to the hospital. A previous flare that occurred within a year before vaccination was associated with an increased risk of flare post vaccination (relative risk, 5.52; 95% confidence interval, 2.17-14.03; P < .0001).

Side effects – including swelling, soreness, fever, chills, fatigue, joint and muscle pain, nausea, and headache – were reported in 45% of participants (n = 316) after their first dose and in 53% of the 343 participants who received a second dose. There was no notable difference in the likelihood of side effects across gender and age or in patients who received mRNA vaccines, compared with vaccines with other modes of action. Patients who reported side effects after the first dose were more likely to also report them after the second, compared with those who reported none (109 [81%] of 135 vs. 72 [35%] of 205; RR, 2.30; 95% CI, 1.88-2.82; P < .0001).

In the majority of cases (2,232 of 2,683), the side effects were of minor or moderate intensity and did not affect the participants’ ability to perform daily tasks. The study found no significant association between side effects and a SLE flare and SLE medications or previous SLE disease manifestations.

When asked to comment on the study, Amit Saxena, MD, of the Lupus Center at New York University Langone Health, said: “What we are seeing is pretty mild to moderate in terms of follow-up side effects or lupus-related activity. Several studies have shown this amongst our autoimmune rheumatology cohort, as well as what I’ve seen clinically in my own patients. More than anything else, numbers are the most important, and this is a large study.”

He acknowledged the benefits of going directly to patients to gauge their responses and reactions, giving them the opportunity to share concerns that physicians may not think about.

“As rheumatologists, we tend to focus on certain things that might not necessarily be what the patients themselves focus on,” he said. “I think the fact that this questionnaire dealt with a lot of what people complain about – fatigue, sore arm, things that we know are part of getting the vaccine – they aren’t necessarily things we capture with tools that screen for lupus flares, for example.”

More than anything, Dr. Saxena commended the study’s timeliness. “Patients are constantly asking us about the vaccine, and there’s so much misinformation,” he said. “People say, ‘Because I have lupus, I was told not to get vaccinated.’ I don’t know where they get that information from; we are telling everyone to get it, especially our lupus patients.”

The authors recognized their study’s main limitation as the self-reported and subjective nature of the survey, which they attempted to mitigate by asking for medically confirmed flares only. They noted, however, that the short median time between vaccination and flare onset could be caused by patients confusing expected side effects for something more serious, meaning the 3% figure “could be an overestimation of the actual flare rate.”

“Vaccination is recommended for patients with rheumatic and musculoskeletal diseases according to the American College of Rheumatology,” they added, “irrespective of disease activity and severity.”

Several authors reported potential conflicts of interest, including receiving consultancy fees and grants from Pfizer, GlaxoSmithKline, AbbVie, and Janssen, all unrelated to the study.

With 49% of the U.S. population fully vaccinated against SARS-CoV-2, a new study highlights the degree of vaccine hesitancy among patients with rheumatic disease to get the vaccine.

Halfpoint Images/Moment/Getty Images

The international study, published in May 2021 in Rheumatology, suggests that, of 1,258 patients surveyed worldwide, approximately 40% of patients said they would decline the vaccine.

“Sometimes it’s helpful to talk through their concerns,” said Jeffrey Curtis, MD, MPH, a University of Alabama at Birmingham rheumatologist who leads the American College of Rheumatology COVID-19 vaccine task force. Dr. Curtis recently reviewed the current literature on COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases (RMDs) at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

COVID-19 vaccinations for patients with autoimmune inflammatory rheumatic disease (AIIRD) is not straightforward. The immune response can be blunted by existing treatments and disease flares can occur.

Courtesy UAB Photo

The latest version of COVID-19 vaccination guidance for patients with RMDs from the ACR addresses vaccine use and implementation strategies. The guidance was issued as conditional or provisional because of the lack of evidence. Its principals are largely based on accepted practice for other vaccines. The guidance is routinely updated as new evidence becomes available. In his presentation at GRAPPA, Dr. Curtis reviewed the latest version of the guidance, which he emphasized is a guidance only and not meant to replace clinical judgment or shared decision-making with patients.

“This is a platform for you to start from as you are thinking about and discussing with your patient what might be best for him or her,” he said.
 

Concerns about impact of disease activity, treatments on effectiveness

Dr. Curtis highlighted some controversial aspects of COVID-19 vaccines, including heterogeneity of rheumatic diseases and treatment. Patients with AIIRD, including psoriatic arthritis, spondyloarthritis, RA, and lupus, are at higher risk for hospitalized COVID-19 and worse outcomes, and as such, they are prioritized for vaccination by the Centers for Disease Control and Prevention.

However, for AIIRD patients, the immune response to COVID-19 vaccination can be “blunted,” according to one study. This may be because of glucocorticoid use or high disease activity. Immunomodulatory therapies, such as methotrexate, rituximab, and abatacept, are known to diminish vaccine response in general. The evidence is less clear for tumor necrosis factor and Janus kinase inhibitors, but they are thought to have the same impact on vaccine effectiveness, Dr. Curtis said. But in these cases, if the effect of a COVID-19 vaccine drops from 90% to 70%, the benefits of vaccination still far outweighs the risk of contracting COVID-19.

“Although we don’t have strong data with clinical outcomes for autoimmune disease or inflammatory disease patients, I’ll run a hypothetical and say: ‘Look, if this vaccine starts 90%-95% effective, even if it’s only 70% effective in somebody with lupus or vasculitis or someone who is taking a higher dose of steroids, I’ll take 70% over nothing if you chose to be vaccinated,’ ” he said.

The benefit of vaccination also outweighs the potential risk of disease flare, he said. The risk is real, but to date, no studies have pointed to a significant risk of disease flare or worsening. However, there have been reported cases of myocardial infarction.

Autoimmune manifestations after vaccination vs. after infection

Researchers writing in the June 29, 2021, issue of JAMA Cardiology described case reports of acute myocarditis in 23 people who received the BNT162b2-mRNA (Pfizer-BioNTech) or mRNA-1273 (Moderna) messenger RNA (mRNA) COVID-19 vaccines. Plus, there been subsequent reports of myocarditis in other patients, wrote David K. Shay, MD, MPH, in an accompanying editorial. Dr. Shay is a member of the CDC COVID-19 Response Team.

“What do we know about this possible association between myocarditis and immunization with mRNA-based COVID-19 vaccines, and what remains unclear? Acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism,” he said.

The cases of myocarditis are concerning, Dr. Curtis said, but the risk is very low with relatively few cases reported among 161 million fully vaccinated people in the United States.

“Certainly, we’re not seeking to minimize that, but the risk of getting COVID and some of the downstream sequelae (autoimmune manifestations) almost certainly outweigh the risks for some of the autoimmune manifestations or worsening [condition],” he said.

A nationwide cohort study from Denmark of 58,052 patients with inflammatory rheumatic disease published in December 2020 in Rheumatology, found that patients with COVID-19 who had an inflammatory rheumatic disease were more likely to be admitted to the hospital, compared with COVID-19 patients without rheumatic disease. Patients with rheumatic disease had a higher risk of a severe COVID-19 outcome, but it was not a statistically significant difference, said Dr. Curtis, adding that the individual factors such as age and treatment currently received largely determines the risk. The strongest associations between hospitalization for COVID-19 and rheumatic disease were found among patients with RA, vasculitis, and connective tissue disease. Dr. Curtis noted that his own new study results show that risk of death from a COVID-19 infection is higher for patients who have RA or psoriatic arthritis.

There have been published case reports of patients who have developed new-onset lupus, vasculitis, Kawasaki disease, multiple sclerosis, autoimmune cytopenias, and other manifestations after a COVID-19 infection. “These authors suggest that perhaps there is a transient influence on the immune system that leads to a loss of self-tolerance to antigens,” Dr. Curtis said. “Some patients may have an underlying predisposition to autoimmunity in which infections just unmask as we sometimes see with other infections – chronic hepatitis for example.”
 

Antibody tests not recommended

In its COVID-19 guidance, the ACR, like the Food and Drug Administration, recommends health care providers not to routinely order antibody tests for IgM or IgG to assess immunity after a person has been vaccinated or to assess the need for vaccination in an unvaccinated person. More research is needed to determine if antibodies provide protection, and if so, for how long and how much. Plus, the antibody testing process is not clear cut, so ordering the wrong test is possible, Dr. Curtis said. The tests should clearly differentiate between spike proteins or nucleocapsid proteins.

“The bottom line is that you might be ordering the wrong lab test. Even if you’re ordering the right lab test, I would assert that you probably don’t know what to do with the result. I would then ask you, ‘Does it mean they are protected? Does it mean they are not protected? What are you going to do with the results?’ ” he asked.

Kevin Winthrop, MD, MPH, a specialist in infectious diseases at Oregon Health & Science University, Portland, said that, at this point, it’s too early to know what antibody tests mean. “I think it is tempting to test some people, especially patients on B-cell depletion therapy and those on mycophenolate mofetil (MMF). Outside of those two types of [disease-modifying antirheumatic drug] users, I wouldn’t be tempted to test. We don’t know how well protected they are, but we assume they are protected to some extent,” he said. “They’re probably partially protected and as such, they should take the same precautions they were taking a year ago: masking and avoidance. I think that’s just how it’s going to be for those folks for another year until we get this thing sorted out.”
 

Modifications to existing rheumatic disease therapies

In its COVID-19 vaccine guidance, the ACR issued recommendations for some common rheumatic disease therapeutics before and/or after the COVID-19 vaccine is administered. The modifications are limited to MMF, methotrexate, JAK inhibitors, subcutaneous abatacept, acetaminophen, and NSAIDs. The recommendations include: hold mycophenolate for 1 week after vaccination if disease is stable; for patients with well-controlled disease, hold methotrexate for 1 week after each of the two mRNA vaccine doses; for patients with well-controlled disease receiving the Johnson & Johnson vaccine, hold methotrexate for 2 weeks after receiving the vaccine; hold JAK inhibitors for 1 week after each dose; for abatacept subcutaneous, hold treatment for 1 week before and after the first dose; and in patients with stable disease, hold acetaminophen and NSAIDs for 24 hours before vaccination, because taking either before vaccination could blunt the vaccine response, Dr. Curtis said.

Holding medication, such as methotrexate, could risk having a flare-up of disease. One study showed the rate of disease flare-up because of withholding standard treatment may be up to 11%, compared with 5.1% in patients who did not hold treatment, he said.

“The point is, if you hold some of these therapies, whether methotrexate or tofacitinib, arthritis will get a little bit worse,” Dr. Curtis said.

A study published on the preprint server medRxiv found that immunosuppressive therapies blunted the response of SARS-CoV-2 vaccines in patients with chronic inflammatory diseases, most significantly with glucocorticoids and B-cell therapies.

“That’s what’s led to a lot of the guidance statements about holding treatments for a week or 2 for rituximab. If you’re giving it at 6-month intervals, you want to schedule the vaccine dose or series at about month 5, or a month before the next cycle,” he said.

Talking with patients about COVID-19 vaccination

In talking with patients about vaccine safety, Dr. Curtis recommends addressing a few common misperceptions. First, COVID-19 viruses were not created with a live-attenuated virus (which would be contraindicated for immunosuppressed patients). “You can put patients’ mind at ease that none of the vaccine candidates or platforms – even those that say viral vector – put patients at risk for contracting the infection. These are nonreplicating. So, it’s like you extracted the engine that would allow this virus to replicate,” he said.

Of three COVID-19 vaccinations available in the United States, is one better than the other? The ACR COVID-19 vaccine task force did not reach a consensus on safety profiles of the vaccines because, without head-to-head comparisons, it’s impossible to know, he said.

In talking with patients, review the protocol for continuing with prescribed treatment modalities before the patient receives a COVID-19 vaccine. Safety concerns and concerns about the possibility of having a disease flare-up should be addressed, he said.

With 49% of the U.S. population fully vaccinated against SARS-CoV-2, a new study highlights the degree of vaccine hesitancy among patients with rheumatic disease to get the vaccine.

Halfpoint Images/Moment/Getty Images

The international study, published in May 2021 in Rheumatology, suggests that, of 1,258 patients surveyed worldwide, approximately 40% of patients said they would decline the vaccine.

“Sometimes it’s helpful to talk through their concerns,” said Jeffrey Curtis, MD, MPH, a University of Alabama at Birmingham rheumatologist who leads the American College of Rheumatology COVID-19 vaccine task force. Dr. Curtis recently reviewed the current literature on COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases (RMDs) at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

COVID-19 vaccinations for patients with autoimmune inflammatory rheumatic disease (AIIRD) is not straightforward. The immune response can be blunted by existing treatments and disease flares can occur.

Courtesy UAB Photo

The latest version of COVID-19 vaccination guidance for patients with RMDs from the ACR addresses vaccine use and implementation strategies. The guidance was issued as conditional or provisional because of the lack of evidence. Its principals are largely based on accepted practice for other vaccines. The guidance is routinely updated as new evidence becomes available. In his presentation at GRAPPA, Dr. Curtis reviewed the latest version of the guidance, which he emphasized is a guidance only and not meant to replace clinical judgment or shared decision-making with patients.

“This is a platform for you to start from as you are thinking about and discussing with your patient what might be best for him or her,” he said.
 

Concerns about impact of disease activity, treatments on effectiveness

Dr. Curtis highlighted some controversial aspects of COVID-19 vaccines, including heterogeneity of rheumatic diseases and treatment. Patients with AIIRD, including psoriatic arthritis, spondyloarthritis, RA, and lupus, are at higher risk for hospitalized COVID-19 and worse outcomes, and as such, they are prioritized for vaccination by the Centers for Disease Control and Prevention.

However, for AIIRD patients, the immune response to COVID-19 vaccination can be “blunted,” according to one study. This may be because of glucocorticoid use or high disease activity. Immunomodulatory therapies, such as methotrexate, rituximab, and abatacept, are known to diminish vaccine response in general. The evidence is less clear for tumor necrosis factor and Janus kinase inhibitors, but they are thought to have the same impact on vaccine effectiveness, Dr. Curtis said. But in these cases, if the effect of a COVID-19 vaccine drops from 90% to 70%, the benefits of vaccination still far outweighs the risk of contracting COVID-19.

“Although we don’t have strong data with clinical outcomes for autoimmune disease or inflammatory disease patients, I’ll run a hypothetical and say: ‘Look, if this vaccine starts 90%-95% effective, even if it’s only 70% effective in somebody with lupus or vasculitis or someone who is taking a higher dose of steroids, I’ll take 70% over nothing if you chose to be vaccinated,’ ” he said.

The benefit of vaccination also outweighs the potential risk of disease flare, he said. The risk is real, but to date, no studies have pointed to a significant risk of disease flare or worsening. However, there have been reported cases of myocardial infarction.

Autoimmune manifestations after vaccination vs. after infection

Researchers writing in the June 29, 2021, issue of JAMA Cardiology described case reports of acute myocarditis in 23 people who received the BNT162b2-mRNA (Pfizer-BioNTech) or mRNA-1273 (Moderna) messenger RNA (mRNA) COVID-19 vaccines. Plus, there been subsequent reports of myocarditis in other patients, wrote David K. Shay, MD, MPH, in an accompanying editorial. Dr. Shay is a member of the CDC COVID-19 Response Team.

“What do we know about this possible association between myocarditis and immunization with mRNA-based COVID-19 vaccines, and what remains unclear? Acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism,” he said.

The cases of myocarditis are concerning, Dr. Curtis said, but the risk is very low with relatively few cases reported among 161 million fully vaccinated people in the United States.

“Certainly, we’re not seeking to minimize that, but the risk of getting COVID and some of the downstream sequelae (autoimmune manifestations) almost certainly outweigh the risks for some of the autoimmune manifestations or worsening [condition],” he said.

A nationwide cohort study from Denmark of 58,052 patients with inflammatory rheumatic disease published in December 2020 in Rheumatology, found that patients with COVID-19 who had an inflammatory rheumatic disease were more likely to be admitted to the hospital, compared with COVID-19 patients without rheumatic disease. Patients with rheumatic disease had a higher risk of a severe COVID-19 outcome, but it was not a statistically significant difference, said Dr. Curtis, adding that the individual factors such as age and treatment currently received largely determines the risk. The strongest associations between hospitalization for COVID-19 and rheumatic disease were found among patients with RA, vasculitis, and connective tissue disease. Dr. Curtis noted that his own new study results show that risk of death from a COVID-19 infection is higher for patients who have RA or psoriatic arthritis.

There have been published case reports of patients who have developed new-onset lupus, vasculitis, Kawasaki disease, multiple sclerosis, autoimmune cytopenias, and other manifestations after a COVID-19 infection. “These authors suggest that perhaps there is a transient influence on the immune system that leads to a loss of self-tolerance to antigens,” Dr. Curtis said. “Some patients may have an underlying predisposition to autoimmunity in which infections just unmask as we sometimes see with other infections – chronic hepatitis for example.”
 

Antibody tests not recommended

In its COVID-19 guidance, the ACR, like the Food and Drug Administration, recommends health care providers not to routinely order antibody tests for IgM or IgG to assess immunity after a person has been vaccinated or to assess the need for vaccination in an unvaccinated person. More research is needed to determine if antibodies provide protection, and if so, for how long and how much. Plus, the antibody testing process is not clear cut, so ordering the wrong test is possible, Dr. Curtis said. The tests should clearly differentiate between spike proteins or nucleocapsid proteins.

“The bottom line is that you might be ordering the wrong lab test. Even if you’re ordering the right lab test, I would assert that you probably don’t know what to do with the result. I would then ask you, ‘Does it mean they are protected? Does it mean they are not protected? What are you going to do with the results?’ ” he asked.

Kevin Winthrop, MD, MPH, a specialist in infectious diseases at Oregon Health & Science University, Portland, said that, at this point, it’s too early to know what antibody tests mean. “I think it is tempting to test some people, especially patients on B-cell depletion therapy and those on mycophenolate mofetil (MMF). Outside of those two types of [disease-modifying antirheumatic drug] users, I wouldn’t be tempted to test. We don’t know how well protected they are, but we assume they are protected to some extent,” he said. “They’re probably partially protected and as such, they should take the same precautions they were taking a year ago: masking and avoidance. I think that’s just how it’s going to be for those folks for another year until we get this thing sorted out.”
 

Modifications to existing rheumatic disease therapies

In its COVID-19 vaccine guidance, the ACR issued recommendations for some common rheumatic disease therapeutics before and/or after the COVID-19 vaccine is administered. The modifications are limited to MMF, methotrexate, JAK inhibitors, subcutaneous abatacept, acetaminophen, and NSAIDs. The recommendations include: hold mycophenolate for 1 week after vaccination if disease is stable; for patients with well-controlled disease, hold methotrexate for 1 week after each of the two mRNA vaccine doses; for patients with well-controlled disease receiving the Johnson & Johnson vaccine, hold methotrexate for 2 weeks after receiving the vaccine; hold JAK inhibitors for 1 week after each dose; for abatacept subcutaneous, hold treatment for 1 week before and after the first dose; and in patients with stable disease, hold acetaminophen and NSAIDs for 24 hours before vaccination, because taking either before vaccination could blunt the vaccine response, Dr. Curtis said.

Holding medication, such as methotrexate, could risk having a flare-up of disease. One study showed the rate of disease flare-up because of withholding standard treatment may be up to 11%, compared with 5.1% in patients who did not hold treatment, he said.

“The point is, if you hold some of these therapies, whether methotrexate or tofacitinib, arthritis will get a little bit worse,” Dr. Curtis said.

A study published on the preprint server medRxiv found that immunosuppressive therapies blunted the response of SARS-CoV-2 vaccines in patients with chronic inflammatory diseases, most significantly with glucocorticoids and B-cell therapies.

“That’s what’s led to a lot of the guidance statements about holding treatments for a week or 2 for rituximab. If you’re giving it at 6-month intervals, you want to schedule the vaccine dose or series at about month 5, or a month before the next cycle,” he said.

Talking with patients about COVID-19 vaccination

In talking with patients about vaccine safety, Dr. Curtis recommends addressing a few common misperceptions. First, COVID-19 viruses were not created with a live-attenuated virus (which would be contraindicated for immunosuppressed patients). “You can put patients’ mind at ease that none of the vaccine candidates or platforms – even those that say viral vector – put patients at risk for contracting the infection. These are nonreplicating. So, it’s like you extracted the engine that would allow this virus to replicate,” he said.

Of three COVID-19 vaccinations available in the United States, is one better than the other? The ACR COVID-19 vaccine task force did not reach a consensus on safety profiles of the vaccines because, without head-to-head comparisons, it’s impossible to know, he said.

In talking with patients, review the protocol for continuing with prescribed treatment modalities before the patient receives a COVID-19 vaccine. Safety concerns and concerns about the possibility of having a disease flare-up should be addressed, he said.

With 49% of the U.S. population fully vaccinated against SARS-CoV-2, a new study highlights the degree of vaccine hesitancy among patients with rheumatic disease to get the vaccine.

Halfpoint Images/Moment/Getty Images

The international study, published in May 2021 in Rheumatology, suggests that, of 1,258 patients surveyed worldwide, approximately 40% of patients said they would decline the vaccine.

“Sometimes it’s helpful to talk through their concerns,” said Jeffrey Curtis, MD, MPH, a University of Alabama at Birmingham rheumatologist who leads the American College of Rheumatology COVID-19 vaccine task force. Dr. Curtis recently reviewed the current literature on COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases (RMDs) at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

COVID-19 vaccinations for patients with autoimmune inflammatory rheumatic disease (AIIRD) is not straightforward. The immune response can be blunted by existing treatments and disease flares can occur.

Courtesy UAB Photo

The latest version of COVID-19 vaccination guidance for patients with RMDs from the ACR addresses vaccine use and implementation strategies. The guidance was issued as conditional or provisional because of the lack of evidence. Its principals are largely based on accepted practice for other vaccines. The guidance is routinely updated as new evidence becomes available. In his presentation at GRAPPA, Dr. Curtis reviewed the latest version of the guidance, which he emphasized is a guidance only and not meant to replace clinical judgment or shared decision-making with patients.

“This is a platform for you to start from as you are thinking about and discussing with your patient what might be best for him or her,” he said.
 

Concerns about impact of disease activity, treatments on effectiveness

Dr. Curtis highlighted some controversial aspects of COVID-19 vaccines, including heterogeneity of rheumatic diseases and treatment. Patients with AIIRD, including psoriatic arthritis, spondyloarthritis, RA, and lupus, are at higher risk for hospitalized COVID-19 and worse outcomes, and as such, they are prioritized for vaccination by the Centers for Disease Control and Prevention.

However, for AIIRD patients, the immune response to COVID-19 vaccination can be “blunted,” according to one study. This may be because of glucocorticoid use or high disease activity. Immunomodulatory therapies, such as methotrexate, rituximab, and abatacept, are known to diminish vaccine response in general. The evidence is less clear for tumor necrosis factor and Janus kinase inhibitors, but they are thought to have the same impact on vaccine effectiveness, Dr. Curtis said. But in these cases, if the effect of a COVID-19 vaccine drops from 90% to 70%, the benefits of vaccination still far outweighs the risk of contracting COVID-19.

“Although we don’t have strong data with clinical outcomes for autoimmune disease or inflammatory disease patients, I’ll run a hypothetical and say: ‘Look, if this vaccine starts 90%-95% effective, even if it’s only 70% effective in somebody with lupus or vasculitis or someone who is taking a higher dose of steroids, I’ll take 70% over nothing if you chose to be vaccinated,’ ” he said.

The benefit of vaccination also outweighs the potential risk of disease flare, he said. The risk is real, but to date, no studies have pointed to a significant risk of disease flare or worsening. However, there have been reported cases of myocardial infarction.

Autoimmune manifestations after vaccination vs. after infection

Researchers writing in the June 29, 2021, issue of JAMA Cardiology described case reports of acute myocarditis in 23 people who received the BNT162b2-mRNA (Pfizer-BioNTech) or mRNA-1273 (Moderna) messenger RNA (mRNA) COVID-19 vaccines. Plus, there been subsequent reports of myocarditis in other patients, wrote David K. Shay, MD, MPH, in an accompanying editorial. Dr. Shay is a member of the CDC COVID-19 Response Team.

“What do we know about this possible association between myocarditis and immunization with mRNA-based COVID-19 vaccines, and what remains unclear? Acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism,” he said.

The cases of myocarditis are concerning, Dr. Curtis said, but the risk is very low with relatively few cases reported among 161 million fully vaccinated people in the United States.

“Certainly, we’re not seeking to minimize that, but the risk of getting COVID and some of the downstream sequelae (autoimmune manifestations) almost certainly outweigh the risks for some of the autoimmune manifestations or worsening [condition],” he said.

A nationwide cohort study from Denmark of 58,052 patients with inflammatory rheumatic disease published in December 2020 in Rheumatology, found that patients with COVID-19 who had an inflammatory rheumatic disease were more likely to be admitted to the hospital, compared with COVID-19 patients without rheumatic disease. Patients with rheumatic disease had a higher risk of a severe COVID-19 outcome, but it was not a statistically significant difference, said Dr. Curtis, adding that the individual factors such as age and treatment currently received largely determines the risk. The strongest associations between hospitalization for COVID-19 and rheumatic disease were found among patients with RA, vasculitis, and connective tissue disease. Dr. Curtis noted that his own new study results show that risk of death from a COVID-19 infection is higher for patients who have RA or psoriatic arthritis.

There have been published case reports of patients who have developed new-onset lupus, vasculitis, Kawasaki disease, multiple sclerosis, autoimmune cytopenias, and other manifestations after a COVID-19 infection. “These authors suggest that perhaps there is a transient influence on the immune system that leads to a loss of self-tolerance to antigens,” Dr. Curtis said. “Some patients may have an underlying predisposition to autoimmunity in which infections just unmask as we sometimes see with other infections – chronic hepatitis for example.”
 

Antibody tests not recommended

In its COVID-19 guidance, the ACR, like the Food and Drug Administration, recommends health care providers not to routinely order antibody tests for IgM or IgG to assess immunity after a person has been vaccinated or to assess the need for vaccination in an unvaccinated person. More research is needed to determine if antibodies provide protection, and if so, for how long and how much. Plus, the antibody testing process is not clear cut, so ordering the wrong test is possible, Dr. Curtis said. The tests should clearly differentiate between spike proteins or nucleocapsid proteins.

“The bottom line is that you might be ordering the wrong lab test. Even if you’re ordering the right lab test, I would assert that you probably don’t know what to do with the result. I would then ask you, ‘Does it mean they are protected? Does it mean they are not protected? What are you going to do with the results?’ ” he asked.

Kevin Winthrop, MD, MPH, a specialist in infectious diseases at Oregon Health & Science University, Portland, said that, at this point, it’s too early to know what antibody tests mean. “I think it is tempting to test some people, especially patients on B-cell depletion therapy and those on mycophenolate mofetil (MMF). Outside of those two types of [disease-modifying antirheumatic drug] users, I wouldn’t be tempted to test. We don’t know how well protected they are, but we assume they are protected to some extent,” he said. “They’re probably partially protected and as such, they should take the same precautions they were taking a year ago: masking and avoidance. I think that’s just how it’s going to be for those folks for another year until we get this thing sorted out.”
 

Modifications to existing rheumatic disease therapies

In its COVID-19 vaccine guidance, the ACR issued recommendations for some common rheumatic disease therapeutics before and/or after the COVID-19 vaccine is administered. The modifications are limited to MMF, methotrexate, JAK inhibitors, subcutaneous abatacept, acetaminophen, and NSAIDs. The recommendations include: hold mycophenolate for 1 week after vaccination if disease is stable; for patients with well-controlled disease, hold methotrexate for 1 week after each of the two mRNA vaccine doses; for patients with well-controlled disease receiving the Johnson & Johnson vaccine, hold methotrexate for 2 weeks after receiving the vaccine; hold JAK inhibitors for 1 week after each dose; for abatacept subcutaneous, hold treatment for 1 week before and after the first dose; and in patients with stable disease, hold acetaminophen and NSAIDs for 24 hours before vaccination, because taking either before vaccination could blunt the vaccine response, Dr. Curtis said.

Holding medication, such as methotrexate, could risk having a flare-up of disease. One study showed the rate of disease flare-up because of withholding standard treatment may be up to 11%, compared with 5.1% in patients who did not hold treatment, he said.

“The point is, if you hold some of these therapies, whether methotrexate or tofacitinib, arthritis will get a little bit worse,” Dr. Curtis said.

A study published on the preprint server medRxiv found that immunosuppressive therapies blunted the response of SARS-CoV-2 vaccines in patients with chronic inflammatory diseases, most significantly with glucocorticoids and B-cell therapies.

“That’s what’s led to a lot of the guidance statements about holding treatments for a week or 2 for rituximab. If you’re giving it at 6-month intervals, you want to schedule the vaccine dose or series at about month 5, or a month before the next cycle,” he said.

Talking with patients about COVID-19 vaccination

In talking with patients about vaccine safety, Dr. Curtis recommends addressing a few common misperceptions. First, COVID-19 viruses were not created with a live-attenuated virus (which would be contraindicated for immunosuppressed patients). “You can put patients’ mind at ease that none of the vaccine candidates or platforms – even those that say viral vector – put patients at risk for contracting the infection. These are nonreplicating. So, it’s like you extracted the engine that would allow this virus to replicate,” he said.

Of three COVID-19 vaccinations available in the United States, is one better than the other? The ACR COVID-19 vaccine task force did not reach a consensus on safety profiles of the vaccines because, without head-to-head comparisons, it’s impossible to know, he said.

In talking with patients, review the protocol for continuing with prescribed treatment modalities before the patient receives a COVID-19 vaccine. Safety concerns and concerns about the possibility of having a disease flare-up should be addressed, he said.

The Food and Drug Administration has approved Octagam 10% as the first intravenous immunoglobulin with an indication specifically for adult dermatomyositis, according to a statement from manufacturer Octapharma USA.

Dermatomyositis is a rare, idiopathic autoimmune disorder that affects approximately 10 out of every million people in the United States, mainly adults in their late 40s to early 60s, according to the company, but children aged 5-15 years can be affected. The disease is characterized by skin rashes, chronic muscle inflammation, progressive muscle weakness, and risk for mortality that is three times higher than for the general population.

There are no previously approved treatments for dermatomyositis prior to Octagam 10%, which also is indicated for chronic immune thrombocytopenic purpura in adults.

The approval for dermatomyositis was based on the results of a phase 3 randomized, double-blind, placebo-controlled clinical trial (the ProDERM trial) that included 95 adult patients at 36 sites worldwide, with 17 sites in the United States. In the trial, 78.7% of patients with dermatomyositis who were randomized to receive 2 g/kg of Octagam 10% every 4 weeks showed response at 16 weeks, compared with 43.8% of patients who received placebo. Response was based on the 2016 American College of Rheumatology/European Alliance of Associations for Rheumatology myositis response criteria. Placebo patients who switched to intravenous immunoglobulin (IVIG) during a trial extension had response rates at week 40 similar to the original patients at week 16.

“The study gives clinicians much more confidence in the efficacy and safety of intravenous immunoglobulin and provides valuable information about what type of patient is best suited for the treatment,” Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh and a member of the ProDERM study Steering Committee, said in the Octapharma statement.

Safety and tolerability were similar to profiles seen with other IVIG medications, according to the statement. The medication does carry a boxed warning from its chronic ITP approval, cautioning about the potential for thrombosis, renal dysfunction, and acute renal failure.

The most common adverse reactions reported by dermatomyositis patients in the ProDERM trial were headache, fever, nausea, vomiting, increased blood pressure, chills, musculoskeletal pain, increased heart rate, dyspnea, and reactions at the infusion sites.

Read the full prescribing information here.

The Food and Drug Administration has approved Octagam 10% as the first intravenous immunoglobulin with an indication specifically for adult dermatomyositis, according to a statement from manufacturer Octapharma USA.

Dermatomyositis is a rare, idiopathic autoimmune disorder that affects approximately 10 out of every million people in the United States, mainly adults in their late 40s to early 60s, according to the company, but children aged 5-15 years can be affected. The disease is characterized by skin rashes, chronic muscle inflammation, progressive muscle weakness, and risk for mortality that is three times higher than for the general population.

There are no previously approved treatments for dermatomyositis prior to Octagam 10%, which also is indicated for chronic immune thrombocytopenic purpura in adults.

The approval for dermatomyositis was based on the results of a phase 3 randomized, double-blind, placebo-controlled clinical trial (the ProDERM trial) that included 95 adult patients at 36 sites worldwide, with 17 sites in the United States. In the trial, 78.7% of patients with dermatomyositis who were randomized to receive 2 g/kg of Octagam 10% every 4 weeks showed response at 16 weeks, compared with 43.8% of patients who received placebo. Response was based on the 2016 American College of Rheumatology/European Alliance of Associations for Rheumatology myositis response criteria. Placebo patients who switched to intravenous immunoglobulin (IVIG) during a trial extension had response rates at week 40 similar to the original patients at week 16.

“The study gives clinicians much more confidence in the efficacy and safety of intravenous immunoglobulin and provides valuable information about what type of patient is best suited for the treatment,” Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh and a member of the ProDERM study Steering Committee, said in the Octapharma statement.

Safety and tolerability were similar to profiles seen with other IVIG medications, according to the statement. The medication does carry a boxed warning from its chronic ITP approval, cautioning about the potential for thrombosis, renal dysfunction, and acute renal failure.

The most common adverse reactions reported by dermatomyositis patients in the ProDERM trial were headache, fever, nausea, vomiting, increased blood pressure, chills, musculoskeletal pain, increased heart rate, dyspnea, and reactions at the infusion sites.

Read the full prescribing information here.

The Food and Drug Administration has approved Octagam 10% as the first intravenous immunoglobulin with an indication specifically for adult dermatomyositis, according to a statement from manufacturer Octapharma USA.

Dermatomyositis is a rare, idiopathic autoimmune disorder that affects approximately 10 out of every million people in the United States, mainly adults in their late 40s to early 60s, according to the company, but children aged 5-15 years can be affected. The disease is characterized by skin rashes, chronic muscle inflammation, progressive muscle weakness, and risk for mortality that is three times higher than for the general population.

There are no previously approved treatments for dermatomyositis prior to Octagam 10%, which also is indicated for chronic immune thrombocytopenic purpura in adults.

The approval for dermatomyositis was based on the results of a phase 3 randomized, double-blind, placebo-controlled clinical trial (the ProDERM trial) that included 95 adult patients at 36 sites worldwide, with 17 sites in the United States. In the trial, 78.7% of patients with dermatomyositis who were randomized to receive 2 g/kg of Octagam 10% every 4 weeks showed response at 16 weeks, compared with 43.8% of patients who received placebo. Response was based on the 2016 American College of Rheumatology/European Alliance of Associations for Rheumatology myositis response criteria. Placebo patients who switched to intravenous immunoglobulin (IVIG) during a trial extension had response rates at week 40 similar to the original patients at week 16.

“The study gives clinicians much more confidence in the efficacy and safety of intravenous immunoglobulin and provides valuable information about what type of patient is best suited for the treatment,” Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh and a member of the ProDERM study Steering Committee, said in the Octapharma statement.

Safety and tolerability were similar to profiles seen with other IVIG medications, according to the statement. The medication does carry a boxed warning from its chronic ITP approval, cautioning about the potential for thrombosis, renal dysfunction, and acute renal failure.

The most common adverse reactions reported by dermatomyositis patients in the ProDERM trial were headache, fever, nausea, vomiting, increased blood pressure, chills, musculoskeletal pain, increased heart rate, dyspnea, and reactions at the infusion sites.

Read the full prescribing information here.

Three new guidelines from the American College of Rheumatology, in partnership with the Vasculitis Foundation, offer evidence-based recommendations for managing and treating six different forms of systemic vasculitis.

“It’s not unusual for many rheumatologists to have fairly limited experience caring for patients with vasculitis,” coauthor Sharon Chung, MD, director of the Vasculitis Clinic at the University of California, San Francisco, said in an interview. “And with limited experience comes anxiety and concerns about whether or not one is treating patients appropriately. First and foremost, these guidelines are to help rheumatologists who may not have experience treating patients with vasculitides, to provide them with a framework they can use.”

The guidelines – the first to be produced and endorsed by both the ACR and the Vasculitis Foundation – were published July 8 in both Arthritis & Rheumatology and Arthritis Care & Research.

To assess the recent expansion in diagnostic and treatment options for various forms of vasculitis, the ACR assembled a literature review team, an 11-person patient panel, and a voting panel – made up of 9 adult rheumatologists, 5 pediatric rheumatologists, and 2 patients – to evaluate evidence, provide feedback, and formulate and vote on recommendations, respectively. The guidelines cover six types of vasculitis: one focusing on giant cell arteritis (GCA) and Takayasu arteritis (TAK); one on polyarteritis nodosa (PAN), and another on three forms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV): granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

As with other ACR guidelines, these three were developed via the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which was used to rate the quality of the gathered evidence. For a recommendation to be published, it required 70% consensus or greater from the voting panel.
 

GCA and TAK guideline

Regarding the management and treatment of GCA and TAK, the guideline offers 42 recommendations and three ungraded position statements. Due to the low quality of evidence – “reflecting the paucity of randomized clinical trials in these diseases,” the authors noted – only one of the GCA recommendations and one of the TAK recommendations are strong; the rest are conditional.

For patients with GCA, the guideline strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other notable recommendations include favoring oral glucocorticoids (GCs) with tocilizumab (Actemra) over oral glucocorticoids alone in newly diagnosed GCA, adding a non-GC immunosuppressive agent to oral GCs for GCA patients with active extracranial large vessel involvement, and preferring temporary artery biopsy as their “diagnostic test of choice at this time.”

“The Europeans generally are more comfortable relying on temporal artery ultrasound,” Robert F. Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery, New York, said in an interview. “In this country, possibly in part due to less uniform expertise in performing these ultrasounds, we have not had as much success in terms of accuracy.

These ACR guidelines therefore recommended biopsy to establish the diagnosis in patients with cranial presentations, whereas in the EULAR guidelines, ultrasound was felt to be preferable to biopsy.”

“While we have temporal artery ultrasound available in the United States, we just don’t have the expertise at this point to perform or interpret that test like the European rheumatologists do,” Dr. Chung agreed. “But I think we’re all hopeful that experience with temporal artery ultrasound will improve in the future, so we can use that test instead of an invasive biopsy.”

Dr. Spiera, who was not a coauthor on any of the guidelines, also highlighted the conditional recommendation of noninvasive vascular imaging of the large vessels in patients with newly diagnosed GCA.

“It is well recognized that a substantial portion of patients with GCA have unrecognized evidence of large vessel involvement, and patients with GCA in general are at higher risk of aneurysms later in the disease course,” he said. “These guidelines suggest screening even patients with purely cranial presentations for large vessel involvement with imaging to possibly identify the patients at higher risk for those later complications.

“What they didn’t offer were recommendations on how to follow up on that imaging,” he added, “which is an important and as-yet-unanswered question.”

For patients with TAK, the guideline again strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other conditional recommendations include choosing a non-GC immunosuppressive agent such as methotrexate or a tumor necrosis factor (TNF) inhibitor over tocilizumab as initial therapy because “the efficacy of tocilizumab in TAK is not established at this time.”
 

AAV guideline

Regarding the management and treatment of GPA, MPA, and EGPA, the guideline offers 41 recommendations and 10 ungraded position statements. All recommendations were conditional, and many address GPA and MPA together because, as the authors noted, “pivotal trials have enrolled both groups and presented results for these diseases together.”

One notable recommendation is their preference for rituximab over cyclophosphamide for remission induction and for rituximab over methotrexate or azathioprine for remission maintenance in patients with severe GPA or MPA. “I don’t think this is a surprise to people, but I think it reaffirms where our current practice is moving,” Dr. Chung said.

“The literature supports that in patients with relapsing disease, rituximab works better than cyclophosphamide for remission induction,” Dr. Spiera said. “But in these guidelines, even in new disease, rituximab is suggested as the agent of choice to induce remission. I would say that that is reasonable, but you could make an argument that it’s maybe beyond what the literature supports, particularly in patients with advanced renal insufficiency attributable to that initial vasculitis flare.”

Other recommendations include being against routinely adding plasma exchange to remission induction therapy in GPA or MPA patients with active glomerulonephritis – although they added that it should be considered in patients at high risk of end-stage kidney disease – as well as preferring cyclophosphamide or rituximab over mepolizumab for remission induction in patients with severe EGPA.

“We, to the surprise of many, were more supportive for the use of rituximab in EGPA than others were expecting, given the limited evidence,” Dr. Chung said. “One of the reasons for that is the wide experience we’ve had with rituximab in GPA and MPA, and our recognition that there is a population of patients with EGPA who are ANCA positive who do seem to benefit from rituximab therapy.”

And although the voting panel strongly favored treatment with methotrexate or azathioprine over trimethoprim/sulfamethoxazole for GPA patients in remission, they ultimately labeled the recommendation as conditional “due to the lack of sufficient high-quality evidence comparing the two treatments.”

“There has been progress in terms of well-done clinical trials to inform our decision-making, particularly for ANCA-associated vasculitis, both in terms of how to induce and maintain remission,” Dr. Spiera said. “Though the recommendations were conditional, I think there’s very strong data to support many of them.”

PAN guideline

Regarding the management and treatment of PAN, the guideline offers 16 recommendations – all but one are conditional – and one ungraded position statement. Their strong recommendation was for treatment with TNF inhibitors over GCs in patients with clinical manifestations of deficiency of adenosine deaminase 2, which they asked doctors to consider “in the setting of a PAN-like syndrome with strokes.” Other conditional recommendations include treating patients with newly diagnosed, severe PAN with cyclophosphamide and GCs, as well as the use of abdominal vascular imaging and/or a deep-skin biopsy to help establish a diagnosis.

According to the authors, a fourth guideline on treating and managing Kawasaki syndrome will be released in the coming weeks.

The guidelines were supported by the ACR and the Vasculitis Foundation. Several authors acknowledged potential conflicts of interest, including receiving speaking and consulting fees, research grants, and honoraria from various pharmaceutical companies. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, InflaRx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen.

Three new guidelines from the American College of Rheumatology, in partnership with the Vasculitis Foundation, offer evidence-based recommendations for managing and treating six different forms of systemic vasculitis.

“It’s not unusual for many rheumatologists to have fairly limited experience caring for patients with vasculitis,” coauthor Sharon Chung, MD, director of the Vasculitis Clinic at the University of California, San Francisco, said in an interview. “And with limited experience comes anxiety and concerns about whether or not one is treating patients appropriately. First and foremost, these guidelines are to help rheumatologists who may not have experience treating patients with vasculitides, to provide them with a framework they can use.”

The guidelines – the first to be produced and endorsed by both the ACR and the Vasculitis Foundation – were published July 8 in both Arthritis & Rheumatology and Arthritis Care & Research.

To assess the recent expansion in diagnostic and treatment options for various forms of vasculitis, the ACR assembled a literature review team, an 11-person patient panel, and a voting panel – made up of 9 adult rheumatologists, 5 pediatric rheumatologists, and 2 patients – to evaluate evidence, provide feedback, and formulate and vote on recommendations, respectively. The guidelines cover six types of vasculitis: one focusing on giant cell arteritis (GCA) and Takayasu arteritis (TAK); one on polyarteritis nodosa (PAN), and another on three forms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV): granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

As with other ACR guidelines, these three were developed via the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which was used to rate the quality of the gathered evidence. For a recommendation to be published, it required 70% consensus or greater from the voting panel.
 

GCA and TAK guideline

Regarding the management and treatment of GCA and TAK, the guideline offers 42 recommendations and three ungraded position statements. Due to the low quality of evidence – “reflecting the paucity of randomized clinical trials in these diseases,” the authors noted – only one of the GCA recommendations and one of the TAK recommendations are strong; the rest are conditional.

For patients with GCA, the guideline strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other notable recommendations include favoring oral glucocorticoids (GCs) with tocilizumab (Actemra) over oral glucocorticoids alone in newly diagnosed GCA, adding a non-GC immunosuppressive agent to oral GCs for GCA patients with active extracranial large vessel involvement, and preferring temporary artery biopsy as their “diagnostic test of choice at this time.”

“The Europeans generally are more comfortable relying on temporal artery ultrasound,” Robert F. Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery, New York, said in an interview. “In this country, possibly in part due to less uniform expertise in performing these ultrasounds, we have not had as much success in terms of accuracy.

These ACR guidelines therefore recommended biopsy to establish the diagnosis in patients with cranial presentations, whereas in the EULAR guidelines, ultrasound was felt to be preferable to biopsy.”

“While we have temporal artery ultrasound available in the United States, we just don’t have the expertise at this point to perform or interpret that test like the European rheumatologists do,” Dr. Chung agreed. “But I think we’re all hopeful that experience with temporal artery ultrasound will improve in the future, so we can use that test instead of an invasive biopsy.”

Dr. Spiera, who was not a coauthor on any of the guidelines, also highlighted the conditional recommendation of noninvasive vascular imaging of the large vessels in patients with newly diagnosed GCA.

“It is well recognized that a substantial portion of patients with GCA have unrecognized evidence of large vessel involvement, and patients with GCA in general are at higher risk of aneurysms later in the disease course,” he said. “These guidelines suggest screening even patients with purely cranial presentations for large vessel involvement with imaging to possibly identify the patients at higher risk for those later complications.

“What they didn’t offer were recommendations on how to follow up on that imaging,” he added, “which is an important and as-yet-unanswered question.”

For patients with TAK, the guideline again strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other conditional recommendations include choosing a non-GC immunosuppressive agent such as methotrexate or a tumor necrosis factor (TNF) inhibitor over tocilizumab as initial therapy because “the efficacy of tocilizumab in TAK is not established at this time.”
 

AAV guideline

Regarding the management and treatment of GPA, MPA, and EGPA, the guideline offers 41 recommendations and 10 ungraded position statements. All recommendations were conditional, and many address GPA and MPA together because, as the authors noted, “pivotal trials have enrolled both groups and presented results for these diseases together.”

One notable recommendation is their preference for rituximab over cyclophosphamide for remission induction and for rituximab over methotrexate or azathioprine for remission maintenance in patients with severe GPA or MPA. “I don’t think this is a surprise to people, but I think it reaffirms where our current practice is moving,” Dr. Chung said.

“The literature supports that in patients with relapsing disease, rituximab works better than cyclophosphamide for remission induction,” Dr. Spiera said. “But in these guidelines, even in new disease, rituximab is suggested as the agent of choice to induce remission. I would say that that is reasonable, but you could make an argument that it’s maybe beyond what the literature supports, particularly in patients with advanced renal insufficiency attributable to that initial vasculitis flare.”

Other recommendations include being against routinely adding plasma exchange to remission induction therapy in GPA or MPA patients with active glomerulonephritis – although they added that it should be considered in patients at high risk of end-stage kidney disease – as well as preferring cyclophosphamide or rituximab over mepolizumab for remission induction in patients with severe EGPA.

“We, to the surprise of many, were more supportive for the use of rituximab in EGPA than others were expecting, given the limited evidence,” Dr. Chung said. “One of the reasons for that is the wide experience we’ve had with rituximab in GPA and MPA, and our recognition that there is a population of patients with EGPA who are ANCA positive who do seem to benefit from rituximab therapy.”

And although the voting panel strongly favored treatment with methotrexate or azathioprine over trimethoprim/sulfamethoxazole for GPA patients in remission, they ultimately labeled the recommendation as conditional “due to the lack of sufficient high-quality evidence comparing the two treatments.”

“There has been progress in terms of well-done clinical trials to inform our decision-making, particularly for ANCA-associated vasculitis, both in terms of how to induce and maintain remission,” Dr. Spiera said. “Though the recommendations were conditional, I think there’s very strong data to support many of them.”

PAN guideline

Regarding the management and treatment of PAN, the guideline offers 16 recommendations – all but one are conditional – and one ungraded position statement. Their strong recommendation was for treatment with TNF inhibitors over GCs in patients with clinical manifestations of deficiency of adenosine deaminase 2, which they asked doctors to consider “in the setting of a PAN-like syndrome with strokes.” Other conditional recommendations include treating patients with newly diagnosed, severe PAN with cyclophosphamide and GCs, as well as the use of abdominal vascular imaging and/or a deep-skin biopsy to help establish a diagnosis.

According to the authors, a fourth guideline on treating and managing Kawasaki syndrome will be released in the coming weeks.

The guidelines were supported by the ACR and the Vasculitis Foundation. Several authors acknowledged potential conflicts of interest, including receiving speaking and consulting fees, research grants, and honoraria from various pharmaceutical companies. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, InflaRx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen.

Three new guidelines from the American College of Rheumatology, in partnership with the Vasculitis Foundation, offer evidence-based recommendations for managing and treating six different forms of systemic vasculitis.

“It’s not unusual for many rheumatologists to have fairly limited experience caring for patients with vasculitis,” coauthor Sharon Chung, MD, director of the Vasculitis Clinic at the University of California, San Francisco, said in an interview. “And with limited experience comes anxiety and concerns about whether or not one is treating patients appropriately. First and foremost, these guidelines are to help rheumatologists who may not have experience treating patients with vasculitides, to provide them with a framework they can use.”

The guidelines – the first to be produced and endorsed by both the ACR and the Vasculitis Foundation – were published July 8 in both Arthritis & Rheumatology and Arthritis Care & Research.

To assess the recent expansion in diagnostic and treatment options for various forms of vasculitis, the ACR assembled a literature review team, an 11-person patient panel, and a voting panel – made up of 9 adult rheumatologists, 5 pediatric rheumatologists, and 2 patients – to evaluate evidence, provide feedback, and formulate and vote on recommendations, respectively. The guidelines cover six types of vasculitis: one focusing on giant cell arteritis (GCA) and Takayasu arteritis (TAK); one on polyarteritis nodosa (PAN), and another on three forms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV): granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

As with other ACR guidelines, these three were developed via the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which was used to rate the quality of the gathered evidence. For a recommendation to be published, it required 70% consensus or greater from the voting panel.
 

GCA and TAK guideline

Regarding the management and treatment of GCA and TAK, the guideline offers 42 recommendations and three ungraded position statements. Due to the low quality of evidence – “reflecting the paucity of randomized clinical trials in these diseases,” the authors noted – only one of the GCA recommendations and one of the TAK recommendations are strong; the rest are conditional.

For patients with GCA, the guideline strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other notable recommendations include favoring oral glucocorticoids (GCs) with tocilizumab (Actemra) over oral glucocorticoids alone in newly diagnosed GCA, adding a non-GC immunosuppressive agent to oral GCs for GCA patients with active extracranial large vessel involvement, and preferring temporary artery biopsy as their “diagnostic test of choice at this time.”

“The Europeans generally are more comfortable relying on temporal artery ultrasound,” Robert F. Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery, New York, said in an interview. “In this country, possibly in part due to less uniform expertise in performing these ultrasounds, we have not had as much success in terms of accuracy.

These ACR guidelines therefore recommended biopsy to establish the diagnosis in patients with cranial presentations, whereas in the EULAR guidelines, ultrasound was felt to be preferable to biopsy.”

“While we have temporal artery ultrasound available in the United States, we just don’t have the expertise at this point to perform or interpret that test like the European rheumatologists do,” Dr. Chung agreed. “But I think we’re all hopeful that experience with temporal artery ultrasound will improve in the future, so we can use that test instead of an invasive biopsy.”

Dr. Spiera, who was not a coauthor on any of the guidelines, also highlighted the conditional recommendation of noninvasive vascular imaging of the large vessels in patients with newly diagnosed GCA.

“It is well recognized that a substantial portion of patients with GCA have unrecognized evidence of large vessel involvement, and patients with GCA in general are at higher risk of aneurysms later in the disease course,” he said. “These guidelines suggest screening even patients with purely cranial presentations for large vessel involvement with imaging to possibly identify the patients at higher risk for those later complications.

“What they didn’t offer were recommendations on how to follow up on that imaging,” he added, “which is an important and as-yet-unanswered question.”

For patients with TAK, the guideline again strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other conditional recommendations include choosing a non-GC immunosuppressive agent such as methotrexate or a tumor necrosis factor (TNF) inhibitor over tocilizumab as initial therapy because “the efficacy of tocilizumab in TAK is not established at this time.”
 

AAV guideline

Regarding the management and treatment of GPA, MPA, and EGPA, the guideline offers 41 recommendations and 10 ungraded position statements. All recommendations were conditional, and many address GPA and MPA together because, as the authors noted, “pivotal trials have enrolled both groups and presented results for these diseases together.”

One notable recommendation is their preference for rituximab over cyclophosphamide for remission induction and for rituximab over methotrexate or azathioprine for remission maintenance in patients with severe GPA or MPA. “I don’t think this is a surprise to people, but I think it reaffirms where our current practice is moving,” Dr. Chung said.

“The literature supports that in patients with relapsing disease, rituximab works better than cyclophosphamide for remission induction,” Dr. Spiera said. “But in these guidelines, even in new disease, rituximab is suggested as the agent of choice to induce remission. I would say that that is reasonable, but you could make an argument that it’s maybe beyond what the literature supports, particularly in patients with advanced renal insufficiency attributable to that initial vasculitis flare.”

Other recommendations include being against routinely adding plasma exchange to remission induction therapy in GPA or MPA patients with active glomerulonephritis – although they added that it should be considered in patients at high risk of end-stage kidney disease – as well as preferring cyclophosphamide or rituximab over mepolizumab for remission induction in patients with severe EGPA.

“We, to the surprise of many, were more supportive for the use of rituximab in EGPA than others were expecting, given the limited evidence,” Dr. Chung said. “One of the reasons for that is the wide experience we’ve had with rituximab in GPA and MPA, and our recognition that there is a population of patients with EGPA who are ANCA positive who do seem to benefit from rituximab therapy.”

And although the voting panel strongly favored treatment with methotrexate or azathioprine over trimethoprim/sulfamethoxazole for GPA patients in remission, they ultimately labeled the recommendation as conditional “due to the lack of sufficient high-quality evidence comparing the two treatments.”

“There has been progress in terms of well-done clinical trials to inform our decision-making, particularly for ANCA-associated vasculitis, both in terms of how to induce and maintain remission,” Dr. Spiera said. “Though the recommendations were conditional, I think there’s very strong data to support many of them.”

PAN guideline

Regarding the management and treatment of PAN, the guideline offers 16 recommendations – all but one are conditional – and one ungraded position statement. Their strong recommendation was for treatment with TNF inhibitors over GCs in patients with clinical manifestations of deficiency of adenosine deaminase 2, which they asked doctors to consider “in the setting of a PAN-like syndrome with strokes.” Other conditional recommendations include treating patients with newly diagnosed, severe PAN with cyclophosphamide and GCs, as well as the use of abdominal vascular imaging and/or a deep-skin biopsy to help establish a diagnosis.

According to the authors, a fourth guideline on treating and managing Kawasaki syndrome will be released in the coming weeks.

The guidelines were supported by the ACR and the Vasculitis Foundation. Several authors acknowledged potential conflicts of interest, including receiving speaking and consulting fees, research grants, and honoraria from various pharmaceutical companies. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, InflaRx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen.

The overactive bladder treatment mirabegron (Myrbetriq) is one of three new drugs to be linked to cases of drug-associated antineutrophil cytoplasmic antibody–associated vasculitis (DA-AAV) according to pharmacovigilance data.

Artfoliophoto/Thinkstock

The other two drugs are the antiviral agent sofosbuvir (Sovaldi) and the tyrosine kinase inhibitor nintedanib (Ofev), which is indicated for chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype.

The study findings also strengthen previously suspected associations, Samuel Deshayes, MD, of Caen (France) University Hospital and coauthors report in Arthritis & Rheumatology. This includes associations between hydralazine, propylthiouracil, thiamazole, minocycline, and carbimazole to name a few more of the 15 drugs where associations were found.

“These data imply specific prescriber attention to these drugs and argue for experimental studies on AAV pathophysiology with [the] recent drugs,” Dr. Deshayes and colleagues wrote.

Identifying whether AAV could be due to drug treatment is important as there have been suggestions that this may confer a better prognosis than for primary AAV. In addition, “withdrawal of the culprit drug” may be enough to treat the patient in milder cases, the researchers suggested.

That said, the researchers acknowledged that it can be difficult to attribute AAV to a specific drug, particularly as data are often from case reports or small series of patients and, until now, research had considered older medications.

To update current knowledge and include newer treatments, Dr. Deshayes and associates took data from the World Health Organization pharmacovigilance database (VigiBase) and performed a retrospective analysis.

They collected data on all adverse drug reactions (ADRs) reported using the Medical Dictionary for Drug Regulatory Activities preferred term ‘anti-neutrophil’ cytoplasmic antibody positive vasculitis’ from its introduction in 2006 up until November 2020.

Drugs used in the management of AAV, such as azathioprine, cyclophosphamide, leflunomide, and methotrexate, among others, were not included in the analysis “due to potential indication bias,” they explained.

Among 483 individual “deduplicated” case safety reports, most cases of DA-AAV were reported in women (71.2% of cases) and the median age at onset was 62 years. The median time to develop AAV after drug initiation was 9 months.

DA-AAV was considered serious in almost all (98%) of the reported cases, meaning that it was life-threatening, had resulted in or had prolonged hospital treatment, caused significant or persistent disability or other anomalies such as birth defects, or resulted in the death of the individual. With regard to the latter, DA-AAV was reported as fatal in 8.9% of cases.

The highest rates of reported DA-AAV were seen in people treated with the antihypertensive drug hydralazine, the antithyroid drugs propylthiouracil, thiamazole, and carbimazole, the antibiotic minocycline, mirabegron, sofosbuvir, and nintedanib.

A further seven drugs were also linked to cases of AAV, bringing the total to list to 15 drugs associated with overreporting of AAV. This included the heavy metal antagonist penicillamine, the influenza vaccine, the gout medication allopurinol, the anti-tuberculosis drug rifampin, the antiviral agent peginterferon alfa-2b, the anti-asthma drug montelukast, and the anti-cholesterol agent rosuvastatin.

Dr. Deshayes and coauthors pointed out that the associations do not imply causality. The data mining approach used allowed for the “automated detection of drug safety signals associated with rare events such as AAV,” they said.

There are limitations, they acknowledged, which are common to studies that use pharmacovigilance data. For one, “notoriety bias” could be at play. This is where there is an “increased number of reports after safety alerts in the media.” Missing data, “including delay between the introduction of the drug and AAV,” could be a factor, as could “bias related to its retrospective and declarative design.”

The study received no commercial funding. All study authors declared no competing interests.

The overactive bladder treatment mirabegron (Myrbetriq) is one of three new drugs to be linked to cases of drug-associated antineutrophil cytoplasmic antibody–associated vasculitis (DA-AAV) according to pharmacovigilance data.

Artfoliophoto/Thinkstock

The other two drugs are the antiviral agent sofosbuvir (Sovaldi) and the tyrosine kinase inhibitor nintedanib (Ofev), which is indicated for chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype.

The study findings also strengthen previously suspected associations, Samuel Deshayes, MD, of Caen (France) University Hospital and coauthors report in Arthritis & Rheumatology. This includes associations between hydralazine, propylthiouracil, thiamazole, minocycline, and carbimazole to name a few more of the 15 drugs where associations were found.

“These data imply specific prescriber attention to these drugs and argue for experimental studies on AAV pathophysiology with [the] recent drugs,” Dr. Deshayes and colleagues wrote.

Identifying whether AAV could be due to drug treatment is important as there have been suggestions that this may confer a better prognosis than for primary AAV. In addition, “withdrawal of the culprit drug” may be enough to treat the patient in milder cases, the researchers suggested.

That said, the researchers acknowledged that it can be difficult to attribute AAV to a specific drug, particularly as data are often from case reports or small series of patients and, until now, research had considered older medications.

To update current knowledge and include newer treatments, Dr. Deshayes and associates took data from the World Health Organization pharmacovigilance database (VigiBase) and performed a retrospective analysis.

They collected data on all adverse drug reactions (ADRs) reported using the Medical Dictionary for Drug Regulatory Activities preferred term ‘anti-neutrophil’ cytoplasmic antibody positive vasculitis’ from its introduction in 2006 up until November 2020.

Drugs used in the management of AAV, such as azathioprine, cyclophosphamide, leflunomide, and methotrexate, among others, were not included in the analysis “due to potential indication bias,” they explained.

Among 483 individual “deduplicated” case safety reports, most cases of DA-AAV were reported in women (71.2% of cases) and the median age at onset was 62 years. The median time to develop AAV after drug initiation was 9 months.

DA-AAV was considered serious in almost all (98%) of the reported cases, meaning that it was life-threatening, had resulted in or had prolonged hospital treatment, caused significant or persistent disability or other anomalies such as birth defects, or resulted in the death of the individual. With regard to the latter, DA-AAV was reported as fatal in 8.9% of cases.

The highest rates of reported DA-AAV were seen in people treated with the antihypertensive drug hydralazine, the antithyroid drugs propylthiouracil, thiamazole, and carbimazole, the antibiotic minocycline, mirabegron, sofosbuvir, and nintedanib.

A further seven drugs were also linked to cases of AAV, bringing the total to list to 15 drugs associated with overreporting of AAV. This included the heavy metal antagonist penicillamine, the influenza vaccine, the gout medication allopurinol, the anti-tuberculosis drug rifampin, the antiviral agent peginterferon alfa-2b, the anti-asthma drug montelukast, and the anti-cholesterol agent rosuvastatin.

Dr. Deshayes and coauthors pointed out that the associations do not imply causality. The data mining approach used allowed for the “automated detection of drug safety signals associated with rare events such as AAV,” they said.

There are limitations, they acknowledged, which are common to studies that use pharmacovigilance data. For one, “notoriety bias” could be at play. This is where there is an “increased number of reports after safety alerts in the media.” Missing data, “including delay between the introduction of the drug and AAV,” could be a factor, as could “bias related to its retrospective and declarative design.”

The study received no commercial funding. All study authors declared no competing interests.

The overactive bladder treatment mirabegron (Myrbetriq) is one of three new drugs to be linked to cases of drug-associated antineutrophil cytoplasmic antibody–associated vasculitis (DA-AAV) according to pharmacovigilance data.

Artfoliophoto/Thinkstock

The other two drugs are the antiviral agent sofosbuvir (Sovaldi) and the tyrosine kinase inhibitor nintedanib (Ofev), which is indicated for chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype.

The study findings also strengthen previously suspected associations, Samuel Deshayes, MD, of Caen (France) University Hospital and coauthors report in Arthritis & Rheumatology. This includes associations between hydralazine, propylthiouracil, thiamazole, minocycline, and carbimazole to name a few more of the 15 drugs where associations were found.

“These data imply specific prescriber attention to these drugs and argue for experimental studies on AAV pathophysiology with [the] recent drugs,” Dr. Deshayes and colleagues wrote.

Identifying whether AAV could be due to drug treatment is important as there have been suggestions that this may confer a better prognosis than for primary AAV. In addition, “withdrawal of the culprit drug” may be enough to treat the patient in milder cases, the researchers suggested.

That said, the researchers acknowledged that it can be difficult to attribute AAV to a specific drug, particularly as data are often from case reports or small series of patients and, until now, research had considered older medications.

To update current knowledge and include newer treatments, Dr. Deshayes and associates took data from the World Health Organization pharmacovigilance database (VigiBase) and performed a retrospective analysis.

They collected data on all adverse drug reactions (ADRs) reported using the Medical Dictionary for Drug Regulatory Activities preferred term ‘anti-neutrophil’ cytoplasmic antibody positive vasculitis’ from its introduction in 2006 up until November 2020.

Drugs used in the management of AAV, such as azathioprine, cyclophosphamide, leflunomide, and methotrexate, among others, were not included in the analysis “due to potential indication bias,” they explained.

Among 483 individual “deduplicated” case safety reports, most cases of DA-AAV were reported in women (71.2% of cases) and the median age at onset was 62 years. The median time to develop AAV after drug initiation was 9 months.

DA-AAV was considered serious in almost all (98%) of the reported cases, meaning that it was life-threatening, had resulted in or had prolonged hospital treatment, caused significant or persistent disability or other anomalies such as birth defects, or resulted in the death of the individual. With regard to the latter, DA-AAV was reported as fatal in 8.9% of cases.

The highest rates of reported DA-AAV were seen in people treated with the antihypertensive drug hydralazine, the antithyroid drugs propylthiouracil, thiamazole, and carbimazole, the antibiotic minocycline, mirabegron, sofosbuvir, and nintedanib.

A further seven drugs were also linked to cases of AAV, bringing the total to list to 15 drugs associated with overreporting of AAV. This included the heavy metal antagonist penicillamine, the influenza vaccine, the gout medication allopurinol, the anti-tuberculosis drug rifampin, the antiviral agent peginterferon alfa-2b, the anti-asthma drug montelukast, and the anti-cholesterol agent rosuvastatin.

Dr. Deshayes and coauthors pointed out that the associations do not imply causality. The data mining approach used allowed for the “automated detection of drug safety signals associated with rare events such as AAV,” they said.

There are limitations, they acknowledged, which are common to studies that use pharmacovigilance data. For one, “notoriety bias” could be at play. This is where there is an “increased number of reports after safety alerts in the media.” Missing data, “including delay between the introduction of the drug and AAV,” could be a factor, as could “bias related to its retrospective and declarative design.”

The study received no commercial funding. All study authors declared no competing interests.

Different kinds of neuropsychiatric (NP) events in patients with systemic lupus erythematosus (SLE) have substantial variability in their occurrence, resolution, and recurrence over time, as well as in their predictors, according to new research from a large, prospective, international, inception cohort study.

Because “multiple NP events due to different causes may present concurrently in individual patients, the findings emphasize the importance of recognizing attribution of NP events as a determinant of clinical outcome,” John G. Hanly, MD, of Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, N.S., and colleagues wrote in Arthritis & Rheumatology.

In a previous study of the same group of 1,827 patients with SLE, NP events occurred in about half and approximately one-third of these events were deemed disease related. They also “occurred most frequently around the diagnosis of SLE and had a significant negative impact on health-related quality of life,” the researchers wrote.

Researchers involved with the Systemic Lupus International Collaborating Clinics recruited the 1,827 adults with SLE over an 11-year period during 1999-2011 from a total of 31 sites in Europe, Asia, and North America. The average age of the patients at study enrollment was 35 years, 89% were women, and 49% were White. The mean disease duration was 5.6 months, and 70% of patients were taking corticosteroids at enrollment.

Over an average follow-up period of 7.6 years, 955 patients (52.3%) experienced a single neuropsychiatric event, and 493 (27.0%) experienced two or more events; the total number of unique NP events was 1,910. Most of these unique events (92%) involved the central nervous system, and 8.4% involved the peripheral nervous system.

The researchers used multistate models to attribute NP events to SLE based on factors that included the temporal onset of NP events in relation to SLE diagnosis, concurrent non-SLE factors, and NP events that are common in healthy controls. The four states in the multistate models were no NP events, no current NP event but a history of at least one event, new or ongoing NP events, and death. The results included a multivariate analysis of a model involving 492 observed transitions into new or ongoing NP events.

In the multivariate analysis, factors positively associated with SLE-attributed NP events included male sex (hazard ratio, 1.35; P = .028), concurrent non-SLE NP events excluding headache (HR, 1.83; P < .001), active SLE based on the Systemic Lupus Erythematosus Disease Activity Index 2000 (HR, 1.19; P = .012), and corticosteroid use (HR, 1.59; P = .008). The researchers also found that SLE-attributed NP events were negatively associated with Asian race/ethnicity, postsecondary education, and use of immunosuppressive drugs.

Another multivariate analysis found that non-SLE NP events were positively associated with only concurrent SLE-attributed NP events excluding headache (HR, 2.31; P < .001), but negative associations were seen with non-U.S. African race/ethnicity and Asian race/ethnicity.

The researchers found that SLE-attributed NP events had higher rates of resolution, compared with non-SLE NP events, with the exception of headache, which had similar resolution for both event groups.

“Resolution of SLE events was more likely in patients with Asian race/ethnicity and those with Central/Focal nervous system disease with no effect seen for age at diagnosis,” the researchers noted. “For non-SLE NP events, African race/ethnicity at non-U.S. sites and younger age at diagnosis was associated with a better outcome.”

The study findings were limited by several factors including the predominantly White patient population and the clustering of NP events into limited categories, which may have reduced the identification of more specific associations, the researchers noted. Also, the assessment of NP event outcomes did not include patient perceptions, and the relatively short follow-up period does not allow for assessment of later NP events such as cerebrovascular disease. However, “despite these limitations the current study provides valuable data on the presentation, outcome and predictors of NP disease in SLE patients enrolled in a long-term, international, disease inception cohort,” the researchers concluded.

The study received no outside funding. Dr. Hanly was supported by a grant from the Canadian Institutes of Health Research but had no financial conflicts to disclose. Several coauthors received grant support from various institutions, but not from industry, and had no financial conflicts to disclose.

Different kinds of neuropsychiatric (NP) events in patients with systemic lupus erythematosus (SLE) have substantial variability in their occurrence, resolution, and recurrence over time, as well as in their predictors, according to new research from a large, prospective, international, inception cohort study.

Because “multiple NP events due to different causes may present concurrently in individual patients, the findings emphasize the importance of recognizing attribution of NP events as a determinant of clinical outcome,” John G. Hanly, MD, of Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, N.S., and colleagues wrote in Arthritis & Rheumatology.

In a previous study of the same group of 1,827 patients with SLE, NP events occurred in about half and approximately one-third of these events were deemed disease related. They also “occurred most frequently around the diagnosis of SLE and had a significant negative impact on health-related quality of life,” the researchers wrote.

Researchers involved with the Systemic Lupus International Collaborating Clinics recruited the 1,827 adults with SLE over an 11-year period during 1999-2011 from a total of 31 sites in Europe, Asia, and North America. The average age of the patients at study enrollment was 35 years, 89% were women, and 49% were White. The mean disease duration was 5.6 months, and 70% of patients were taking corticosteroids at enrollment.

Over an average follow-up period of 7.6 years, 955 patients (52.3%) experienced a single neuropsychiatric event, and 493 (27.0%) experienced two or more events; the total number of unique NP events was 1,910. Most of these unique events (92%) involved the central nervous system, and 8.4% involved the peripheral nervous system.

The researchers used multistate models to attribute NP events to SLE based on factors that included the temporal onset of NP events in relation to SLE diagnosis, concurrent non-SLE factors, and NP events that are common in healthy controls. The four states in the multistate models were no NP events, no current NP event but a history of at least one event, new or ongoing NP events, and death. The results included a multivariate analysis of a model involving 492 observed transitions into new or ongoing NP events.

In the multivariate analysis, factors positively associated with SLE-attributed NP events included male sex (hazard ratio, 1.35; P = .028), concurrent non-SLE NP events excluding headache (HR, 1.83; P < .001), active SLE based on the Systemic Lupus Erythematosus Disease Activity Index 2000 (HR, 1.19; P = .012), and corticosteroid use (HR, 1.59; P = .008). The researchers also found that SLE-attributed NP events were negatively associated with Asian race/ethnicity, postsecondary education, and use of immunosuppressive drugs.

Another multivariate analysis found that non-SLE NP events were positively associated with only concurrent SLE-attributed NP events excluding headache (HR, 2.31; P < .001), but negative associations were seen with non-U.S. African race/ethnicity and Asian race/ethnicity.

The researchers found that SLE-attributed NP events had higher rates of resolution, compared with non-SLE NP events, with the exception of headache, which had similar resolution for both event groups.

“Resolution of SLE events was more likely in patients with Asian race/ethnicity and those with Central/Focal nervous system disease with no effect seen for age at diagnosis,” the researchers noted. “For non-SLE NP events, African race/ethnicity at non-U.S. sites and younger age at diagnosis was associated with a better outcome.”

The study findings were limited by several factors including the predominantly White patient population and the clustering of NP events into limited categories, which may have reduced the identification of more specific associations, the researchers noted. Also, the assessment of NP event outcomes did not include patient perceptions, and the relatively short follow-up period does not allow for assessment of later NP events such as cerebrovascular disease. However, “despite these limitations the current study provides valuable data on the presentation, outcome and predictors of NP disease in SLE patients enrolled in a long-term, international, disease inception cohort,” the researchers concluded.

The study received no outside funding. Dr. Hanly was supported by a grant from the Canadian Institutes of Health Research but had no financial conflicts to disclose. Several coauthors received grant support from various institutions, but not from industry, and had no financial conflicts to disclose.

Different kinds of neuropsychiatric (NP) events in patients with systemic lupus erythematosus (SLE) have substantial variability in their occurrence, resolution, and recurrence over time, as well as in their predictors, according to new research from a large, prospective, international, inception cohort study.

Because “multiple NP events due to different causes may present concurrently in individual patients, the findings emphasize the importance of recognizing attribution of NP events as a determinant of clinical outcome,” John G. Hanly, MD, of Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, N.S., and colleagues wrote in Arthritis & Rheumatology.

In a previous study of the same group of 1,827 patients with SLE, NP events occurred in about half and approximately one-third of these events were deemed disease related. They also “occurred most frequently around the diagnosis of SLE and had a significant negative impact on health-related quality of life,” the researchers wrote.

Researchers involved with the Systemic Lupus International Collaborating Clinics recruited the 1,827 adults with SLE over an 11-year period during 1999-2011 from a total of 31 sites in Europe, Asia, and North America. The average age of the patients at study enrollment was 35 years, 89% were women, and 49% were White. The mean disease duration was 5.6 months, and 70% of patients were taking corticosteroids at enrollment.

Over an average follow-up period of 7.6 years, 955 patients (52.3%) experienced a single neuropsychiatric event, and 493 (27.0%) experienced two or more events; the total number of unique NP events was 1,910. Most of these unique events (92%) involved the central nervous system, and 8.4% involved the peripheral nervous system.

The researchers used multistate models to attribute NP events to SLE based on factors that included the temporal onset of NP events in relation to SLE diagnosis, concurrent non-SLE factors, and NP events that are common in healthy controls. The four states in the multistate models were no NP events, no current NP event but a history of at least one event, new or ongoing NP events, and death. The results included a multivariate analysis of a model involving 492 observed transitions into new or ongoing NP events.

In the multivariate analysis, factors positively associated with SLE-attributed NP events included male sex (hazard ratio, 1.35; P = .028), concurrent non-SLE NP events excluding headache (HR, 1.83; P < .001), active SLE based on the Systemic Lupus Erythematosus Disease Activity Index 2000 (HR, 1.19; P = .012), and corticosteroid use (HR, 1.59; P = .008). The researchers also found that SLE-attributed NP events were negatively associated with Asian race/ethnicity, postsecondary education, and use of immunosuppressive drugs.

Another multivariate analysis found that non-SLE NP events were positively associated with only concurrent SLE-attributed NP events excluding headache (HR, 2.31; P < .001), but negative associations were seen with non-U.S. African race/ethnicity and Asian race/ethnicity.

The researchers found that SLE-attributed NP events had higher rates of resolution, compared with non-SLE NP events, with the exception of headache, which had similar resolution for both event groups.

“Resolution of SLE events was more likely in patients with Asian race/ethnicity and those with Central/Focal nervous system disease with no effect seen for age at diagnosis,” the researchers noted. “For non-SLE NP events, African race/ethnicity at non-U.S. sites and younger age at diagnosis was associated with a better outcome.”

The study findings were limited by several factors including the predominantly White patient population and the clustering of NP events into limited categories, which may have reduced the identification of more specific associations, the researchers noted. Also, the assessment of NP event outcomes did not include patient perceptions, and the relatively short follow-up period does not allow for assessment of later NP events such as cerebrovascular disease. However, “despite these limitations the current study provides valuable data on the presentation, outcome and predictors of NP disease in SLE patients enrolled in a long-term, international, disease inception cohort,” the researchers concluded.

The study received no outside funding. Dr. Hanly was supported by a grant from the Canadian Institutes of Health Research but had no financial conflicts to disclose. Several coauthors received grant support from various institutions, but not from industry, and had no financial conflicts to disclose.

Lupus images in medical resource materials underrepresent patients with skin of color, based on data from a review of more than 1,400 images published between 2014 and 2019 in materials from a university’s online medical library.

Courtesy Dr. Catalina Matiz

Patients with skin of color who develop lupus tend to present earlier and with more severe cases, and often experience worse outcomes, compared with other populations, wrote Amaad Rana, MD, of Washington University, St. Louis, and colleagues. Medical resources in general have historically underrepresented patients of color, and the researchers reviewed lupus materials for a similar publication bias.

In a study published in Arthritis Care & Research, the investigators identified 1,417 images in rheumatology, dermatology, and internal medicine resources, including 119 medical textbooks, 15 medical journals, 2 online image libraries, and the online image collections of Google and UpToDate. An additional 24 images came from skin of color atlases.

Excluding the skin of color atlases, 56.4% of the images represented light skin, 35.1% showed medium skin, and 8.5% showed dark skin. Overall, publishers were more than twice as likely to portray light skin tones and were significantly less likely to portray dark skin tones (odds ratios, 2.59 and 0.19, respectively), compared with an equal representation of skin tones; however, the difference was not significant for portrayal of medium skin tones (OR, 1.08).

By specialty, dermatology was more inclusive of skin of color images than rheumatology or internal medicine, although the internal medicine sample size was too small for comparable analysis, the researchers noted. Dermatology textbooks were 2.42 times more likely and rheumatology textbooks were 4.87 times more likely to depict light skin tones than an equal representation of light, medium, and dark skin tones.

The researchers rated the skin color in the images using the New Immigrant Survey Skin Color Scale and categorized the images as representing light (NISSCS scores, 1-2), medium (NISSCS scores, 3-5), or dark skin (NISSCS scores, 6-10). Medical journals had the most images of dark skin, excluding skin of color atlases. In a comparison of specialties, dermatology materials included the most images of medium and darker skin tones.

The underrepresentation of skin of color patients can contribute to a limited knowledge of lupus presentation that could lead to disparate health outcomes, the researchers noted.

The study findings were limited by several factors, including the review of only the online textbooks and journals available through the medical library of a single university, the researchers noted. In addition, definitions of light, medium, and dark skin tones were variable among studies, and the researchers did not distinguish among lupus pathologies.

“Further research is needed to quantitatively assess the influence these materials have on healthcare providers’ ability to care for patients with lupus and SOC, and new material and strategies will be required to correct this disparity and promote equitable representation,” the researchers emphasized. “Ultimately, this will arm practitioners with the resources to competently treat patients with any skin color and work towards reducing disparities in health outcomes.”

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

Lupus images in medical resource materials underrepresent patients with skin of color, based on data from a review of more than 1,400 images published between 2014 and 2019 in materials from a university’s online medical library.

Courtesy Dr. Catalina Matiz

Patients with skin of color who develop lupus tend to present earlier and with more severe cases, and often experience worse outcomes, compared with other populations, wrote Amaad Rana, MD, of Washington University, St. Louis, and colleagues. Medical resources in general have historically underrepresented patients of color, and the researchers reviewed lupus materials for a similar publication bias.

In a study published in Arthritis Care & Research, the investigators identified 1,417 images in rheumatology, dermatology, and internal medicine resources, including 119 medical textbooks, 15 medical journals, 2 online image libraries, and the online image collections of Google and UpToDate. An additional 24 images came from skin of color atlases.

Excluding the skin of color atlases, 56.4% of the images represented light skin, 35.1% showed medium skin, and 8.5% showed dark skin. Overall, publishers were more than twice as likely to portray light skin tones and were significantly less likely to portray dark skin tones (odds ratios, 2.59 and 0.19, respectively), compared with an equal representation of skin tones; however, the difference was not significant for portrayal of medium skin tones (OR, 1.08).

By specialty, dermatology was more inclusive of skin of color images than rheumatology or internal medicine, although the internal medicine sample size was too small for comparable analysis, the researchers noted. Dermatology textbooks were 2.42 times more likely and rheumatology textbooks were 4.87 times more likely to depict light skin tones than an equal representation of light, medium, and dark skin tones.

The researchers rated the skin color in the images using the New Immigrant Survey Skin Color Scale and categorized the images as representing light (NISSCS scores, 1-2), medium (NISSCS scores, 3-5), or dark skin (NISSCS scores, 6-10). Medical journals had the most images of dark skin, excluding skin of color atlases. In a comparison of specialties, dermatology materials included the most images of medium and darker skin tones.

The underrepresentation of skin of color patients can contribute to a limited knowledge of lupus presentation that could lead to disparate health outcomes, the researchers noted.

The study findings were limited by several factors, including the review of only the online textbooks and journals available through the medical library of a single university, the researchers noted. In addition, definitions of light, medium, and dark skin tones were variable among studies, and the researchers did not distinguish among lupus pathologies.

“Further research is needed to quantitatively assess the influence these materials have on healthcare providers’ ability to care for patients with lupus and SOC, and new material and strategies will be required to correct this disparity and promote equitable representation,” the researchers emphasized. “Ultimately, this will arm practitioners with the resources to competently treat patients with any skin color and work towards reducing disparities in health outcomes.”

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

Lupus images in medical resource materials underrepresent patients with skin of color, based on data from a review of more than 1,400 images published between 2014 and 2019 in materials from a university’s online medical library.

Courtesy Dr. Catalina Matiz

Patients with skin of color who develop lupus tend to present earlier and with more severe cases, and often experience worse outcomes, compared with other populations, wrote Amaad Rana, MD, of Washington University, St. Louis, and colleagues. Medical resources in general have historically underrepresented patients of color, and the researchers reviewed lupus materials for a similar publication bias.

In a study published in Arthritis Care & Research, the investigators identified 1,417 images in rheumatology, dermatology, and internal medicine resources, including 119 medical textbooks, 15 medical journals, 2 online image libraries, and the online image collections of Google and UpToDate. An additional 24 images came from skin of color atlases.

Excluding the skin of color atlases, 56.4% of the images represented light skin, 35.1% showed medium skin, and 8.5% showed dark skin. Overall, publishers were more than twice as likely to portray light skin tones and were significantly less likely to portray dark skin tones (odds ratios, 2.59 and 0.19, respectively), compared with an equal representation of skin tones; however, the difference was not significant for portrayal of medium skin tones (OR, 1.08).

By specialty, dermatology was more inclusive of skin of color images than rheumatology or internal medicine, although the internal medicine sample size was too small for comparable analysis, the researchers noted. Dermatology textbooks were 2.42 times more likely and rheumatology textbooks were 4.87 times more likely to depict light skin tones than an equal representation of light, medium, and dark skin tones.

The researchers rated the skin color in the images using the New Immigrant Survey Skin Color Scale and categorized the images as representing light (NISSCS scores, 1-2), medium (NISSCS scores, 3-5), or dark skin (NISSCS scores, 6-10). Medical journals had the most images of dark skin, excluding skin of color atlases. In a comparison of specialties, dermatology materials included the most images of medium and darker skin tones.

The underrepresentation of skin of color patients can contribute to a limited knowledge of lupus presentation that could lead to disparate health outcomes, the researchers noted.

The study findings were limited by several factors, including the review of only the online textbooks and journals available through the medical library of a single university, the researchers noted. In addition, definitions of light, medium, and dark skin tones were variable among studies, and the researchers did not distinguish among lupus pathologies.

“Further research is needed to quantitatively assess the influence these materials have on healthcare providers’ ability to care for patients with lupus and SOC, and new material and strategies will be required to correct this disparity and promote equitable representation,” the researchers emphasized. “Ultimately, this will arm practitioners with the resources to competently treat patients with any skin color and work towards reducing disparities in health outcomes.”

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

Quantitative assessment of the extent of interstitial lung disease in patients with systemic sclerosis and levels of certain proteins in bronchoalveolar lavage samples have potential for predicting mortality and disease progression, according to two analyses of data from the Scleroderma Lung Study I and II.

The analyses, presented at the annual European Congress of Rheumatology, aim to improve current prognostic abilities in patients with systemic sclerosis–interstitial lung disease (SSc-ILD). Although forced vital capacity is commonly used as a biomarker for survival in many SSc-ILD trials, other factors can affect FVC, such as respiratory muscle weakness and skin fibrosis. Further, FVC correlates poorly with patient-reported outcomes, explained first author Elizabeth Volkmann, MD, director of the scleroderma program at the University of California, Los Angeles, and the founder and codirector of the UCLA connective tissue disease–related interstitial lung disease program.

Dr. Volkmann presented two studies that investigated the potential of radiographic and protein biomarkers for predicting mortality and identifying patients at risk for ILD progression. The biomarkers may also help to identify patients who would benefit most from immunosuppressive therapy.

The first study found that tracking the quantitative extent of ILD (QILD) over time with high-resolution CT (HRCT) predicted poorer outcomes and could therefore act as a surrogate endpoint for mortality among patients with SSc-ILD. The other study identified associations between specific proteins from bronchoalveolar lavage (BAL) and the likelihood of ILD progression, although some associations were treatment dependent.

Jacob M. van Laar, MD, PhD, professor of rheumatology at the University Medical Center Utrecht (the Netherlands), who was not involved in the study, found the results intriguing and noted the importance of further validation in research before these biomarkers are considered for clinical use.

“It would be wonderful if we can tailor therapy based on BAL biomarkers in the future, as clinicians often struggle to decide on selection, timing, and duration of immunosuppressive treatment,” Dr. van Laar told this news organization. “This has become even more relevant with the introduction of new drugs such as nintedanib.”
 

Extent of ILD progression as a surrogate for mortality

Scleroderma Lung Study I involved 158 patients with SSc-ILD who were randomly assigned to receive either cyclophosphamide or placebo for 12 months. Scleroderma Lung Study II included 142 patients with SSc-ILD who were randomly assigned to receive either mycophenolate for 24 months or cyclophosphamide for 12 months followed by placebo for 12 months.

The researchers calculated QILD in the whole lung at baseline, at 12 months in the first trial, and at 24 months in the second trial. However, only 82 participants from the first trial and 90 participants from the second trial underwent HRCT. Demographic and disease characteristics were similar between the two groups on follow-up scans.

Follow-up continued for 12 years for patients in the first trial and 8 years in the second. The researchers compared survival rates between the 41% of participants from the first study and 31% of participants from the second study who had poorer QILD scores (at least a 2% increase) with the participants who had stable or improved scores (less than 2% increase).

Participants from both trials had significantly poorer long-term survival if their QILD scores had increased by at least 2% at follow-up (P = .01 for I; P = .019 for II). The association was no longer significant after adjustment for baseline FVC, age, and modified Rodnan skin score in the first trial (hazard ratio, 1.98; P = .089), but it remained significant for participants of the second trial (HR, 3.86; P = .014).

“Data from two independent trial cohorts demonstrated that radiographic progression of SSc-ILD at 1 and 2 years is associated with worse long-term survival,” Dr. Volkmann told attendees.

However, FVC did not significantly predict risk of mortality in either trial.

“To me, the most striking finding from the first study was that change in QILD performed better as a predictor of survival than change in FVC,” Dr. van Laar said in an interview. “This indicates QILD is fit for purpose and worth including in future clinical trials.”

Limitations of the study included lack of HRCT for all participants in the trials and the difference in timing (1 year and 2 years) of HRCT assessment between the two trials. The greater hazard ratio for worsened QILD in the second trial may suggest that assessment at 2 years provides more reliable data as a biomarker, Dr. Volkmann said.

“QILD may represent a better proxy for how a patient feels, functions, and survives than FVC,” she said.
 

Treatment-dependent biomarkers for worsening lung fibrosis

In the second study, the researchers looked for any associations between changes in the radiographic extent of SSc-ILD and 68 proteins from BAL.

“Being able to risk-stratify patients with interstitial lung disease at the time of diagnosis and predict which patients are likely to have a stable versus progressive disease course is critical for making important treatment decisions for these patients,” Dr. Volkmann told attendees.

The second study she presented involved Scleroderma Lung Study I. Of the 158 participants, 144 underwent a bronchoscopy, yielding BAL protein samples from 103 participants. The researchers determined the extent of radiographic fibrosis in the whole lung with quantitative imaging analysis of HRCT of the chest at baseline and 12 months.

Although the researchers identified several statistically significant associations between certain proteins and changes in radiographic fibrosis, “baseline protein levels were differentially associated with the course of ILD based on treatment status,” she told attendees.

For example, increased levels of the following proteins were linked to poor radiographic fibrosis scores for patients who received placebo:

• Granulocyte-macrophage colony-stimulating factor
• Interleukin-1
• Monocyte chemoattractant protein–3
• Chemokine ligand–5
• Transforming growth factor–beta
• Hepatocyte growth factor
• Stem cell factor
• IL-4
• TGF-alpha

Yet increases in these proteins predicted improvement in radiographic fibrosis in patients who had taken cyclophosphamide.

Independently of treatment, the researchers also identified an association between higher levels of fractalkine and poorer radiographic fibrosis scores and between higher IL-7 levels and improved radiographic fibrosis scores.

After adjusting for treatment arm and baseline severity of ILD, significant associations remained between change in radiographic fibrosis score and IL-1, MCP-3, surfactant protein C, IL-7 and CCL-5 levels.

“Biomarker discovery is really central to our ability to risk stratify patients with SSc-ILD,” Dr. Volkmann told attendees. “Understanding how biomarkers predict outcomes in treated and untreated patients may improve personalized medicine to patients with SSc-ILD and could also reveal novel treatment targets.”

Dr. van Laar said in an interview that this study’s biggest strength lay in its large sample size and in the comprehensiveness of the biomarkers studied.

“The findings are interesting from a research perspective and potentially relevant for clinical practice, but the utility of measuring biomarkers in BAL should be further studied for predictive value on clinical endpoints,” Dr. van Laar said. “BAL is an invasive procedure [that] is not routinely done.”

The research was funded by the National Institutes of Health. Dr. Volkmann has consulted for Boehringer Ingelheim and received grant funding from Corbus, Forbius, and Kadmon. Dr. van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Quantitative assessment of the extent of interstitial lung disease in patients with systemic sclerosis and levels of certain proteins in bronchoalveolar lavage samples have potential for predicting mortality and disease progression, according to two analyses of data from the Scleroderma Lung Study I and II.

The analyses, presented at the annual European Congress of Rheumatology, aim to improve current prognostic abilities in patients with systemic sclerosis–interstitial lung disease (SSc-ILD). Although forced vital capacity is commonly used as a biomarker for survival in many SSc-ILD trials, other factors can affect FVC, such as respiratory muscle weakness and skin fibrosis. Further, FVC correlates poorly with patient-reported outcomes, explained first author Elizabeth Volkmann, MD, director of the scleroderma program at the University of California, Los Angeles, and the founder and codirector of the UCLA connective tissue disease–related interstitial lung disease program.

Dr. Volkmann presented two studies that investigated the potential of radiographic and protein biomarkers for predicting mortality and identifying patients at risk for ILD progression. The biomarkers may also help to identify patients who would benefit most from immunosuppressive therapy.

The first study found that tracking the quantitative extent of ILD (QILD) over time with high-resolution CT (HRCT) predicted poorer outcomes and could therefore act as a surrogate endpoint for mortality among patients with SSc-ILD. The other study identified associations between specific proteins from bronchoalveolar lavage (BAL) and the likelihood of ILD progression, although some associations were treatment dependent.

Jacob M. van Laar, MD, PhD, professor of rheumatology at the University Medical Center Utrecht (the Netherlands), who was not involved in the study, found the results intriguing and noted the importance of further validation in research before these biomarkers are considered for clinical use.

“It would be wonderful if we can tailor therapy based on BAL biomarkers in the future, as clinicians often struggle to decide on selection, timing, and duration of immunosuppressive treatment,” Dr. van Laar told this news organization. “This has become even more relevant with the introduction of new drugs such as nintedanib.”
 

Extent of ILD progression as a surrogate for mortality

Scleroderma Lung Study I involved 158 patients with SSc-ILD who were randomly assigned to receive either cyclophosphamide or placebo for 12 months. Scleroderma Lung Study II included 142 patients with SSc-ILD who were randomly assigned to receive either mycophenolate for 24 months or cyclophosphamide for 12 months followed by placebo for 12 months.

The researchers calculated QILD in the whole lung at baseline, at 12 months in the first trial, and at 24 months in the second trial. However, only 82 participants from the first trial and 90 participants from the second trial underwent HRCT. Demographic and disease characteristics were similar between the two groups on follow-up scans.

Follow-up continued for 12 years for patients in the first trial and 8 years in the second. The researchers compared survival rates between the 41% of participants from the first study and 31% of participants from the second study who had poorer QILD scores (at least a 2% increase) with the participants who had stable or improved scores (less than 2% increase).

Participants from both trials had significantly poorer long-term survival if their QILD scores had increased by at least 2% at follow-up (P = .01 for I; P = .019 for II). The association was no longer significant after adjustment for baseline FVC, age, and modified Rodnan skin score in the first trial (hazard ratio, 1.98; P = .089), but it remained significant for participants of the second trial (HR, 3.86; P = .014).

“Data from two independent trial cohorts demonstrated that radiographic progression of SSc-ILD at 1 and 2 years is associated with worse long-term survival,” Dr. Volkmann told attendees.

However, FVC did not significantly predict risk of mortality in either trial.

“To me, the most striking finding from the first study was that change in QILD performed better as a predictor of survival than change in FVC,” Dr. van Laar said in an interview. “This indicates QILD is fit for purpose and worth including in future clinical trials.”

Limitations of the study included lack of HRCT for all participants in the trials and the difference in timing (1 year and 2 years) of HRCT assessment between the two trials. The greater hazard ratio for worsened QILD in the second trial may suggest that assessment at 2 years provides more reliable data as a biomarker, Dr. Volkmann said.

“QILD may represent a better proxy for how a patient feels, functions, and survives than FVC,” she said.
 

Treatment-dependent biomarkers for worsening lung fibrosis

In the second study, the researchers looked for any associations between changes in the radiographic extent of SSc-ILD and 68 proteins from BAL.

“Being able to risk-stratify patients with interstitial lung disease at the time of diagnosis and predict which patients are likely to have a stable versus progressive disease course is critical for making important treatment decisions for these patients,” Dr. Volkmann told attendees.

The second study she presented involved Scleroderma Lung Study I. Of the 158 participants, 144 underwent a bronchoscopy, yielding BAL protein samples from 103 participants. The researchers determined the extent of radiographic fibrosis in the whole lung with quantitative imaging analysis of HRCT of the chest at baseline and 12 months.

Although the researchers identified several statistically significant associations between certain proteins and changes in radiographic fibrosis, “baseline protein levels were differentially associated with the course of ILD based on treatment status,” she told attendees.

For example, increased levels of the following proteins were linked to poor radiographic fibrosis scores for patients who received placebo:

• Granulocyte-macrophage colony-stimulating factor
• Interleukin-1
• Monocyte chemoattractant protein–3
• Chemokine ligand–5
• Transforming growth factor–beta
• Hepatocyte growth factor
• Stem cell factor
• IL-4
• TGF-alpha

Yet increases in these proteins predicted improvement in radiographic fibrosis in patients who had taken cyclophosphamide.

Independently of treatment, the researchers also identified an association between higher levels of fractalkine and poorer radiographic fibrosis scores and between higher IL-7 levels and improved radiographic fibrosis scores.

After adjusting for treatment arm and baseline severity of ILD, significant associations remained between change in radiographic fibrosis score and IL-1, MCP-3, surfactant protein C, IL-7 and CCL-5 levels.

“Biomarker discovery is really central to our ability to risk stratify patients with SSc-ILD,” Dr. Volkmann told attendees. “Understanding how biomarkers predict outcomes in treated and untreated patients may improve personalized medicine to patients with SSc-ILD and could also reveal novel treatment targets.”

Dr. van Laar said in an interview that this study’s biggest strength lay in its large sample size and in the comprehensiveness of the biomarkers studied.

“The findings are interesting from a research perspective and potentially relevant for clinical practice, but the utility of measuring biomarkers in BAL should be further studied for predictive value on clinical endpoints,” Dr. van Laar said. “BAL is an invasive procedure [that] is not routinely done.”

The research was funded by the National Institutes of Health. Dr. Volkmann has consulted for Boehringer Ingelheim and received grant funding from Corbus, Forbius, and Kadmon. Dr. van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Quantitative assessment of the extent of interstitial lung disease in patients with systemic sclerosis and levels of certain proteins in bronchoalveolar lavage samples have potential for predicting mortality and disease progression, according to two analyses of data from the Scleroderma Lung Study I and II.

The analyses, presented at the annual European Congress of Rheumatology, aim to improve current prognostic abilities in patients with systemic sclerosis–interstitial lung disease (SSc-ILD). Although forced vital capacity is commonly used as a biomarker for survival in many SSc-ILD trials, other factors can affect FVC, such as respiratory muscle weakness and skin fibrosis. Further, FVC correlates poorly with patient-reported outcomes, explained first author Elizabeth Volkmann, MD, director of the scleroderma program at the University of California, Los Angeles, and the founder and codirector of the UCLA connective tissue disease–related interstitial lung disease program.

Dr. Volkmann presented two studies that investigated the potential of radiographic and protein biomarkers for predicting mortality and identifying patients at risk for ILD progression. The biomarkers may also help to identify patients who would benefit most from immunosuppressive therapy.

The first study found that tracking the quantitative extent of ILD (QILD) over time with high-resolution CT (HRCT) predicted poorer outcomes and could therefore act as a surrogate endpoint for mortality among patients with SSc-ILD. The other study identified associations between specific proteins from bronchoalveolar lavage (BAL) and the likelihood of ILD progression, although some associations were treatment dependent.

Jacob M. van Laar, MD, PhD, professor of rheumatology at the University Medical Center Utrecht (the Netherlands), who was not involved in the study, found the results intriguing and noted the importance of further validation in research before these biomarkers are considered for clinical use.

“It would be wonderful if we can tailor therapy based on BAL biomarkers in the future, as clinicians often struggle to decide on selection, timing, and duration of immunosuppressive treatment,” Dr. van Laar told this news organization. “This has become even more relevant with the introduction of new drugs such as nintedanib.”
 

Extent of ILD progression as a surrogate for mortality

Scleroderma Lung Study I involved 158 patients with SSc-ILD who were randomly assigned to receive either cyclophosphamide or placebo for 12 months. Scleroderma Lung Study II included 142 patients with SSc-ILD who were randomly assigned to receive either mycophenolate for 24 months or cyclophosphamide for 12 months followed by placebo for 12 months.

The researchers calculated QILD in the whole lung at baseline, at 12 months in the first trial, and at 24 months in the second trial. However, only 82 participants from the first trial and 90 participants from the second trial underwent HRCT. Demographic and disease characteristics were similar between the two groups on follow-up scans.

Follow-up continued for 12 years for patients in the first trial and 8 years in the second. The researchers compared survival rates between the 41% of participants from the first study and 31% of participants from the second study who had poorer QILD scores (at least a 2% increase) with the participants who had stable or improved scores (less than 2% increase).

Participants from both trials had significantly poorer long-term survival if their QILD scores had increased by at least 2% at follow-up (P = .01 for I; P = .019 for II). The association was no longer significant after adjustment for baseline FVC, age, and modified Rodnan skin score in the first trial (hazard ratio, 1.98; P = .089), but it remained significant for participants of the second trial (HR, 3.86; P = .014).

“Data from two independent trial cohorts demonstrated that radiographic progression of SSc-ILD at 1 and 2 years is associated with worse long-term survival,” Dr. Volkmann told attendees.

However, FVC did not significantly predict risk of mortality in either trial.

“To me, the most striking finding from the first study was that change in QILD performed better as a predictor of survival than change in FVC,” Dr. van Laar said in an interview. “This indicates QILD is fit for purpose and worth including in future clinical trials.”

Limitations of the study included lack of HRCT for all participants in the trials and the difference in timing (1 year and 2 years) of HRCT assessment between the two trials. The greater hazard ratio for worsened QILD in the second trial may suggest that assessment at 2 years provides more reliable data as a biomarker, Dr. Volkmann said.

“QILD may represent a better proxy for how a patient feels, functions, and survives than FVC,” she said.
 

Treatment-dependent biomarkers for worsening lung fibrosis

In the second study, the researchers looked for any associations between changes in the radiographic extent of SSc-ILD and 68 proteins from BAL.

“Being able to risk-stratify patients with interstitial lung disease at the time of diagnosis and predict which patients are likely to have a stable versus progressive disease course is critical for making important treatment decisions for these patients,” Dr. Volkmann told attendees.

The second study she presented involved Scleroderma Lung Study I. Of the 158 participants, 144 underwent a bronchoscopy, yielding BAL protein samples from 103 participants. The researchers determined the extent of radiographic fibrosis in the whole lung with quantitative imaging analysis of HRCT of the chest at baseline and 12 months.

Although the researchers identified several statistically significant associations between certain proteins and changes in radiographic fibrosis, “baseline protein levels were differentially associated with the course of ILD based on treatment status,” she told attendees.

For example, increased levels of the following proteins were linked to poor radiographic fibrosis scores for patients who received placebo:

• Granulocyte-macrophage colony-stimulating factor
• Interleukin-1
• Monocyte chemoattractant protein–3
• Chemokine ligand–5
• Transforming growth factor–beta
• Hepatocyte growth factor
• Stem cell factor
• IL-4
• TGF-alpha

Yet increases in these proteins predicted improvement in radiographic fibrosis in patients who had taken cyclophosphamide.

Independently of treatment, the researchers also identified an association between higher levels of fractalkine and poorer radiographic fibrosis scores and between higher IL-7 levels and improved radiographic fibrosis scores.

After adjusting for treatment arm and baseline severity of ILD, significant associations remained between change in radiographic fibrosis score and IL-1, MCP-3, surfactant protein C, IL-7 and CCL-5 levels.

“Biomarker discovery is really central to our ability to risk stratify patients with SSc-ILD,” Dr. Volkmann told attendees. “Understanding how biomarkers predict outcomes in treated and untreated patients may improve personalized medicine to patients with SSc-ILD and could also reveal novel treatment targets.”

Dr. van Laar said in an interview that this study’s biggest strength lay in its large sample size and in the comprehensiveness of the biomarkers studied.

“The findings are interesting from a research perspective and potentially relevant for clinical practice, but the utility of measuring biomarkers in BAL should be further studied for predictive value on clinical endpoints,” Dr. van Laar said. “BAL is an invasive procedure [that] is not routinely done.”

The research was funded by the National Institutes of Health. Dr. Volkmann has consulted for Boehringer Ingelheim and received grant funding from Corbus, Forbius, and Kadmon. Dr. van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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