Spondyloarthropathies

A new protocol designed to help patients in rheumatology clinics quit smoking proved both efficient and effective in referring willing participants to free tobacco quit lines.

seanika/ThinkStock

“Rheumatology visits provide a unique opportunity to address smoking as a chronic modifiable risk factor in populations at high risk for cardiovascular disease, pulmonary disease, and rheumatic disease progression,” wrote Christie M. Bartels, MD, chief of the division of rheumatology at the University of Wisconsin, Madison, and colleagues. The study was published in Arthritis Care & Research.

To assess the effectiveness of implementing a smoking cessation protocol for patients with rheumatic diseases, the researchers launched a quasi-experimental cohort study in which their Quit Connect protocol was tested at three rheumatology clinics. Adapting the Ask, Advise, Connect primary care protocol to a new setting, nurses and medical assistants were trained to use electronic health record (EHR) prompts that would check if patients who smoked were ready to quit within 30 days, advise them to do so, and then use electronic referrals to connect them to state-run tobacco quit lines. An extended baseline period – October 2012 to March 2016 – was compared to a 6-month intervention period from April to October 2016.

Across 54,090 pre- and postimplementation rheumatology clinic visits, 4,601 were with current smokers. Demographics were similar across both periods: The mean age of the patients was 51 years, about two-thirds were female, and 85% were White.

Clinicians’ assessment of tobacco use before and after implementation of the program stayed steady at 96% of patient visits, but the percentage of tobacco users’ visits that included checking for readiness to quit within the next 30 days rose from 3% (135 of 4,078) to 80% (421 of 523).

Before the implementation of the program, 0.6% of eligible visits with current smokers included a quit-line referral offer. After implementation, 93 (18%) of the 523 smokers who visited – 122 of whom said they were ready to quit – were offered referrals, a 26-fold increase. Of the 93 offered referrals, 66 (71%) accepted and 16 set a quit date or reported having quit; 11 accepted counseling services and nicotine replacement.

Although clinic staff reported encountering several obstacles, such as the need to craft nonthreatening language for challenging patients, they also contributed their own talking points that were included in the EHR tools and desktop brochures. On average, the protocol took less than 90 seconds to perform.

Rheumatologists can make headway on patients quitting smoking

“While smoking cessation programs require time and resources to implement, this study suggests a role for evidence-based protocols within rheumatology centers,” Medha Barbhaiya, MD, a rheumatologist at the Hospital for Special Surgery in New York, said in an interview. “Given that current smokers are at an increased risk of developing more severe rheumatic disease and cardiovascular disease, and patients often visit their rheumatologist multiple times yearly, rheumatologists may be well-positioned to address smoking cessation with patients.”

In regard to next steps, she noted that “while future large studies in diverse cohorts are needed to confirm these findings, implementing a formal smoking cessation protocol within rheumatology centers may provide a unique opportunity for rheumatologists to directly help patients modify their disease risk, leading to improved health outcomes.”

The authors acknowledged their study’s limitations, including the fact that it was a prepost design and not a randomized trial. They also recognized that many tobacco users require 8-10 attempts before permanently quitting, likely lessening the lasting impact of the short-term study. They did cite expert analysis, however, that says “connecting patients to evidence-based resources makes them more likely to permanently quit.”

The study was supported in part by Pfizer’s office of Independent Grants for Learning and Change and by a grant collaboration from the University of Wisconsin Clinical and Translational Science Award and the University of Wisconsin School of Medicine and Public Health’s Wisconsin Partnership Program, through the NIH National Center for Advancing Translational Sciences.

A new protocol designed to help patients in rheumatology clinics quit smoking proved both efficient and effective in referring willing participants to free tobacco quit lines.

seanika/ThinkStock

“Rheumatology visits provide a unique opportunity to address smoking as a chronic modifiable risk factor in populations at high risk for cardiovascular disease, pulmonary disease, and rheumatic disease progression,” wrote Christie M. Bartels, MD, chief of the division of rheumatology at the University of Wisconsin, Madison, and colleagues. The study was published in Arthritis Care & Research.

To assess the effectiveness of implementing a smoking cessation protocol for patients with rheumatic diseases, the researchers launched a quasi-experimental cohort study in which their Quit Connect protocol was tested at three rheumatology clinics. Adapting the Ask, Advise, Connect primary care protocol to a new setting, nurses and medical assistants were trained to use electronic health record (EHR) prompts that would check if patients who smoked were ready to quit within 30 days, advise them to do so, and then use electronic referrals to connect them to state-run tobacco quit lines. An extended baseline period – October 2012 to March 2016 – was compared to a 6-month intervention period from April to October 2016.

Across 54,090 pre- and postimplementation rheumatology clinic visits, 4,601 were with current smokers. Demographics were similar across both periods: The mean age of the patients was 51 years, about two-thirds were female, and 85% were White.

Clinicians’ assessment of tobacco use before and after implementation of the program stayed steady at 96% of patient visits, but the percentage of tobacco users’ visits that included checking for readiness to quit within the next 30 days rose from 3% (135 of 4,078) to 80% (421 of 523).

Before the implementation of the program, 0.6% of eligible visits with current smokers included a quit-line referral offer. After implementation, 93 (18%) of the 523 smokers who visited – 122 of whom said they were ready to quit – were offered referrals, a 26-fold increase. Of the 93 offered referrals, 66 (71%) accepted and 16 set a quit date or reported having quit; 11 accepted counseling services and nicotine replacement.

Although clinic staff reported encountering several obstacles, such as the need to craft nonthreatening language for challenging patients, they also contributed their own talking points that were included in the EHR tools and desktop brochures. On average, the protocol took less than 90 seconds to perform.

Rheumatologists can make headway on patients quitting smoking

“While smoking cessation programs require time and resources to implement, this study suggests a role for evidence-based protocols within rheumatology centers,” Medha Barbhaiya, MD, a rheumatologist at the Hospital for Special Surgery in New York, said in an interview. “Given that current smokers are at an increased risk of developing more severe rheumatic disease and cardiovascular disease, and patients often visit their rheumatologist multiple times yearly, rheumatologists may be well-positioned to address smoking cessation with patients.”

In regard to next steps, she noted that “while future large studies in diverse cohorts are needed to confirm these findings, implementing a formal smoking cessation protocol within rheumatology centers may provide a unique opportunity for rheumatologists to directly help patients modify their disease risk, leading to improved health outcomes.”

The authors acknowledged their study’s limitations, including the fact that it was a prepost design and not a randomized trial. They also recognized that many tobacco users require 8-10 attempts before permanently quitting, likely lessening the lasting impact of the short-term study. They did cite expert analysis, however, that says “connecting patients to evidence-based resources makes them more likely to permanently quit.”

The study was supported in part by Pfizer’s office of Independent Grants for Learning and Change and by a grant collaboration from the University of Wisconsin Clinical and Translational Science Award and the University of Wisconsin School of Medicine and Public Health’s Wisconsin Partnership Program, through the NIH National Center for Advancing Translational Sciences.

A new protocol designed to help patients in rheumatology clinics quit smoking proved both efficient and effective in referring willing participants to free tobacco quit lines.

seanika/ThinkStock

“Rheumatology visits provide a unique opportunity to address smoking as a chronic modifiable risk factor in populations at high risk for cardiovascular disease, pulmonary disease, and rheumatic disease progression,” wrote Christie M. Bartels, MD, chief of the division of rheumatology at the University of Wisconsin, Madison, and colleagues. The study was published in Arthritis Care & Research.

To assess the effectiveness of implementing a smoking cessation protocol for patients with rheumatic diseases, the researchers launched a quasi-experimental cohort study in which their Quit Connect protocol was tested at three rheumatology clinics. Adapting the Ask, Advise, Connect primary care protocol to a new setting, nurses and medical assistants were trained to use electronic health record (EHR) prompts that would check if patients who smoked were ready to quit within 30 days, advise them to do so, and then use electronic referrals to connect them to state-run tobacco quit lines. An extended baseline period – October 2012 to March 2016 – was compared to a 6-month intervention period from April to October 2016.

Across 54,090 pre- and postimplementation rheumatology clinic visits, 4,601 were with current smokers. Demographics were similar across both periods: The mean age of the patients was 51 years, about two-thirds were female, and 85% were White.

Clinicians’ assessment of tobacco use before and after implementation of the program stayed steady at 96% of patient visits, but the percentage of tobacco users’ visits that included checking for readiness to quit within the next 30 days rose from 3% (135 of 4,078) to 80% (421 of 523).

Before the implementation of the program, 0.6% of eligible visits with current smokers included a quit-line referral offer. After implementation, 93 (18%) of the 523 smokers who visited – 122 of whom said they were ready to quit – were offered referrals, a 26-fold increase. Of the 93 offered referrals, 66 (71%) accepted and 16 set a quit date or reported having quit; 11 accepted counseling services and nicotine replacement.

Although clinic staff reported encountering several obstacles, such as the need to craft nonthreatening language for challenging patients, they also contributed their own talking points that were included in the EHR tools and desktop brochures. On average, the protocol took less than 90 seconds to perform.

Rheumatologists can make headway on patients quitting smoking

“While smoking cessation programs require time and resources to implement, this study suggests a role for evidence-based protocols within rheumatology centers,” Medha Barbhaiya, MD, a rheumatologist at the Hospital for Special Surgery in New York, said in an interview. “Given that current smokers are at an increased risk of developing more severe rheumatic disease and cardiovascular disease, and patients often visit their rheumatologist multiple times yearly, rheumatologists may be well-positioned to address smoking cessation with patients.”

In regard to next steps, she noted that “while future large studies in diverse cohorts are needed to confirm these findings, implementing a formal smoking cessation protocol within rheumatology centers may provide a unique opportunity for rheumatologists to directly help patients modify their disease risk, leading to improved health outcomes.”

The authors acknowledged their study’s limitations, including the fact that it was a prepost design and not a randomized trial. They also recognized that many tobacco users require 8-10 attempts before permanently quitting, likely lessening the lasting impact of the short-term study. They did cite expert analysis, however, that says “connecting patients to evidence-based resources makes them more likely to permanently quit.”

The study was supported in part by Pfizer’s office of Independent Grants for Learning and Change and by a grant collaboration from the University of Wisconsin Clinical and Translational Science Award and the University of Wisconsin School of Medicine and Public Health’s Wisconsin Partnership Program, through the NIH National Center for Advancing Translational Sciences.

Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).

NoSystem images/Getty Images

“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.

Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.

A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.

In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.

After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.

Evidence has ‘unclear clinical significance’

“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.

Courtesy Dr. Joel M. Gelfand

“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
 

Focus on the second dose of a two-dose regimen

“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”

Courtesy UAB Photo

He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.

“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
 

Debating the cause of weakened immune responses

“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.

“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?

“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”

That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”

The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.

Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).

NoSystem images/Getty Images

“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.

Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.

A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.

In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.

After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.

Evidence has ‘unclear clinical significance’

“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.

Courtesy Dr. Joel M. Gelfand

“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
 

Focus on the second dose of a two-dose regimen

“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”

Courtesy UAB Photo

He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.

“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
 

Debating the cause of weakened immune responses

“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.

“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?

“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”

That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”

The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.

Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).

NoSystem images/Getty Images

“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.

Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.

A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.

In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.

After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.

Evidence has ‘unclear clinical significance’

“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.

Courtesy Dr. Joel M. Gelfand

“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
 

Focus on the second dose of a two-dose regimen

“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”

Courtesy UAB Photo

He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.

“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
 

Debating the cause of weakened immune responses

“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.

“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?

“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”

That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”

The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.

Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.

peterschreiber_media/iStock/Getty Images

In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.

The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.

Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.

None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.

“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.

Antibody responses

In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.

The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.

Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.

The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.

Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.

Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.

peterschreiber_media/iStock/Getty Images

In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.

The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.

Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.

None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.

“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.

Antibody responses

In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.

The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.

Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.

The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.

Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.

Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.

peterschreiber_media/iStock/Getty Images

In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.

The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.

Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.

None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.

“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.

Antibody responses

In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.

The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.

Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.

The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.

Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.

The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.

In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.

“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”

The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.

The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”

[email protected]

The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.

In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.

“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”

The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.

The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”

[email protected]

The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.

In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.

“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”

The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.

The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”

[email protected]

Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.

“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.

This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.

Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.

Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.

This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
 

Delayed onset and resolution of rheumatologic immune-related adverse events

“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.

Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.

Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
 

Flares of preexisting rheumatic diseases

These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.

Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.

“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.

He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.

“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.

Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.

[email protected]

Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.

“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.

This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.

Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.

Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.

This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
 

Delayed onset and resolution of rheumatologic immune-related adverse events

“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.

Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.

Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
 

Flares of preexisting rheumatic diseases

These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.

Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.

“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.

He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.

“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.

Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.

[email protected]

Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.

“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.

This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.

Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.

Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.

This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
 

Delayed onset and resolution of rheumatologic immune-related adverse events

“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.

Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.

Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
 

Flares of preexisting rheumatic diseases

These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.

Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.

“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.

He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.

“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.

Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.

[email protected]

Rheumatologists can look forward to the likely regulatory approval of the oral Janus kinase inhibitors tofacitinib and upadacitinib for the treatment of axial spondyloarthritis in the first half of 2021, speakers predicted at the 2021 Rheumatology Winter Clinical Symposium.

This will be a major advance in the treatment of axial spondyloarthritis (axSpA) and promises to be one of the overall highlights of the coming year in rheumatology, according to the speakers. Both medications are now under Food and Drug Administration review for the proposed new indication.

“My sense is within the next 6 months we’re going to have two different oral JAK inhibitors that offer a new option for our ankylosing spondylitis and axial spondyloarthritis patients,” predicted Eric M. Ruderman, MD, professor of medicine (rheumatology) at Northwestern University, Chicago.

Alexis R. Ogdie, MD, MSCE, noted that, at present, only two classes of potent medications are available for treatment of axial spondyloarthritis: tumor necrosis factor (TNF) inhibitors and anti–interleukin-17 biologics.

“I think it would be so exciting to have more treatment options. To have only two classes of drugs you can use for this disease is not enough,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.

She and her fellow panelists also highlighted other recent key developments in axSpA, including epidemiologic evidence that case numbers are climbing sharply, identification of two previously unrecognized common comorbidities, a successful biologic remission induction and maintenance dose–reduction strategy, data on the best and worst biologics for patients with anterior uveitis, and evidence regarding next-step therapy in axSpA patients who’ve had an inadequate response to a TNF inhibitor.
 

The JAK inhibitors are coming

Oral tofacitinib (Xeljanz) at 5 mg twice daily was the focus of a pivotal phase 3, double-blind, 16-week, placebo-controlled clinical trial including 269 patients with axSpA. The results were presented at the 2020 annual meeting of the American College of Rheumatology. The primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 20). This was accomplished in 56.4% of patients on tofacitinib and 29.4% of placebo-treated controls. The ASAS 40 response rate was even more impressive: 40.6% with the JAK inhibitor, compared with 12.5% with placebo. There was one serious infection in the tofacitinib group, but no cases of venous thromboembolism, interstitial lung disease, opportunistic infection, major adverse cardiovascular events, or malignancy in this brief 4-month study.

Also now under FDA review are data from SELECT-AXIS 1, a phase 2/3, double-blind trial in which 187 biologic-naive patients with ankylosing spondylitis were randomized to 14 weeks of upadacitinib (Rinvoq) at 15 mg once daily or placebo. The primary endpoint, an ASAS 40 response, occurred in 51.6% of patients on the JAK inhibitor and half as many controls.

“They saw improvement in MRI scores with upadacitinib, so there’s biologic plausibility to this,” Dr. Ruderman noted.

He predicted the JAK inhibitors are going to have a big impact in clinical practice, especially in men.

“I have a lot of ankylosing spondylitis and axial spondyloarthritis patients on NSAIDs who I’m not convinced are doing as well as they could, but they push back every time I raise the possibility of going on a biologic,” the rheumatologist said. “I suspect that, given the rapid response with JAK inhibitors here, as in rheumatoid arthritis, it might be a little bit easier to persuade these people to give this a try for 4-6 weeks and then see how much better they are. It’s a pill. You don’t have to give yourself a shot.”

Dr. Ogdie predicted the new oral agents will bring more axSpA patients into rheumatologists’ offices.

“I think it’ll be kind of like the apremilast effect in psoriasis, where the drug got a lot more people into the market,” she said.

U.S. ankylosing spondylitis prevalence rising

The diagnostic prevalence of axSpA in the United States increased by 86% between 2006 and 2014 in a retrospective analysis based on Medicare fee-for-service claims data. A separate analysis using IBM MarketScan data for the same years was confirmatory, showing a 56% increase, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham reported at the 2020 annual meeting of the European League Against Rheumatism (EULAR), now known as the European Alliance of Associations for Rheumatology.

“I think the take home is we’re seeing more of this. Some of this is likely due to increased awareness and inclusion of nonradiographic disease,” according to Dr. Ruderman.
 

Two previously overlooked comorbidities

It’s well recognized that 5%-10% of patients with axSpA have concurrent inflammatory bowel disease. But how about irritable bowel syndrome (IBS)?

A study of 186 Swedish patients with axSpA in the population-based SPARTAKUS registry, none with inflammatory bowel disease, concluded that 30% of them met ROME III diagnostic criteria for IBS, compared with 16% of healthy controls. Of note, the axSpA patients with comorbid IBS had significantly worse axSpA disease outcomes, compared with those without IBS as measured by pain, fatigue, and quality-of-life scores, as well as significantly greater disease activity on the Bath Ankylosing Spondylitis Disease Activity Index.

New-onset inflammatory back pain occurred in a hefty 24% of 513 Saudi patients placed on isotretinoin for acne. About 42% of those with inflammatory back pain displayed evidence of sacroiliitis on MRI. Moreover, 52% of patients with MRI-proven sacroiliitis fulfilled ASAS criteria for axSpA. In this longitudinal study, the MRI abnormalities and back pain symptoms completely resolved after isotretinoin discontinuation, but it took a long time: up to 9 months.

“When you see these people with inflammatory back pain on isotretinoin, I think it’s important that before you saddle them with a diagnosis that they have axSpA – a diagnosis that will go with them forever – give them time off drug, because this can look like the real thing. It’s something to think about as these pretty young kids come in to see you with back pain: Always ask about their medication history because it could be important,” Dr. Ruderman said.

A successful biologic remission induction-and-maintenance strategy

The phase 3b, multicenter C-OPTIMISE study sought to determine the best strategy for avoiding axSpA flares once sustained clinical remission has been achieved with a TNF inhibitor, in this case certolizumab pegol (Cimzia). The first part of the trial involved 736 patients with early axSpA, including 329 with nonradiographic disease. During the 48-week open-label induction period, 43.9% of patients achieved sustained clinical remission at the approved dose of 200 mg every 2 weeks, with similar success rates in radiographic and nonradiographic axSpA.

Those in sustained remission were then randomized double blind to one of three groups: an additional 48 weeks of certolizumab pegol at the full maintenance dose of 200 mg every 2 weeks, reduced maintenance dosing at 200 mg every 4 weeks, or placebo. During this period, 83.7% of the group who continued on full-dose certolizumab remained flare free, as did 79% of those on the reduced maintenance dose. In contrast, only 20.2% of patients in whom the biologic was completely withdrawn remained flare free. The investigators concluded that certolizumab dose reduction is a winning strategy for maintenance of clinical remission, as it reduces costs and limits long-term exposure to immunosuppressive therapy while maintaining clinical benefits.
 

All biologics aren’t equal when it comes to anterior uveitis risk

An analysis of Swedish Rheumatology Quality Register data presented at the 2020 EULAR meeting concluded that, among 3,568 patients started on one of four biologics for treatment of spondyloarthritis, the incidence of anterior uveitis was 2.9 per 100 patient-years in those on infliximab (Remicade), 4.0 per 100 patient-years with adalimumab (Humira), 6.8 per 100 patient-years with secukinumab (Cosentyx), and 7.5 per 100 patient-years with etanercept (Enbrel).

Bruce Jancin/MDedge News

“This is important information for us in the clinic. The big question has been, do we see a reduced risk of anterior uveitis with secukinumab, an interleukin-17 inhibitor,” observed RWCS director Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

“When I’ve switched people with uveitis to secukinumab or ixekizumab [Taltz], I do see it come back. So I think it’s important to have these data out there,” Dr. Ogdie said.

Certolizumab pegol markedly reduced the incidence of anterior uveitis flares in patients with radiographic and nonradiographic axSpA and a history of recurrent uveitis flares in the ongoing phase 4 C-VIEW study. In the 48 weeks prior to going on certolizumab pegol, the 89 participants included in this analysis had an acute anterior uveitis incidence of 1.5 episodes per patient; during their first 48 weeks on the TNF inhibitor, the rate plunged to 0.2 episodes, representing an 87% reduction.
 

Secukinumab ‘not the obvious choice’ after inadequate response to a TNF inhibitor

While it might seem logical to turn to an IL-17 inhibitor in patients with an inadequate response to one or more TNF inhibitors, two recently published studies suggest that starting secukinumab is not more effective than trying yet another TNF inhibitor.

A retrospective analysis of Swiss registry data on next-step therapy in 390 axSpA patients who had withdrawn from one or more TNF inhibitors concluded that efficacy at 1 year in the 106 who switched to secukinumab wasn’t significantly different than in the 284 who moved on to another TNF inhibitor.

Similarly, an analysis of 10,583 courses of biologic therapy in 8,050 axSpA patients in five Nordic registries concluded that secukinumab and adalimumab as second-line therapy in patients with inadequate response to an initial TNF inhibitor performed similarly through 1 year of follow-up. However, in patients who’d previously failed to respond to two or three different biologic agents, adalimumab proved superior to the interleukin-17 inhibitor.

“These are two studies that don’t support the intuitive notion of trying a drug with a different mechanism of action when a patient has an inadequate response to a TNF inhibitor. It’s not clear that’s going to make a difference. It doesn’t mean secukinumab can’t work, but it means secukinumab is not the obvious choice,” Dr. Ruderman commented.

All three speakers reported financial relationships with numerous pharmaceutical companies.

[email protected]

Rheumatologists can look forward to the likely regulatory approval of the oral Janus kinase inhibitors tofacitinib and upadacitinib for the treatment of axial spondyloarthritis in the first half of 2021, speakers predicted at the 2021 Rheumatology Winter Clinical Symposium.

This will be a major advance in the treatment of axial spondyloarthritis (axSpA) and promises to be one of the overall highlights of the coming year in rheumatology, according to the speakers. Both medications are now under Food and Drug Administration review for the proposed new indication.

“My sense is within the next 6 months we’re going to have two different oral JAK inhibitors that offer a new option for our ankylosing spondylitis and axial spondyloarthritis patients,” predicted Eric M. Ruderman, MD, professor of medicine (rheumatology) at Northwestern University, Chicago.

Alexis R. Ogdie, MD, MSCE, noted that, at present, only two classes of potent medications are available for treatment of axial spondyloarthritis: tumor necrosis factor (TNF) inhibitors and anti–interleukin-17 biologics.

“I think it would be so exciting to have more treatment options. To have only two classes of drugs you can use for this disease is not enough,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.

She and her fellow panelists also highlighted other recent key developments in axSpA, including epidemiologic evidence that case numbers are climbing sharply, identification of two previously unrecognized common comorbidities, a successful biologic remission induction and maintenance dose–reduction strategy, data on the best and worst biologics for patients with anterior uveitis, and evidence regarding next-step therapy in axSpA patients who’ve had an inadequate response to a TNF inhibitor.
 

The JAK inhibitors are coming

Oral tofacitinib (Xeljanz) at 5 mg twice daily was the focus of a pivotal phase 3, double-blind, 16-week, placebo-controlled clinical trial including 269 patients with axSpA. The results were presented at the 2020 annual meeting of the American College of Rheumatology. The primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 20). This was accomplished in 56.4% of patients on tofacitinib and 29.4% of placebo-treated controls. The ASAS 40 response rate was even more impressive: 40.6% with the JAK inhibitor, compared with 12.5% with placebo. There was one serious infection in the tofacitinib group, but no cases of venous thromboembolism, interstitial lung disease, opportunistic infection, major adverse cardiovascular events, or malignancy in this brief 4-month study.

Also now under FDA review are data from SELECT-AXIS 1, a phase 2/3, double-blind trial in which 187 biologic-naive patients with ankylosing spondylitis were randomized to 14 weeks of upadacitinib (Rinvoq) at 15 mg once daily or placebo. The primary endpoint, an ASAS 40 response, occurred in 51.6% of patients on the JAK inhibitor and half as many controls.

“They saw improvement in MRI scores with upadacitinib, so there’s biologic plausibility to this,” Dr. Ruderman noted.

He predicted the JAK inhibitors are going to have a big impact in clinical practice, especially in men.

“I have a lot of ankylosing spondylitis and axial spondyloarthritis patients on NSAIDs who I’m not convinced are doing as well as they could, but they push back every time I raise the possibility of going on a biologic,” the rheumatologist said. “I suspect that, given the rapid response with JAK inhibitors here, as in rheumatoid arthritis, it might be a little bit easier to persuade these people to give this a try for 4-6 weeks and then see how much better they are. It’s a pill. You don’t have to give yourself a shot.”

Dr. Ogdie predicted the new oral agents will bring more axSpA patients into rheumatologists’ offices.

“I think it’ll be kind of like the apremilast effect in psoriasis, where the drug got a lot more people into the market,” she said.

U.S. ankylosing spondylitis prevalence rising

The diagnostic prevalence of axSpA in the United States increased by 86% between 2006 and 2014 in a retrospective analysis based on Medicare fee-for-service claims data. A separate analysis using IBM MarketScan data for the same years was confirmatory, showing a 56% increase, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham reported at the 2020 annual meeting of the European League Against Rheumatism (EULAR), now known as the European Alliance of Associations for Rheumatology.

“I think the take home is we’re seeing more of this. Some of this is likely due to increased awareness and inclusion of nonradiographic disease,” according to Dr. Ruderman.
 

Two previously overlooked comorbidities

It’s well recognized that 5%-10% of patients with axSpA have concurrent inflammatory bowel disease. But how about irritable bowel syndrome (IBS)?

A study of 186 Swedish patients with axSpA in the population-based SPARTAKUS registry, none with inflammatory bowel disease, concluded that 30% of them met ROME III diagnostic criteria for IBS, compared with 16% of healthy controls. Of note, the axSpA patients with comorbid IBS had significantly worse axSpA disease outcomes, compared with those without IBS as measured by pain, fatigue, and quality-of-life scores, as well as significantly greater disease activity on the Bath Ankylosing Spondylitis Disease Activity Index.

New-onset inflammatory back pain occurred in a hefty 24% of 513 Saudi patients placed on isotretinoin for acne. About 42% of those with inflammatory back pain displayed evidence of sacroiliitis on MRI. Moreover, 52% of patients with MRI-proven sacroiliitis fulfilled ASAS criteria for axSpA. In this longitudinal study, the MRI abnormalities and back pain symptoms completely resolved after isotretinoin discontinuation, but it took a long time: up to 9 months.

“When you see these people with inflammatory back pain on isotretinoin, I think it’s important that before you saddle them with a diagnosis that they have axSpA – a diagnosis that will go with them forever – give them time off drug, because this can look like the real thing. It’s something to think about as these pretty young kids come in to see you with back pain: Always ask about their medication history because it could be important,” Dr. Ruderman said.

A successful biologic remission induction-and-maintenance strategy

The phase 3b, multicenter C-OPTIMISE study sought to determine the best strategy for avoiding axSpA flares once sustained clinical remission has been achieved with a TNF inhibitor, in this case certolizumab pegol (Cimzia). The first part of the trial involved 736 patients with early axSpA, including 329 with nonradiographic disease. During the 48-week open-label induction period, 43.9% of patients achieved sustained clinical remission at the approved dose of 200 mg every 2 weeks, with similar success rates in radiographic and nonradiographic axSpA.

Those in sustained remission were then randomized double blind to one of three groups: an additional 48 weeks of certolizumab pegol at the full maintenance dose of 200 mg every 2 weeks, reduced maintenance dosing at 200 mg every 4 weeks, or placebo. During this period, 83.7% of the group who continued on full-dose certolizumab remained flare free, as did 79% of those on the reduced maintenance dose. In contrast, only 20.2% of patients in whom the biologic was completely withdrawn remained flare free. The investigators concluded that certolizumab dose reduction is a winning strategy for maintenance of clinical remission, as it reduces costs and limits long-term exposure to immunosuppressive therapy while maintaining clinical benefits.
 

All biologics aren’t equal when it comes to anterior uveitis risk

An analysis of Swedish Rheumatology Quality Register data presented at the 2020 EULAR meeting concluded that, among 3,568 patients started on one of four biologics for treatment of spondyloarthritis, the incidence of anterior uveitis was 2.9 per 100 patient-years in those on infliximab (Remicade), 4.0 per 100 patient-years with adalimumab (Humira), 6.8 per 100 patient-years with secukinumab (Cosentyx), and 7.5 per 100 patient-years with etanercept (Enbrel).

Bruce Jancin/MDedge News

“This is important information for us in the clinic. The big question has been, do we see a reduced risk of anterior uveitis with secukinumab, an interleukin-17 inhibitor,” observed RWCS director Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

“When I’ve switched people with uveitis to secukinumab or ixekizumab [Taltz], I do see it come back. So I think it’s important to have these data out there,” Dr. Ogdie said.

Certolizumab pegol markedly reduced the incidence of anterior uveitis flares in patients with radiographic and nonradiographic axSpA and a history of recurrent uveitis flares in the ongoing phase 4 C-VIEW study. In the 48 weeks prior to going on certolizumab pegol, the 89 participants included in this analysis had an acute anterior uveitis incidence of 1.5 episodes per patient; during their first 48 weeks on the TNF inhibitor, the rate plunged to 0.2 episodes, representing an 87% reduction.
 

Secukinumab ‘not the obvious choice’ after inadequate response to a TNF inhibitor

While it might seem logical to turn to an IL-17 inhibitor in patients with an inadequate response to one or more TNF inhibitors, two recently published studies suggest that starting secukinumab is not more effective than trying yet another TNF inhibitor.

A retrospective analysis of Swiss registry data on next-step therapy in 390 axSpA patients who had withdrawn from one or more TNF inhibitors concluded that efficacy at 1 year in the 106 who switched to secukinumab wasn’t significantly different than in the 284 who moved on to another TNF inhibitor.

Similarly, an analysis of 10,583 courses of biologic therapy in 8,050 axSpA patients in five Nordic registries concluded that secukinumab and adalimumab as second-line therapy in patients with inadequate response to an initial TNF inhibitor performed similarly through 1 year of follow-up. However, in patients who’d previously failed to respond to two or three different biologic agents, adalimumab proved superior to the interleukin-17 inhibitor.

“These are two studies that don’t support the intuitive notion of trying a drug with a different mechanism of action when a patient has an inadequate response to a TNF inhibitor. It’s not clear that’s going to make a difference. It doesn’t mean secukinumab can’t work, but it means secukinumab is not the obvious choice,” Dr. Ruderman commented.

All three speakers reported financial relationships with numerous pharmaceutical companies.

[email protected]

Rheumatologists can look forward to the likely regulatory approval of the oral Janus kinase inhibitors tofacitinib and upadacitinib for the treatment of axial spondyloarthritis in the first half of 2021, speakers predicted at the 2021 Rheumatology Winter Clinical Symposium.

This will be a major advance in the treatment of axial spondyloarthritis (axSpA) and promises to be one of the overall highlights of the coming year in rheumatology, according to the speakers. Both medications are now under Food and Drug Administration review for the proposed new indication.

“My sense is within the next 6 months we’re going to have two different oral JAK inhibitors that offer a new option for our ankylosing spondylitis and axial spondyloarthritis patients,” predicted Eric M. Ruderman, MD, professor of medicine (rheumatology) at Northwestern University, Chicago.

Alexis R. Ogdie, MD, MSCE, noted that, at present, only two classes of potent medications are available for treatment of axial spondyloarthritis: tumor necrosis factor (TNF) inhibitors and anti–interleukin-17 biologics.

“I think it would be so exciting to have more treatment options. To have only two classes of drugs you can use for this disease is not enough,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.

She and her fellow panelists also highlighted other recent key developments in axSpA, including epidemiologic evidence that case numbers are climbing sharply, identification of two previously unrecognized common comorbidities, a successful biologic remission induction and maintenance dose–reduction strategy, data on the best and worst biologics for patients with anterior uveitis, and evidence regarding next-step therapy in axSpA patients who’ve had an inadequate response to a TNF inhibitor.
 

The JAK inhibitors are coming

Oral tofacitinib (Xeljanz) at 5 mg twice daily was the focus of a pivotal phase 3, double-blind, 16-week, placebo-controlled clinical trial including 269 patients with axSpA. The results were presented at the 2020 annual meeting of the American College of Rheumatology. The primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 20). This was accomplished in 56.4% of patients on tofacitinib and 29.4% of placebo-treated controls. The ASAS 40 response rate was even more impressive: 40.6% with the JAK inhibitor, compared with 12.5% with placebo. There was one serious infection in the tofacitinib group, but no cases of venous thromboembolism, interstitial lung disease, opportunistic infection, major adverse cardiovascular events, or malignancy in this brief 4-month study.

Also now under FDA review are data from SELECT-AXIS 1, a phase 2/3, double-blind trial in which 187 biologic-naive patients with ankylosing spondylitis were randomized to 14 weeks of upadacitinib (Rinvoq) at 15 mg once daily or placebo. The primary endpoint, an ASAS 40 response, occurred in 51.6% of patients on the JAK inhibitor and half as many controls.

“They saw improvement in MRI scores with upadacitinib, so there’s biologic plausibility to this,” Dr. Ruderman noted.

He predicted the JAK inhibitors are going to have a big impact in clinical practice, especially in men.

“I have a lot of ankylosing spondylitis and axial spondyloarthritis patients on NSAIDs who I’m not convinced are doing as well as they could, but they push back every time I raise the possibility of going on a biologic,” the rheumatologist said. “I suspect that, given the rapid response with JAK inhibitors here, as in rheumatoid arthritis, it might be a little bit easier to persuade these people to give this a try for 4-6 weeks and then see how much better they are. It’s a pill. You don’t have to give yourself a shot.”

Dr. Ogdie predicted the new oral agents will bring more axSpA patients into rheumatologists’ offices.

“I think it’ll be kind of like the apremilast effect in psoriasis, where the drug got a lot more people into the market,” she said.

U.S. ankylosing spondylitis prevalence rising

The diagnostic prevalence of axSpA in the United States increased by 86% between 2006 and 2014 in a retrospective analysis based on Medicare fee-for-service claims data. A separate analysis using IBM MarketScan data for the same years was confirmatory, showing a 56% increase, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham reported at the 2020 annual meeting of the European League Against Rheumatism (EULAR), now known as the European Alliance of Associations for Rheumatology.

“I think the take home is we’re seeing more of this. Some of this is likely due to increased awareness and inclusion of nonradiographic disease,” according to Dr. Ruderman.
 

Two previously overlooked comorbidities

It’s well recognized that 5%-10% of patients with axSpA have concurrent inflammatory bowel disease. But how about irritable bowel syndrome (IBS)?

A study of 186 Swedish patients with axSpA in the population-based SPARTAKUS registry, none with inflammatory bowel disease, concluded that 30% of them met ROME III diagnostic criteria for IBS, compared with 16% of healthy controls. Of note, the axSpA patients with comorbid IBS had significantly worse axSpA disease outcomes, compared with those without IBS as measured by pain, fatigue, and quality-of-life scores, as well as significantly greater disease activity on the Bath Ankylosing Spondylitis Disease Activity Index.

New-onset inflammatory back pain occurred in a hefty 24% of 513 Saudi patients placed on isotretinoin for acne. About 42% of those with inflammatory back pain displayed evidence of sacroiliitis on MRI. Moreover, 52% of patients with MRI-proven sacroiliitis fulfilled ASAS criteria for axSpA. In this longitudinal study, the MRI abnormalities and back pain symptoms completely resolved after isotretinoin discontinuation, but it took a long time: up to 9 months.

“When you see these people with inflammatory back pain on isotretinoin, I think it’s important that before you saddle them with a diagnosis that they have axSpA – a diagnosis that will go with them forever – give them time off drug, because this can look like the real thing. It’s something to think about as these pretty young kids come in to see you with back pain: Always ask about their medication history because it could be important,” Dr. Ruderman said.

A successful biologic remission induction-and-maintenance strategy

The phase 3b, multicenter C-OPTIMISE study sought to determine the best strategy for avoiding axSpA flares once sustained clinical remission has been achieved with a TNF inhibitor, in this case certolizumab pegol (Cimzia). The first part of the trial involved 736 patients with early axSpA, including 329 with nonradiographic disease. During the 48-week open-label induction period, 43.9% of patients achieved sustained clinical remission at the approved dose of 200 mg every 2 weeks, with similar success rates in radiographic and nonradiographic axSpA.

Those in sustained remission were then randomized double blind to one of three groups: an additional 48 weeks of certolizumab pegol at the full maintenance dose of 200 mg every 2 weeks, reduced maintenance dosing at 200 mg every 4 weeks, or placebo. During this period, 83.7% of the group who continued on full-dose certolizumab remained flare free, as did 79% of those on the reduced maintenance dose. In contrast, only 20.2% of patients in whom the biologic was completely withdrawn remained flare free. The investigators concluded that certolizumab dose reduction is a winning strategy for maintenance of clinical remission, as it reduces costs and limits long-term exposure to immunosuppressive therapy while maintaining clinical benefits.
 

All biologics aren’t equal when it comes to anterior uveitis risk

An analysis of Swedish Rheumatology Quality Register data presented at the 2020 EULAR meeting concluded that, among 3,568 patients started on one of four biologics for treatment of spondyloarthritis, the incidence of anterior uveitis was 2.9 per 100 patient-years in those on infliximab (Remicade), 4.0 per 100 patient-years with adalimumab (Humira), 6.8 per 100 patient-years with secukinumab (Cosentyx), and 7.5 per 100 patient-years with etanercept (Enbrel).

Bruce Jancin/MDedge News

“This is important information for us in the clinic. The big question has been, do we see a reduced risk of anterior uveitis with secukinumab, an interleukin-17 inhibitor,” observed RWCS director Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

“When I’ve switched people with uveitis to secukinumab or ixekizumab [Taltz], I do see it come back. So I think it’s important to have these data out there,” Dr. Ogdie said.

Certolizumab pegol markedly reduced the incidence of anterior uveitis flares in patients with radiographic and nonradiographic axSpA and a history of recurrent uveitis flares in the ongoing phase 4 C-VIEW study. In the 48 weeks prior to going on certolizumab pegol, the 89 participants included in this analysis had an acute anterior uveitis incidence of 1.5 episodes per patient; during their first 48 weeks on the TNF inhibitor, the rate plunged to 0.2 episodes, representing an 87% reduction.
 

Secukinumab ‘not the obvious choice’ after inadequate response to a TNF inhibitor

While it might seem logical to turn to an IL-17 inhibitor in patients with an inadequate response to one or more TNF inhibitors, two recently published studies suggest that starting secukinumab is not more effective than trying yet another TNF inhibitor.

A retrospective analysis of Swiss registry data on next-step therapy in 390 axSpA patients who had withdrawn from one or more TNF inhibitors concluded that efficacy at 1 year in the 106 who switched to secukinumab wasn’t significantly different than in the 284 who moved on to another TNF inhibitor.

Similarly, an analysis of 10,583 courses of biologic therapy in 8,050 axSpA patients in five Nordic registries concluded that secukinumab and adalimumab as second-line therapy in patients with inadequate response to an initial TNF inhibitor performed similarly through 1 year of follow-up. However, in patients who’d previously failed to respond to two or three different biologic agents, adalimumab proved superior to the interleukin-17 inhibitor.

“These are two studies that don’t support the intuitive notion of trying a drug with a different mechanism of action when a patient has an inadequate response to a TNF inhibitor. It’s not clear that’s going to make a difference. It doesn’t mean secukinumab can’t work, but it means secukinumab is not the obvious choice,” Dr. Ruderman commented.

All three speakers reported financial relationships with numerous pharmaceutical companies.

[email protected]

People with rheumatic diseases should get vaccinated against SARS-CoV-2 as soon as possible, the American College of Rheumatology (ACR) recommends.

Choreograph/iStock/Getty Images

“It may be that people with rheumatic diseases are at increased risk of developing COVID or serious COVID-related complications,” Jonathan Hausmann, MD, assistant professor of medicine at Harvard Medical School, Boston, said in an ACR podcast. “So the need to prevent COVID-19 is incredibly important in this group of patients.”

The guidelines recommend a delay in vaccination only in rare circumstances, such as for patients with very severe illness or who have recently been administered rituximab, Jeffrey R. Curtis, MD, MPH, lead author of the guidelines, said in the podcast.

“Our members have been inundated with questions and concerns from their patients on whether they should receive the vaccine,” ACR President David Karp, MD, PhD, said in a press release.

So the ACR convened a panel of nine rheumatologists, two infectious disease specialists, and two public health experts. Over the course of 8 weeks, the task force reviewed the literature and agreed on recommendations. The organization posted a summary of the guidelines on its website after its board of directors approved it Feb. 8. The paper is pending journal peer review.
 

Some risks are real

The task force confined its research to the COVID-19 vaccines being offered by Pfizer and Moderna because they are currently the only ones approved by the Food and Drug Administration. It found no reason to distinguish between the two vaccines in its recommendations.

Because little research has directly addressed the question concerning COVID-19 vaccination for patients with rheumatic diseases, the task force extrapolated from data on other vaccinations in people with rheumatic disease and on the COVID-19 vaccinations in other populations.

It analyzed reports that other types of vaccination, such as for influenza, triggered flares of rheumatic conditions. “It is really individual case reports or small cohorts where there may be a somewhat higher incidence of flare, but it’s usually not very large in its magnitude nor duration,” said Dr. Curtis of the University of Alabama at Birmingham.

The task force also considered the possibility that vaccinations could lead to a new autoimmune disorder, such as Guillain-Barré syndrome or Bell palsy. The risk is real, the task force decided, but not significant enough to influence their recommendations.

Likewise, in immunocompromised people, vaccinations with live virus, such as those for shingles, might trigger the infection the vaccination is meant to prevent. But this can’t happen with the Pfizer and Moderna COVID-19 vaccines because they contain messenger RNA instead of live viruses, Dr. Curtis said.

Courtesy University of Alabama at Birmingham

How well does it work?

One unanswered question is whether the COVID-19 vaccines work as well for patients with rheumatic diseases. The task force was reassured by data showing efficacy across a range of subgroups, including some with immunosenescence, Dr. Curtis said. “But until we have data in rheumatology patients, we’re just not going to know,” he said.

The guidelines specify that some drug regimens be modified when patients are vaccinated.

For patients taking rituximab, vaccination should be delayed, but only for those who are able to maintain safe social distancing to reduce the risk for COVID-19 exposure, Dr. Curtis said. “If somebody has just gotten rituximab recently, it might be more ideal to complete the vaccine series about 2-4 weeks before the next rituximab dose,” he said. “So if you are giving that therapy, say, at 6-month intervals, if you could vaccinate them at around month 5 from the most recent rituximab cycle, that might be more ideal.”

The guidance calls for withholding JAK inhibitors for a week after each vaccine dose is administered.

It calls for holding SQ abatacept 1 week prior and 1 week after the first COVID-19 vaccine dose, with no interruption after the second dose.

For abatacept IV, clinicians should “time vaccine administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total).” It recommends no medication adjustment for the second vaccine dose.

For cyclophosphamide, the guidance recommends timing administration to occur about a week after each vaccine dose, when feasible.

None of this advice should supersede clinical judgment, Dr. Curtis said.

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

People with rheumatic diseases should get vaccinated against SARS-CoV-2 as soon as possible, the American College of Rheumatology (ACR) recommends.

Choreograph/iStock/Getty Images

“It may be that people with rheumatic diseases are at increased risk of developing COVID or serious COVID-related complications,” Jonathan Hausmann, MD, assistant professor of medicine at Harvard Medical School, Boston, said in an ACR podcast. “So the need to prevent COVID-19 is incredibly important in this group of patients.”

The guidelines recommend a delay in vaccination only in rare circumstances, such as for patients with very severe illness or who have recently been administered rituximab, Jeffrey R. Curtis, MD, MPH, lead author of the guidelines, said in the podcast.

“Our members have been inundated with questions and concerns from their patients on whether they should receive the vaccine,” ACR President David Karp, MD, PhD, said in a press release.

So the ACR convened a panel of nine rheumatologists, two infectious disease specialists, and two public health experts. Over the course of 8 weeks, the task force reviewed the literature and agreed on recommendations. The organization posted a summary of the guidelines on its website after its board of directors approved it Feb. 8. The paper is pending journal peer review.
 

Some risks are real

The task force confined its research to the COVID-19 vaccines being offered by Pfizer and Moderna because they are currently the only ones approved by the Food and Drug Administration. It found no reason to distinguish between the two vaccines in its recommendations.

Because little research has directly addressed the question concerning COVID-19 vaccination for patients with rheumatic diseases, the task force extrapolated from data on other vaccinations in people with rheumatic disease and on the COVID-19 vaccinations in other populations.

It analyzed reports that other types of vaccination, such as for influenza, triggered flares of rheumatic conditions. “It is really individual case reports or small cohorts where there may be a somewhat higher incidence of flare, but it’s usually not very large in its magnitude nor duration,” said Dr. Curtis of the University of Alabama at Birmingham.

The task force also considered the possibility that vaccinations could lead to a new autoimmune disorder, such as Guillain-Barré syndrome or Bell palsy. The risk is real, the task force decided, but not significant enough to influence their recommendations.

Likewise, in immunocompromised people, vaccinations with live virus, such as those for shingles, might trigger the infection the vaccination is meant to prevent. But this can’t happen with the Pfizer and Moderna COVID-19 vaccines because they contain messenger RNA instead of live viruses, Dr. Curtis said.

Courtesy University of Alabama at Birmingham

How well does it work?

One unanswered question is whether the COVID-19 vaccines work as well for patients with rheumatic diseases. The task force was reassured by data showing efficacy across a range of subgroups, including some with immunosenescence, Dr. Curtis said. “But until we have data in rheumatology patients, we’re just not going to know,” he said.

The guidelines specify that some drug regimens be modified when patients are vaccinated.

For patients taking rituximab, vaccination should be delayed, but only for those who are able to maintain safe social distancing to reduce the risk for COVID-19 exposure, Dr. Curtis said. “If somebody has just gotten rituximab recently, it might be more ideal to complete the vaccine series about 2-4 weeks before the next rituximab dose,” he said. “So if you are giving that therapy, say, at 6-month intervals, if you could vaccinate them at around month 5 from the most recent rituximab cycle, that might be more ideal.”

The guidance calls for withholding JAK inhibitors for a week after each vaccine dose is administered.

It calls for holding SQ abatacept 1 week prior and 1 week after the first COVID-19 vaccine dose, with no interruption after the second dose.

For abatacept IV, clinicians should “time vaccine administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total).” It recommends no medication adjustment for the second vaccine dose.

For cyclophosphamide, the guidance recommends timing administration to occur about a week after each vaccine dose, when feasible.

None of this advice should supersede clinical judgment, Dr. Curtis said.

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

People with rheumatic diseases should get vaccinated against SARS-CoV-2 as soon as possible, the American College of Rheumatology (ACR) recommends.

Choreograph/iStock/Getty Images

“It may be that people with rheumatic diseases are at increased risk of developing COVID or serious COVID-related complications,” Jonathan Hausmann, MD, assistant professor of medicine at Harvard Medical School, Boston, said in an ACR podcast. “So the need to prevent COVID-19 is incredibly important in this group of patients.”

The guidelines recommend a delay in vaccination only in rare circumstances, such as for patients with very severe illness or who have recently been administered rituximab, Jeffrey R. Curtis, MD, MPH, lead author of the guidelines, said in the podcast.

“Our members have been inundated with questions and concerns from their patients on whether they should receive the vaccine,” ACR President David Karp, MD, PhD, said in a press release.

So the ACR convened a panel of nine rheumatologists, two infectious disease specialists, and two public health experts. Over the course of 8 weeks, the task force reviewed the literature and agreed on recommendations. The organization posted a summary of the guidelines on its website after its board of directors approved it Feb. 8. The paper is pending journal peer review.
 

Some risks are real

The task force confined its research to the COVID-19 vaccines being offered by Pfizer and Moderna because they are currently the only ones approved by the Food and Drug Administration. It found no reason to distinguish between the two vaccines in its recommendations.

Because little research has directly addressed the question concerning COVID-19 vaccination for patients with rheumatic diseases, the task force extrapolated from data on other vaccinations in people with rheumatic disease and on the COVID-19 vaccinations in other populations.

It analyzed reports that other types of vaccination, such as for influenza, triggered flares of rheumatic conditions. “It is really individual case reports or small cohorts where there may be a somewhat higher incidence of flare, but it’s usually not very large in its magnitude nor duration,” said Dr. Curtis of the University of Alabama at Birmingham.

The task force also considered the possibility that vaccinations could lead to a new autoimmune disorder, such as Guillain-Barré syndrome or Bell palsy. The risk is real, the task force decided, but not significant enough to influence their recommendations.

Likewise, in immunocompromised people, vaccinations with live virus, such as those for shingles, might trigger the infection the vaccination is meant to prevent. But this can’t happen with the Pfizer and Moderna COVID-19 vaccines because they contain messenger RNA instead of live viruses, Dr. Curtis said.

Courtesy University of Alabama at Birmingham

How well does it work?

One unanswered question is whether the COVID-19 vaccines work as well for patients with rheumatic diseases. The task force was reassured by data showing efficacy across a range of subgroups, including some with immunosenescence, Dr. Curtis said. “But until we have data in rheumatology patients, we’re just not going to know,” he said.

The guidelines specify that some drug regimens be modified when patients are vaccinated.

For patients taking rituximab, vaccination should be delayed, but only for those who are able to maintain safe social distancing to reduce the risk for COVID-19 exposure, Dr. Curtis said. “If somebody has just gotten rituximab recently, it might be more ideal to complete the vaccine series about 2-4 weeks before the next rituximab dose,” he said. “So if you are giving that therapy, say, at 6-month intervals, if you could vaccinate them at around month 5 from the most recent rituximab cycle, that might be more ideal.”

The guidance calls for withholding JAK inhibitors for a week after each vaccine dose is administered.

It calls for holding SQ abatacept 1 week prior and 1 week after the first COVID-19 vaccine dose, with no interruption after the second dose.

For abatacept IV, clinicians should “time vaccine administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total).” It recommends no medication adjustment for the second vaccine dose.

For cyclophosphamide, the guidance recommends timing administration to occur about a week after each vaccine dose, when feasible.

None of this advice should supersede clinical judgment, Dr. Curtis said.

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

Patients with axial spondyloarthritis showed reduced spinal radiographic progression after treatment with tumor necrosis factor (TNF) inhibitors, based on data from 314 adults in a prospective cohort study.

feellife/Thinkstock

Evidence of a link between inflammation and axial damage in patients with axial spondyloarthritis (axSpA) has been reported, and these patients are routinely treated with NSAIDs and TNF inhibitors (TNFi), wrote Alexandre Sepriano, MD, PhD, of Leiden (the Netherlands) University Medical Center, and colleagues.

“However, and despite significant efforts, it remains to be clarified whether there is also an effect of these drugs on axial damage accrual,” they noted.

In a study published in Arthritis & Rheumatology, the researchers recruited consecutive patients from rheumatology practices in Northern Alberta to enroll in the Follow Up Research Cohort in Ankylosing Spondylitis Treatment (ALBERTA FORCAST) observational cohort study. The average age of the patients was 41 years, 74% were men, 83% were HLA-B27 positive, and the average duration of symptoms was 18 years.

Progression was measured via spine radiographs every 2 years for up to 10 years; the radiographs were scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). In addition, the researchers assessed the interaction between TNFi exposure and clinical disease activity using the Ankylosing Spondylitis Disease Activity Score (ASDAS) and the impact on mSASSS every 2 years. The analysis included 442 2-year intervals.

Overall, the researchers found a significant interaction between ASDAS and TNFi at the start of the interval, followed by gradient effect of ASDAS at the start of the interval on mSASSS 2 years later, which was more than twice as high in patients never treated with TNFi (beta = 0.41), compared with patients who were continuously treated with a TNFi (beta = 0.16).

“Similarly, patients treated with TNFi were 30% less likely to develop a new syndesmophyte 2 years later compared to those not treated,” the researchers said.

TNFi also directly slowed progression, as treated patients averaged 0.85 mSASSS units less 2 years later, compared with untreated patients.

Of note, “treatment with NSAIDs during follow-up was neither associated with the outcome nor did it modify or confound the association between TNFi and mSASSS,” the researchers said. In addition, “the direct effect of TNFi on mSASSS was still present after adjusting for a propensity score,” they wrote.

The study results were limited by several factors including the observational design, lack of data on long-term treatment effects, and inability to assess individual TNFi drugs separately, the researchers noted.

However, “the present study informs the rheumatology community by addressing the question as to whether or not TNFi inhibit radiographic progression in axSpA and if this effect is mediated solely by their effects on inflammation, as measured by the ASDAS, or whether additional mechanisms may be relevant,” they emphasized.

“A better understanding of these mechanisms might open avenues to further treatment strategies that might finally lead to effective disease modification in axial SpA,” they concluded.

The ALBERTA FORCAST study was supported by AbbVie. Several authors disclosed financial relationships with AbbVie and other manufacturers of TNFi.

Patients with axial spondyloarthritis showed reduced spinal radiographic progression after treatment with tumor necrosis factor (TNF) inhibitors, based on data from 314 adults in a prospective cohort study.

feellife/Thinkstock

Evidence of a link between inflammation and axial damage in patients with axial spondyloarthritis (axSpA) has been reported, and these patients are routinely treated with NSAIDs and TNF inhibitors (TNFi), wrote Alexandre Sepriano, MD, PhD, of Leiden (the Netherlands) University Medical Center, and colleagues.

“However, and despite significant efforts, it remains to be clarified whether there is also an effect of these drugs on axial damage accrual,” they noted.

In a study published in Arthritis & Rheumatology, the researchers recruited consecutive patients from rheumatology practices in Northern Alberta to enroll in the Follow Up Research Cohort in Ankylosing Spondylitis Treatment (ALBERTA FORCAST) observational cohort study. The average age of the patients was 41 years, 74% were men, 83% were HLA-B27 positive, and the average duration of symptoms was 18 years.

Progression was measured via spine radiographs every 2 years for up to 10 years; the radiographs were scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). In addition, the researchers assessed the interaction between TNFi exposure and clinical disease activity using the Ankylosing Spondylitis Disease Activity Score (ASDAS) and the impact on mSASSS every 2 years. The analysis included 442 2-year intervals.

Overall, the researchers found a significant interaction between ASDAS and TNFi at the start of the interval, followed by gradient effect of ASDAS at the start of the interval on mSASSS 2 years later, which was more than twice as high in patients never treated with TNFi (beta = 0.41), compared with patients who were continuously treated with a TNFi (beta = 0.16).

“Similarly, patients treated with TNFi were 30% less likely to develop a new syndesmophyte 2 years later compared to those not treated,” the researchers said.

TNFi also directly slowed progression, as treated patients averaged 0.85 mSASSS units less 2 years later, compared with untreated patients.

Of note, “treatment with NSAIDs during follow-up was neither associated with the outcome nor did it modify or confound the association between TNFi and mSASSS,” the researchers said. In addition, “the direct effect of TNFi on mSASSS was still present after adjusting for a propensity score,” they wrote.

The study results were limited by several factors including the observational design, lack of data on long-term treatment effects, and inability to assess individual TNFi drugs separately, the researchers noted.

However, “the present study informs the rheumatology community by addressing the question as to whether or not TNFi inhibit radiographic progression in axSpA and if this effect is mediated solely by their effects on inflammation, as measured by the ASDAS, or whether additional mechanisms may be relevant,” they emphasized.

“A better understanding of these mechanisms might open avenues to further treatment strategies that might finally lead to effective disease modification in axial SpA,” they concluded.

The ALBERTA FORCAST study was supported by AbbVie. Several authors disclosed financial relationships with AbbVie and other manufacturers of TNFi.

Patients with axial spondyloarthritis showed reduced spinal radiographic progression after treatment with tumor necrosis factor (TNF) inhibitors, based on data from 314 adults in a prospective cohort study.

feellife/Thinkstock

Evidence of a link between inflammation and axial damage in patients with axial spondyloarthritis (axSpA) has been reported, and these patients are routinely treated with NSAIDs and TNF inhibitors (TNFi), wrote Alexandre Sepriano, MD, PhD, of Leiden (the Netherlands) University Medical Center, and colleagues.

“However, and despite significant efforts, it remains to be clarified whether there is also an effect of these drugs on axial damage accrual,” they noted.

In a study published in Arthritis & Rheumatology, the researchers recruited consecutive patients from rheumatology practices in Northern Alberta to enroll in the Follow Up Research Cohort in Ankylosing Spondylitis Treatment (ALBERTA FORCAST) observational cohort study. The average age of the patients was 41 years, 74% were men, 83% were HLA-B27 positive, and the average duration of symptoms was 18 years.

Progression was measured via spine radiographs every 2 years for up to 10 years; the radiographs were scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). In addition, the researchers assessed the interaction between TNFi exposure and clinical disease activity using the Ankylosing Spondylitis Disease Activity Score (ASDAS) and the impact on mSASSS every 2 years. The analysis included 442 2-year intervals.

Overall, the researchers found a significant interaction between ASDAS and TNFi at the start of the interval, followed by gradient effect of ASDAS at the start of the interval on mSASSS 2 years later, which was more than twice as high in patients never treated with TNFi (beta = 0.41), compared with patients who were continuously treated with a TNFi (beta = 0.16).

“Similarly, patients treated with TNFi were 30% less likely to develop a new syndesmophyte 2 years later compared to those not treated,” the researchers said.

TNFi also directly slowed progression, as treated patients averaged 0.85 mSASSS units less 2 years later, compared with untreated patients.

Of note, “treatment with NSAIDs during follow-up was neither associated with the outcome nor did it modify or confound the association between TNFi and mSASSS,” the researchers said. In addition, “the direct effect of TNFi on mSASSS was still present after adjusting for a propensity score,” they wrote.

The study results were limited by several factors including the observational design, lack of data on long-term treatment effects, and inability to assess individual TNFi drugs separately, the researchers noted.

However, “the present study informs the rheumatology community by addressing the question as to whether or not TNFi inhibit radiographic progression in axSpA and if this effect is mediated solely by their effects on inflammation, as measured by the ASDAS, or whether additional mechanisms may be relevant,” they emphasized.

“A better understanding of these mechanisms might open avenues to further treatment strategies that might finally lead to effective disease modification in axial SpA,” they concluded.

The ALBERTA FORCAST study was supported by AbbVie. Several authors disclosed financial relationships with AbbVie and other manufacturers of TNFi.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

Children with enthesitis-related arthritis often have a high burden of disease and could benefit from medications currently approved for adults with spondyloarthritis, according to a review published in Arthritis Care & Research.

“Enthesitis-related arthritis (ERA) was the JIA [juvenile idiopathic arthritis] category applied to children with spondyloarthritis (SpA), recognizing enthesitis as a defining characteristic,” wrote Pamela F. Weiss, MD, of Children’s Hospital of Philadelphia, and colleagues.

The ERA criteria include “arthritis plus enthesitis; or arthritis or enthesitis plus at least two of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27–associated disease, acute anterior uveitis, and arthritis in a male older than 6 years,” the review authors noted.

“None of the [Food and Drug Administration]–approved therapies for peripheral SpA or nonradiographic axial SpA” have been studied or approved for use in children with ERA, but data support biologic similarity to SpA in adults; notably, studies of the HLA-B27 allele have identified it as a risk factor for both SpA and ERA, they said.
 

Common factors in adult and childhood conditions

“The principal commonalities of children with ERA and axial arthritis, and adults with nonradiographic axial SpA, include enthesitis, arthritis, inflammatory back pain, anterior uveitis, HLA-B27 positivity, and family history of HLA-B27–associated disease,” the review authors wrote.

The first-line treatment for both ERA with axial arthritis and nonradiographic axial SpA is NSAIDs, followed by tumor necrosis factor (TNF) inhibitors if needed, they said. However, conventional disease-modifying antirheumatic drugs (cDMARDs) may be used in cases of peripheral disease affecting five or more joints. Studies of treatment response show similarities between ERA in children and SpA in adults, the authors added, with nearly half of adults with axial disease unable to achieve remission and approximately one-third of children with ERA failing to respond to therapy.

Clinical trials could improve options and outcomes for those with ERA who need advanced therapy and such trials should evaluate response of axial and peripheral disease separately, the review authors emphasized. For example, “Eligibility criteria for children with ERA and axial features could include the presence of some of the following disease features: active inflammatory sacroiliitis based on typical MRI changes according to ASAS/OMERACT [Assessment of SpondyloArthritis international Society/Outcome Measures in Rheumatology Clinical Trials] criteria; elevated CRP [C-reactive protein]; and inadequate response or intolerance to NSAIDs,” they noted. “Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations, it is evident that medications approved for axial or peripheral SpA should be studied in children with ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children,” they concluded.

New data highlight ERA disease burden

The need for additional therapies for ERA patients gained more support from a recent study in which a majority of children with ERA or juvenile psoriatic arthritis (jPsA) used biologics, but those with sacroiliitis in particular showed a significant disease burden despite high biologic use.

The International Leagues Against Rheumatism criteria include seven categories of juvenile idiopathic arthritis, of which ERA and jPsA are the most common; however, characteristics of these children have not been well described, wrote Dax G. Rumsey, MD, of the University of Alberta, Edmonton, and colleagues.

“Children with ERA are more likely to have a clinical picture with predominantly peripheral arthritis, typically described as an oligoarthritis involving the lower limbs with high risk of axial disease, relative to the other categories of JIA,” and report more intense pain and worse health status, compared with children in other categories, the researchers wrote.

To more completely characterize children with ERA and jPsA, the researchers assessed 522 children with ERA and 380 with jPsA. The children were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. The findings were published in a brief report in Arthritis Care & Research.

Overall, 69% of the children took at least one biologic, including 72% with ERA and 64% with jPsA. Biologic use was even higher (81%) among the 28% of patients with sacroiliitis (40% of ERA patients and 12% of jPsA patients). Approximately 36% of the patients with sacroiliitis were positive for HLA-B27. In addition, Physician Global Assessment scores and clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) scores were significantly higher at the first clinical visit with sacroiliitis, compared with the first visit without, which confirms “the clinical impression that active sacroiliitis significantly impacts children and their families,” the researchers said.

The average age at diagnosis was 10.8 years for ERA and 8.2 years for jPsA, and significantly more ERA patients were male (56% vs. 38%). However, more of the patients with sacroiliitis (54%) were female. More than half of the patients reported polyarticular involvement.

The study findings were limited by several factors, including the classification of ERA or jPsA and the reliance on physician diagnoses, as well as the variation in identifying sacroiliitis, the researchers said. However, the results increase understanding of the pathophysiology of ERA and jPsA to help determine optimal treatment, they concluded.
 

Data highlight research and treatment gaps

“Recent research demonstrates a large, unmet medical need in the treatment of JIA with 52%-65% of all JIA patients, including those with ERA and jPsA, having been treated with at least one biologic DMARD and 15%-19% having been treated with an FDA-unapproved biologic. In those with ERA or jPsA, 72%-79% of the children had been treated with a biologic DMARD, although no biologic DMARD has ever been FDA approved for these JIA categories,” Daniel J. Lovell, MD, and Hermine I. Brunner, MD, both with Cincinnati Children’s Hospital Medical Center, wrote in an editorial that accompanied the new study. Dr. Lovell and Dr. Brunner also were coauthors of the review article.

The new study supports findings from other recent publications, the editorialists noted. The new results showed “a significant proportion of the JIA population with active sacroiliitis with high disease burden despite very frequent (over 80% of the population) [treatment] with unstudied and unapproved biologic DMARDs,” they said. “These children with sacroiliitis had significantly greater disease burden with higher physician assessment of disease activity, higher parent assessment of disease impact, and higher disease activity as measured by the Juvenile Idiopathic Arthritis Disease Activity Score, compared to the children with ERA or jPsA without sacroiliitis,” they noted.

Jeff Craven/MDedge News

Previously, “the FDA granted pharmaceutical companies studying new treatments in adult SpA automatic full waivers from doing studies in children for new medications for ‘axial spondyloarthropathies including ankylosing spondylitis’ up until July 2020,” the editorialists said. However, “It is now time now for the pharmaceutical industry to perform FDA-monitored clinical trials of children and adolescents with SpA,” they emphasized. “This will allow for the scientific assessment of proper dosing, efficacy, and safety of the increasing number of new medications that are being licensed by the FDA for the treatment of SpA, such as the anti-TNF, anti–IL[interleukin]-17, and anti–IL-23 biologics, and perhaps JAK [Janus kinase] agents, to address this unmet medical need in these patients with juvenile SpA,” they concluded.

Dr. Weiss disclosed grant support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and financial relationships with Eli Lilly and Pfizer. Dr. Lovell disclosed relationships with companies including Abbott, AbbVie Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Novartis, Pfizer, Takeda, UCB, and Wyeth, as well as serving on the data and safety monitoring board for Forest Research and NIAMS. Dr. Brunner disclosed relationships with companies including Ablynx, AbbVie, AstraZeneca-MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, Genzyme, GlaxoSmithKline, Merck, Novartis, R-Pharm, and Sanofi. The study by Dr. Rumsey and colleagues was supported by Amgen. Dr. Rumsey and colleagues had no relevant financial conflicts to disclose.

SOURCES: Weiss PF et al. Arthritis Care Res. 2020 Dec 5. doi: 10.1002/acr.24529; Rumsey DG et al. Arthritis Care Res. 2020 Dec. 16. doi: 10.1002/acr.24537; Lovell DJ and Brunner HI. Arthritis Care Res. 2020 Dec 16. doi: 10.1002/acr.24536.

Children with enthesitis-related arthritis often have a high burden of disease and could benefit from medications currently approved for adults with spondyloarthritis, according to a review published in Arthritis Care & Research.

“Enthesitis-related arthritis (ERA) was the JIA [juvenile idiopathic arthritis] category applied to children with spondyloarthritis (SpA), recognizing enthesitis as a defining characteristic,” wrote Pamela F. Weiss, MD, of Children’s Hospital of Philadelphia, and colleagues.

The ERA criteria include “arthritis plus enthesitis; or arthritis or enthesitis plus at least two of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27–associated disease, acute anterior uveitis, and arthritis in a male older than 6 years,” the review authors noted.

“None of the [Food and Drug Administration]–approved therapies for peripheral SpA or nonradiographic axial SpA” have been studied or approved for use in children with ERA, but data support biologic similarity to SpA in adults; notably, studies of the HLA-B27 allele have identified it as a risk factor for both SpA and ERA, they said.
 

Common factors in adult and childhood conditions

“The principal commonalities of children with ERA and axial arthritis, and adults with nonradiographic axial SpA, include enthesitis, arthritis, inflammatory back pain, anterior uveitis, HLA-B27 positivity, and family history of HLA-B27–associated disease,” the review authors wrote.

The first-line treatment for both ERA with axial arthritis and nonradiographic axial SpA is NSAIDs, followed by tumor necrosis factor (TNF) inhibitors if needed, they said. However, conventional disease-modifying antirheumatic drugs (cDMARDs) may be used in cases of peripheral disease affecting five or more joints. Studies of treatment response show similarities between ERA in children and SpA in adults, the authors added, with nearly half of adults with axial disease unable to achieve remission and approximately one-third of children with ERA failing to respond to therapy.

Clinical trials could improve options and outcomes for those with ERA who need advanced therapy and such trials should evaluate response of axial and peripheral disease separately, the review authors emphasized. For example, “Eligibility criteria for children with ERA and axial features could include the presence of some of the following disease features: active inflammatory sacroiliitis based on typical MRI changes according to ASAS/OMERACT [Assessment of SpondyloArthritis international Society/Outcome Measures in Rheumatology Clinical Trials] criteria; elevated CRP [C-reactive protein]; and inadequate response or intolerance to NSAIDs,” they noted. “Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations, it is evident that medications approved for axial or peripheral SpA should be studied in children with ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children,” they concluded.

New data highlight ERA disease burden

The need for additional therapies for ERA patients gained more support from a recent study in which a majority of children with ERA or juvenile psoriatic arthritis (jPsA) used biologics, but those with sacroiliitis in particular showed a significant disease burden despite high biologic use.

The International Leagues Against Rheumatism criteria include seven categories of juvenile idiopathic arthritis, of which ERA and jPsA are the most common; however, characteristics of these children have not been well described, wrote Dax G. Rumsey, MD, of the University of Alberta, Edmonton, and colleagues.

“Children with ERA are more likely to have a clinical picture with predominantly peripheral arthritis, typically described as an oligoarthritis involving the lower limbs with high risk of axial disease, relative to the other categories of JIA,” and report more intense pain and worse health status, compared with children in other categories, the researchers wrote.

To more completely characterize children with ERA and jPsA, the researchers assessed 522 children with ERA and 380 with jPsA. The children were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. The findings were published in a brief report in Arthritis Care & Research.

Overall, 69% of the children took at least one biologic, including 72% with ERA and 64% with jPsA. Biologic use was even higher (81%) among the 28% of patients with sacroiliitis (40% of ERA patients and 12% of jPsA patients). Approximately 36% of the patients with sacroiliitis were positive for HLA-B27. In addition, Physician Global Assessment scores and clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) scores were significantly higher at the first clinical visit with sacroiliitis, compared with the first visit without, which confirms “the clinical impression that active sacroiliitis significantly impacts children and their families,” the researchers said.

The average age at diagnosis was 10.8 years for ERA and 8.2 years for jPsA, and significantly more ERA patients were male (56% vs. 38%). However, more of the patients with sacroiliitis (54%) were female. More than half of the patients reported polyarticular involvement.

The study findings were limited by several factors, including the classification of ERA or jPsA and the reliance on physician diagnoses, as well as the variation in identifying sacroiliitis, the researchers said. However, the results increase understanding of the pathophysiology of ERA and jPsA to help determine optimal treatment, they concluded.
 

Data highlight research and treatment gaps

“Recent research demonstrates a large, unmet medical need in the treatment of JIA with 52%-65% of all JIA patients, including those with ERA and jPsA, having been treated with at least one biologic DMARD and 15%-19% having been treated with an FDA-unapproved biologic. In those with ERA or jPsA, 72%-79% of the children had been treated with a biologic DMARD, although no biologic DMARD has ever been FDA approved for these JIA categories,” Daniel J. Lovell, MD, and Hermine I. Brunner, MD, both with Cincinnati Children’s Hospital Medical Center, wrote in an editorial that accompanied the new study. Dr. Lovell and Dr. Brunner also were coauthors of the review article.

The new study supports findings from other recent publications, the editorialists noted. The new results showed “a significant proportion of the JIA population with active sacroiliitis with high disease burden despite very frequent (over 80% of the population) [treatment] with unstudied and unapproved biologic DMARDs,” they said. “These children with sacroiliitis had significantly greater disease burden with higher physician assessment of disease activity, higher parent assessment of disease impact, and higher disease activity as measured by the Juvenile Idiopathic Arthritis Disease Activity Score, compared to the children with ERA or jPsA without sacroiliitis,” they noted.

Jeff Craven/MDedge News

Previously, “the FDA granted pharmaceutical companies studying new treatments in adult SpA automatic full waivers from doing studies in children for new medications for ‘axial spondyloarthropathies including ankylosing spondylitis’ up until July 2020,” the editorialists said. However, “It is now time now for the pharmaceutical industry to perform FDA-monitored clinical trials of children and adolescents with SpA,” they emphasized. “This will allow for the scientific assessment of proper dosing, efficacy, and safety of the increasing number of new medications that are being licensed by the FDA for the treatment of SpA, such as the anti-TNF, anti–IL[interleukin]-17, and anti–IL-23 biologics, and perhaps JAK [Janus kinase] agents, to address this unmet medical need in these patients with juvenile SpA,” they concluded.

Dr. Weiss disclosed grant support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and financial relationships with Eli Lilly and Pfizer. Dr. Lovell disclosed relationships with companies including Abbott, AbbVie Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Novartis, Pfizer, Takeda, UCB, and Wyeth, as well as serving on the data and safety monitoring board for Forest Research and NIAMS. Dr. Brunner disclosed relationships with companies including Ablynx, AbbVie, AstraZeneca-MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, Genzyme, GlaxoSmithKline, Merck, Novartis, R-Pharm, and Sanofi. The study by Dr. Rumsey and colleagues was supported by Amgen. Dr. Rumsey and colleagues had no relevant financial conflicts to disclose.

SOURCES: Weiss PF et al. Arthritis Care Res. 2020 Dec 5. doi: 10.1002/acr.24529; Rumsey DG et al. Arthritis Care Res. 2020 Dec. 16. doi: 10.1002/acr.24537; Lovell DJ and Brunner HI. Arthritis Care Res. 2020 Dec 16. doi: 10.1002/acr.24536.

Children with enthesitis-related arthritis often have a high burden of disease and could benefit from medications currently approved for adults with spondyloarthritis, according to a review published in Arthritis Care & Research.

“Enthesitis-related arthritis (ERA) was the JIA [juvenile idiopathic arthritis] category applied to children with spondyloarthritis (SpA), recognizing enthesitis as a defining characteristic,” wrote Pamela F. Weiss, MD, of Children’s Hospital of Philadelphia, and colleagues.

The ERA criteria include “arthritis plus enthesitis; or arthritis or enthesitis plus at least two of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27–associated disease, acute anterior uveitis, and arthritis in a male older than 6 years,” the review authors noted.

“None of the [Food and Drug Administration]–approved therapies for peripheral SpA or nonradiographic axial SpA” have been studied or approved for use in children with ERA, but data support biologic similarity to SpA in adults; notably, studies of the HLA-B27 allele have identified it as a risk factor for both SpA and ERA, they said.
 

Common factors in adult and childhood conditions

“The principal commonalities of children with ERA and axial arthritis, and adults with nonradiographic axial SpA, include enthesitis, arthritis, inflammatory back pain, anterior uveitis, HLA-B27 positivity, and family history of HLA-B27–associated disease,” the review authors wrote.

The first-line treatment for both ERA with axial arthritis and nonradiographic axial SpA is NSAIDs, followed by tumor necrosis factor (TNF) inhibitors if needed, they said. However, conventional disease-modifying antirheumatic drugs (cDMARDs) may be used in cases of peripheral disease affecting five or more joints. Studies of treatment response show similarities between ERA in children and SpA in adults, the authors added, with nearly half of adults with axial disease unable to achieve remission and approximately one-third of children with ERA failing to respond to therapy.

Clinical trials could improve options and outcomes for those with ERA who need advanced therapy and such trials should evaluate response of axial and peripheral disease separately, the review authors emphasized. For example, “Eligibility criteria for children with ERA and axial features could include the presence of some of the following disease features: active inflammatory sacroiliitis based on typical MRI changes according to ASAS/OMERACT [Assessment of SpondyloArthritis international Society/Outcome Measures in Rheumatology Clinical Trials] criteria; elevated CRP [C-reactive protein]; and inadequate response or intolerance to NSAIDs,” they noted. “Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations, it is evident that medications approved for axial or peripheral SpA should be studied in children with ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children,” they concluded.

New data highlight ERA disease burden

The need for additional therapies for ERA patients gained more support from a recent study in which a majority of children with ERA or juvenile psoriatic arthritis (jPsA) used biologics, but those with sacroiliitis in particular showed a significant disease burden despite high biologic use.

The International Leagues Against Rheumatism criteria include seven categories of juvenile idiopathic arthritis, of which ERA and jPsA are the most common; however, characteristics of these children have not been well described, wrote Dax G. Rumsey, MD, of the University of Alberta, Edmonton, and colleagues.

“Children with ERA are more likely to have a clinical picture with predominantly peripheral arthritis, typically described as an oligoarthritis involving the lower limbs with high risk of axial disease, relative to the other categories of JIA,” and report more intense pain and worse health status, compared with children in other categories, the researchers wrote.

To more completely characterize children with ERA and jPsA, the researchers assessed 522 children with ERA and 380 with jPsA. The children were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. The findings were published in a brief report in Arthritis Care & Research.

Overall, 69% of the children took at least one biologic, including 72% with ERA and 64% with jPsA. Biologic use was even higher (81%) among the 28% of patients with sacroiliitis (40% of ERA patients and 12% of jPsA patients). Approximately 36% of the patients with sacroiliitis were positive for HLA-B27. In addition, Physician Global Assessment scores and clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) scores were significantly higher at the first clinical visit with sacroiliitis, compared with the first visit without, which confirms “the clinical impression that active sacroiliitis significantly impacts children and their families,” the researchers said.

The average age at diagnosis was 10.8 years for ERA and 8.2 years for jPsA, and significantly more ERA patients were male (56% vs. 38%). However, more of the patients with sacroiliitis (54%) were female. More than half of the patients reported polyarticular involvement.

The study findings were limited by several factors, including the classification of ERA or jPsA and the reliance on physician diagnoses, as well as the variation in identifying sacroiliitis, the researchers said. However, the results increase understanding of the pathophysiology of ERA and jPsA to help determine optimal treatment, they concluded.
 

Data highlight research and treatment gaps

“Recent research demonstrates a large, unmet medical need in the treatment of JIA with 52%-65% of all JIA patients, including those with ERA and jPsA, having been treated with at least one biologic DMARD and 15%-19% having been treated with an FDA-unapproved biologic. In those with ERA or jPsA, 72%-79% of the children had been treated with a biologic DMARD, although no biologic DMARD has ever been FDA approved for these JIA categories,” Daniel J. Lovell, MD, and Hermine I. Brunner, MD, both with Cincinnati Children’s Hospital Medical Center, wrote in an editorial that accompanied the new study. Dr. Lovell and Dr. Brunner also were coauthors of the review article.

The new study supports findings from other recent publications, the editorialists noted. The new results showed “a significant proportion of the JIA population with active sacroiliitis with high disease burden despite very frequent (over 80% of the population) [treatment] with unstudied and unapproved biologic DMARDs,” they said. “These children with sacroiliitis had significantly greater disease burden with higher physician assessment of disease activity, higher parent assessment of disease impact, and higher disease activity as measured by the Juvenile Idiopathic Arthritis Disease Activity Score, compared to the children with ERA or jPsA without sacroiliitis,” they noted.

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Previously, “the FDA granted pharmaceutical companies studying new treatments in adult SpA automatic full waivers from doing studies in children for new medications for ‘axial spondyloarthropathies including ankylosing spondylitis’ up until July 2020,” the editorialists said. However, “It is now time now for the pharmaceutical industry to perform FDA-monitored clinical trials of children and adolescents with SpA,” they emphasized. “This will allow for the scientific assessment of proper dosing, efficacy, and safety of the increasing number of new medications that are being licensed by the FDA for the treatment of SpA, such as the anti-TNF, anti–IL[interleukin]-17, and anti–IL-23 biologics, and perhaps JAK [Janus kinase] agents, to address this unmet medical need in these patients with juvenile SpA,” they concluded.

Dr. Weiss disclosed grant support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and financial relationships with Eli Lilly and Pfizer. Dr. Lovell disclosed relationships with companies including Abbott, AbbVie Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Novartis, Pfizer, Takeda, UCB, and Wyeth, as well as serving on the data and safety monitoring board for Forest Research and NIAMS. Dr. Brunner disclosed relationships with companies including Ablynx, AbbVie, AstraZeneca-MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, Genzyme, GlaxoSmithKline, Merck, Novartis, R-Pharm, and Sanofi. The study by Dr. Rumsey and colleagues was supported by Amgen. Dr. Rumsey and colleagues had no relevant financial conflicts to disclose.

SOURCES: Weiss PF et al. Arthritis Care Res. 2020 Dec 5. doi: 10.1002/acr.24529; Rumsey DG et al. Arthritis Care Res. 2020 Dec. 16. doi: 10.1002/acr.24537; Lovell DJ and Brunner HI. Arthritis Care Res. 2020 Dec 16. doi: 10.1002/acr.24536.