Rheumatoid Arthritis

Key clinical point: Withdrawal of methotrexate slightly worsened disease activity without affecting remission rates in patients with rheumatoid arthritis (RA) at target who were treated with the combination of biologic disease-modifying antirheumatic drugs (bDMARD)/targeted synthetic DMARD (tsDMARD) and methotrexate.

Major finding: Withdrawing methotrexate vs maintaining combination therapy increased the disease activity score of 28-joints by 0.20 (95% CI 0.09-0.32) and decreased the proportion of patients achieving low disease activity (risk ratio [RR] 0.88; 95% CI 0.80-0.97); however, the remission rates remained unaffected (RR 0.90; 95% CI 0.81-1.01).

Study details: Findings are from a systematic review and meta-analysis of six randomized controlled trials including 1430 patients with RA at target who were treated with bDMARD or tsDMARD+methotrexate combination therapy, of which 734 withdrew and 696 continued methotrexate.

Disclosures: This study was supported by West China Hospital, Sichuan University. The authors declared no conflicts of interest.

Source: Wang X et al. Withdrawal of MTX in rheumatoid arthritis patients on bDMARD/tsDMARD plus methotrexate at target: A systematic review and meta-analysis. Rheumatology (Oxford). 2022 (Sep 20). Doi: 10.1093/rheumatology/keac515

Key clinical point: Withdrawal of methotrexate slightly worsened disease activity without affecting remission rates in patients with rheumatoid arthritis (RA) at target who were treated with the combination of biologic disease-modifying antirheumatic drugs (bDMARD)/targeted synthetic DMARD (tsDMARD) and methotrexate.

Major finding: Withdrawing methotrexate vs maintaining combination therapy increased the disease activity score of 28-joints by 0.20 (95% CI 0.09-0.32) and decreased the proportion of patients achieving low disease activity (risk ratio [RR] 0.88; 95% CI 0.80-0.97); however, the remission rates remained unaffected (RR 0.90; 95% CI 0.81-1.01).

Study details: Findings are from a systematic review and meta-analysis of six randomized controlled trials including 1430 patients with RA at target who were treated with bDMARD or tsDMARD+methotrexate combination therapy, of which 734 withdrew and 696 continued methotrexate.

Disclosures: This study was supported by West China Hospital, Sichuan University. The authors declared no conflicts of interest.

Source: Wang X et al. Withdrawal of MTX in rheumatoid arthritis patients on bDMARD/tsDMARD plus methotrexate at target: A systematic review and meta-analysis. Rheumatology (Oxford). 2022 (Sep 20). Doi: 10.1093/rheumatology/keac515

Key clinical point: Withdrawal of methotrexate slightly worsened disease activity without affecting remission rates in patients with rheumatoid arthritis (RA) at target who were treated with the combination of biologic disease-modifying antirheumatic drugs (bDMARD)/targeted synthetic DMARD (tsDMARD) and methotrexate.

Major finding: Withdrawing methotrexate vs maintaining combination therapy increased the disease activity score of 28-joints by 0.20 (95% CI 0.09-0.32) and decreased the proportion of patients achieving low disease activity (risk ratio [RR] 0.88; 95% CI 0.80-0.97); however, the remission rates remained unaffected (RR 0.90; 95% CI 0.81-1.01).

Study details: Findings are from a systematic review and meta-analysis of six randomized controlled trials including 1430 patients with RA at target who were treated with bDMARD or tsDMARD+methotrexate combination therapy, of which 734 withdrew and 696 continued methotrexate.

Disclosures: This study was supported by West China Hospital, Sichuan University. The authors declared no conflicts of interest.

Source: Wang X et al. Withdrawal of MTX in rheumatoid arthritis patients on bDMARD/tsDMARD plus methotrexate at target: A systematic review and meta-analysis. Rheumatology (Oxford). 2022 (Sep 20). Doi: 10.1093/rheumatology/keac515

Key clinical point: Ultrasound-detected subclinical inflammation of tendons and joints was better controlled in patients with rheumatoid arthritis (RA) in clinical remission who received the combination therapy of conventional synthetic and biologic disease-modifying antirheumatic drugs (csDMARD+bDMARD) vs csDMARD or bDMARD monotherapy.

Major finding: Grey-scale tenosynovitis (P = .025) and power Doppler (PD) tenosynovitis (P = .047) were better controlled with csDMARD+bDMARD than with csDMARD alone. csDMARD+bDMARD was also associated with better treatment results for PD synovitis vs csDMARD (P = .01) or bDMARD (P = .02) alone.

Study details: Findings are from a longitudinal analysis of the STARTER study including 256 patients with RA in clinical remission who received csDMARD alone, bDMARD alone, or csDMARD+bDMARD.

Disclosures: This study did not receive any specific funding. The authors declared no conflicts of interest.

Source: Parisi S et al. Relationship between the prevalence of subclinical tenosynovitis and treatment in patients with RA in clinical remission: STARTER study. Rheumatology (Oxford). 2022 (Sep 6). Doi: 10.1093/rheumatology/keac518

Key clinical point: Ultrasound-detected subclinical inflammation of tendons and joints was better controlled in patients with rheumatoid arthritis (RA) in clinical remission who received the combination therapy of conventional synthetic and biologic disease-modifying antirheumatic drugs (csDMARD+bDMARD) vs csDMARD or bDMARD monotherapy.

Major finding: Grey-scale tenosynovitis (P = .025) and power Doppler (PD) tenosynovitis (P = .047) were better controlled with csDMARD+bDMARD than with csDMARD alone. csDMARD+bDMARD was also associated with better treatment results for PD synovitis vs csDMARD (P = .01) or bDMARD (P = .02) alone.

Study details: Findings are from a longitudinal analysis of the STARTER study including 256 patients with RA in clinical remission who received csDMARD alone, bDMARD alone, or csDMARD+bDMARD.

Disclosures: This study did not receive any specific funding. The authors declared no conflicts of interest.

Source: Parisi S et al. Relationship between the prevalence of subclinical tenosynovitis and treatment in patients with RA in clinical remission: STARTER study. Rheumatology (Oxford). 2022 (Sep 6). Doi: 10.1093/rheumatology/keac518

Key clinical point: Ultrasound-detected subclinical inflammation of tendons and joints was better controlled in patients with rheumatoid arthritis (RA) in clinical remission who received the combination therapy of conventional synthetic and biologic disease-modifying antirheumatic drugs (csDMARD+bDMARD) vs csDMARD or bDMARD monotherapy.

Major finding: Grey-scale tenosynovitis (P = .025) and power Doppler (PD) tenosynovitis (P = .047) were better controlled with csDMARD+bDMARD than with csDMARD alone. csDMARD+bDMARD was also associated with better treatment results for PD synovitis vs csDMARD (P = .01) or bDMARD (P = .02) alone.

Study details: Findings are from a longitudinal analysis of the STARTER study including 256 patients with RA in clinical remission who received csDMARD alone, bDMARD alone, or csDMARD+bDMARD.

Disclosures: This study did not receive any specific funding. The authors declared no conflicts of interest.

Source: Parisi S et al. Relationship between the prevalence of subclinical tenosynovitis and treatment in patients with RA in clinical remission: STARTER study. Rheumatology (Oxford). 2022 (Sep 6). Doi: 10.1093/rheumatology/keac518

Key clinical point: Patients with rheumatoid arthritis (RA), including those across different phenotypic subgroups, were at an increased risk for severe COVID-19 compared with patients without RA, with a pronounced association being observed in patients with RA-associated interstitial lung disease (RA-ILD).

Major finding: Risk for severe COVID-19 was significantly higher in patients with RA vs. those without RA (adjusted hazard ratio [aHR], 1.75; P < .0001). Risk was persistent among the sub-group of patients who were seropositive (aHR, 1.97; P < .0001) or had erosive disease (aHR, 1.93; P < .0001) and most prominent among patients with RA-ILD (aHR, 2.50; P < .0001).

Study details: Findings are from a retrospective study of 582 patients with RA and 2,875 matched comparators without RA, all of whom had COVID-19.

Disclosures: This study did not receive any funding. Some authors reported receiving research support, consulting fees, and/or grants unrelated to this study from various sources.

Source: Figueroa-Parra G et al. Risk of severe COVID-19 outcomes associated with rheumatoid arthritis and phenotypic subgroups: A retrospective, comparative, multicentre cohort study. Lancet Rheumatol. 2022 (Sep 13). Doi: 10.1016/S2665-9913(22)00227-2.

Key clinical point: Patients with rheumatoid arthritis (RA), including those across different phenotypic subgroups, were at an increased risk for severe COVID-19 compared with patients without RA, with a pronounced association being observed in patients with RA-associated interstitial lung disease (RA-ILD).

Major finding: Risk for severe COVID-19 was significantly higher in patients with RA vs. those without RA (adjusted hazard ratio [aHR], 1.75; P < .0001). Risk was persistent among the sub-group of patients who were seropositive (aHR, 1.97; P < .0001) or had erosive disease (aHR, 1.93; P < .0001) and most prominent among patients with RA-ILD (aHR, 2.50; P < .0001).

Study details: Findings are from a retrospective study of 582 patients with RA and 2,875 matched comparators without RA, all of whom had COVID-19.

Disclosures: This study did not receive any funding. Some authors reported receiving research support, consulting fees, and/or grants unrelated to this study from various sources.

Source: Figueroa-Parra G et al. Risk of severe COVID-19 outcomes associated with rheumatoid arthritis and phenotypic subgroups: A retrospective, comparative, multicentre cohort study. Lancet Rheumatol. 2022 (Sep 13). Doi: 10.1016/S2665-9913(22)00227-2.

Key clinical point: Patients with rheumatoid arthritis (RA), including those across different phenotypic subgroups, were at an increased risk for severe COVID-19 compared with patients without RA, with a pronounced association being observed in patients with RA-associated interstitial lung disease (RA-ILD).

Major finding: Risk for severe COVID-19 was significantly higher in patients with RA vs. those without RA (adjusted hazard ratio [aHR], 1.75; P < .0001). Risk was persistent among the sub-group of patients who were seropositive (aHR, 1.97; P < .0001) or had erosive disease (aHR, 1.93; P < .0001) and most prominent among patients with RA-ILD (aHR, 2.50; P < .0001).

Study details: Findings are from a retrospective study of 582 patients with RA and 2,875 matched comparators without RA, all of whom had COVID-19.

Disclosures: This study did not receive any funding. Some authors reported receiving research support, consulting fees, and/or grants unrelated to this study from various sources.

Source: Figueroa-Parra G et al. Risk of severe COVID-19 outcomes associated with rheumatoid arthritis and phenotypic subgroups: A retrospective, comparative, multicentre cohort study. Lancet Rheumatol. 2022 (Sep 13). Doi: 10.1016/S2665-9913(22)00227-2.

People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).

The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.

The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
 

Expert commentary

This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”

The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.

“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”

The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.

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

People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).

The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.

The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
 

Expert commentary

This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”

The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.

“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”

The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.

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

People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).

The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.

The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
 

Expert commentary

This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”

The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.

“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”

The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.

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

Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.

The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.

These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.

More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.

“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.

Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.

Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).

These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
 

Findings from Echo ORAL Surveillance

“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”

Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.

He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.

“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”

Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.

“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.

Boxed warnings encourage caution, lock treatment sequence

Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.

“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”

If these risks aren’t discussed, he noted, patient trust may falter.

“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”

Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.

Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.

“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”

The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.

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

Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.

The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.

These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.

More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.

“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.

Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.

Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).

These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
 

Findings from Echo ORAL Surveillance

“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”

Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.

He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.

“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”

Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.

“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.

Boxed warnings encourage caution, lock treatment sequence

Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.

“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”

If these risks aren’t discussed, he noted, patient trust may falter.

“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”

Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.

Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.

“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”

The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.

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

Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.

The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.

These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.

More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.

“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.

Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.

Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).

These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
 

Findings from Echo ORAL Surveillance

“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”

Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.

He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.

“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”

Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.

“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.

Boxed warnings encourage caution, lock treatment sequence

Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.

“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”

If these risks aren’t discussed, he noted, patient trust may falter.

“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”

Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.

Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.

“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”

The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.

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

Workers in the hard rock and other mining industries were significantly more likely to develop rheumatoid arthritis than were controls in the general population, based on data from nearly 2,000 individuals.

Although respirable silica exposure has been consistently linked to rheumatoid arthritis (RA) in a variety of occupations including foundry work, construction, and stone crushing and drilling, the association between RA risk and hard rock mining has not been investigated, lead author Paul D. Blanc, MD, of the University of California, San Francisco, and colleagues wrote in a study published in JAMA Network Open.

“Many clinical rheumatologists and most generalists are unaware that what a person does for a living can be a risk factor for rheumatoid arthritis,” Dr. Blanc said in an interview. “This study makes an important contribution to showing that work exposures can more than double the risk of RA,” he said.

“We were surprised by the widespread nature of the work-related risk within and beyond the mining sector,” Dr. Blanc noted. Given the range of potential occupational exposures, his take-home message to rheumatologists is to ask each and every patient about their work history.

The researchers conducted random telephone surveys of 1,988 men aged 50 years and older living in the Four Corners region of the United States (Colorado, New Mexico, and Utah) in counties selected for high levels of pneumoconiosis mortality. The surveys were conducted between Jan. 12, 2021, and May 4, 2021. The mean age of the study population was 68.6 years, and 82.6% were non-Hispanic White. Approximately half reported being former or current smokers.

RA was defined as having a clinician diagnosis, and was further defined by treatment with corticosteroids or disease-modifying antirheumatic drugs (DMARDs).

A total of 262 respondents (13.1%) reported work in surface mining or ore processing, with no underground exposure; 118 respondents (5.9%) reported work in underground hard rock mining; and 62 (3.1%) reported work in underground mining of other type, primarily coal mining.

Overall, after adjusting for age, smoking, and nonmining silica exposure, any mining work was associated with a three- to fourfold increased risk of RA for individuals with a RA diagnosis who were treated with corticosteroids and those treated with DMARDs (odds ratios, 4.12 and 3.30, respectively).

The risk was approximately nine times and six times higher for individuals with a history of underground soft rock mining (mainly coal, no hard rock mining), with odds ratios of 9.74 and 6.42, for those with RA treated with corticosteroids and DMARDs, respectively.

The odds of RA were higher with coal and other underground fossil hydrocarbon mining, compared with underground hard rock mining, the researchers wrote in their discussion. Reasons for this difference could include the longer employment duration for underground coal mining, but also the possibility that “in coal mining, silica inhalation may not be the sole cause, but rather that carbonaceous materials may also be involved etiologically in RA risk in that occupation,” they wrote. No association was found between increased risk of RA and current or former smoking, they noted, in contrast to the researchers’ previous studies of Appalachian coal miners.

The study findings were limited by several factors including the potential for recall bias and misclassified exposure and diagnoses, the researchers noted. Other limitations include the focus on individuals aged 50 years and older in a limited geographic region of the United States and the relatively short time of employment in mining, they said.

However, the results support previous studies showing an increased RA risk with respirable silica exposure, and suggest that clinicians consider mining among other work exposures that could increase the risk for developing RA, the researchers concluded.

Looking ahead, Dr. Blanc said that additional research is needed to tease out disease progression and severity in the face of past occupational exposures.

The study was supported by the Alpha Foundation and the Russell/Engleman Rheumatology Research Center through grants to the researchers. The researchers had no other financial conflicts to disclose.

Workers in the hard rock and other mining industries were significantly more likely to develop rheumatoid arthritis than were controls in the general population, based on data from nearly 2,000 individuals.

Although respirable silica exposure has been consistently linked to rheumatoid arthritis (RA) in a variety of occupations including foundry work, construction, and stone crushing and drilling, the association between RA risk and hard rock mining has not been investigated, lead author Paul D. Blanc, MD, of the University of California, San Francisco, and colleagues wrote in a study published in JAMA Network Open.

“Many clinical rheumatologists and most generalists are unaware that what a person does for a living can be a risk factor for rheumatoid arthritis,” Dr. Blanc said in an interview. “This study makes an important contribution to showing that work exposures can more than double the risk of RA,” he said.

“We were surprised by the widespread nature of the work-related risk within and beyond the mining sector,” Dr. Blanc noted. Given the range of potential occupational exposures, his take-home message to rheumatologists is to ask each and every patient about their work history.

The researchers conducted random telephone surveys of 1,988 men aged 50 years and older living in the Four Corners region of the United States (Colorado, New Mexico, and Utah) in counties selected for high levels of pneumoconiosis mortality. The surveys were conducted between Jan. 12, 2021, and May 4, 2021. The mean age of the study population was 68.6 years, and 82.6% were non-Hispanic White. Approximately half reported being former or current smokers.

RA was defined as having a clinician diagnosis, and was further defined by treatment with corticosteroids or disease-modifying antirheumatic drugs (DMARDs).

A total of 262 respondents (13.1%) reported work in surface mining or ore processing, with no underground exposure; 118 respondents (5.9%) reported work in underground hard rock mining; and 62 (3.1%) reported work in underground mining of other type, primarily coal mining.

Overall, after adjusting for age, smoking, and nonmining silica exposure, any mining work was associated with a three- to fourfold increased risk of RA for individuals with a RA diagnosis who were treated with corticosteroids and those treated with DMARDs (odds ratios, 4.12 and 3.30, respectively).

The risk was approximately nine times and six times higher for individuals with a history of underground soft rock mining (mainly coal, no hard rock mining), with odds ratios of 9.74 and 6.42, for those with RA treated with corticosteroids and DMARDs, respectively.

The odds of RA were higher with coal and other underground fossil hydrocarbon mining, compared with underground hard rock mining, the researchers wrote in their discussion. Reasons for this difference could include the longer employment duration for underground coal mining, but also the possibility that “in coal mining, silica inhalation may not be the sole cause, but rather that carbonaceous materials may also be involved etiologically in RA risk in that occupation,” they wrote. No association was found between increased risk of RA and current or former smoking, they noted, in contrast to the researchers’ previous studies of Appalachian coal miners.

The study findings were limited by several factors including the potential for recall bias and misclassified exposure and diagnoses, the researchers noted. Other limitations include the focus on individuals aged 50 years and older in a limited geographic region of the United States and the relatively short time of employment in mining, they said.

However, the results support previous studies showing an increased RA risk with respirable silica exposure, and suggest that clinicians consider mining among other work exposures that could increase the risk for developing RA, the researchers concluded.

Looking ahead, Dr. Blanc said that additional research is needed to tease out disease progression and severity in the face of past occupational exposures.

The study was supported by the Alpha Foundation and the Russell/Engleman Rheumatology Research Center through grants to the researchers. The researchers had no other financial conflicts to disclose.

Workers in the hard rock and other mining industries were significantly more likely to develop rheumatoid arthritis than were controls in the general population, based on data from nearly 2,000 individuals.

Although respirable silica exposure has been consistently linked to rheumatoid arthritis (RA) in a variety of occupations including foundry work, construction, and stone crushing and drilling, the association between RA risk and hard rock mining has not been investigated, lead author Paul D. Blanc, MD, of the University of California, San Francisco, and colleagues wrote in a study published in JAMA Network Open.

“Many clinical rheumatologists and most generalists are unaware that what a person does for a living can be a risk factor for rheumatoid arthritis,” Dr. Blanc said in an interview. “This study makes an important contribution to showing that work exposures can more than double the risk of RA,” he said.

“We were surprised by the widespread nature of the work-related risk within and beyond the mining sector,” Dr. Blanc noted. Given the range of potential occupational exposures, his take-home message to rheumatologists is to ask each and every patient about their work history.

The researchers conducted random telephone surveys of 1,988 men aged 50 years and older living in the Four Corners region of the United States (Colorado, New Mexico, and Utah) in counties selected for high levels of pneumoconiosis mortality. The surveys were conducted between Jan. 12, 2021, and May 4, 2021. The mean age of the study population was 68.6 years, and 82.6% were non-Hispanic White. Approximately half reported being former or current smokers.

RA was defined as having a clinician diagnosis, and was further defined by treatment with corticosteroids or disease-modifying antirheumatic drugs (DMARDs).

A total of 262 respondents (13.1%) reported work in surface mining or ore processing, with no underground exposure; 118 respondents (5.9%) reported work in underground hard rock mining; and 62 (3.1%) reported work in underground mining of other type, primarily coal mining.

Overall, after adjusting for age, smoking, and nonmining silica exposure, any mining work was associated with a three- to fourfold increased risk of RA for individuals with a RA diagnosis who were treated with corticosteroids and those treated with DMARDs (odds ratios, 4.12 and 3.30, respectively).

The risk was approximately nine times and six times higher for individuals with a history of underground soft rock mining (mainly coal, no hard rock mining), with odds ratios of 9.74 and 6.42, for those with RA treated with corticosteroids and DMARDs, respectively.

The odds of RA were higher with coal and other underground fossil hydrocarbon mining, compared with underground hard rock mining, the researchers wrote in their discussion. Reasons for this difference could include the longer employment duration for underground coal mining, but also the possibility that “in coal mining, silica inhalation may not be the sole cause, but rather that carbonaceous materials may also be involved etiologically in RA risk in that occupation,” they wrote. No association was found between increased risk of RA and current or former smoking, they noted, in contrast to the researchers’ previous studies of Appalachian coal miners.

The study findings were limited by several factors including the potential for recall bias and misclassified exposure and diagnoses, the researchers noted. Other limitations include the focus on individuals aged 50 years and older in a limited geographic region of the United States and the relatively short time of employment in mining, they said.

However, the results support previous studies showing an increased RA risk with respirable silica exposure, and suggest that clinicians consider mining among other work exposures that could increase the risk for developing RA, the researchers concluded.

Looking ahead, Dr. Blanc said that additional research is needed to tease out disease progression and severity in the face of past occupational exposures.

The study was supported by the Alpha Foundation and the Russell/Engleman Rheumatology Research Center through grants to the researchers. The researchers had no other financial conflicts to disclose.

People who develop long COVID may be responding more strongly to a non–SARS-CoV-2 virus they encountered in the past than to SARS-CoV-2, a study by researchers at Harvard Medical School suggests.

Long COVID, also called postacute sequelae of COVID-19 (PASC), causes various symptoms that persist at least 4 weeks after the initial SARS-CoV-2 infection, they write in the preprint server medRxiv. Four authors explained their research into possible mechanisms of long COVID in an interview.

“Immunity to non-COVID endemic coronaviruses may play a role in who develops PASC,” co–lead author Jonathan D. Herman, MD, PhD, said. “There’s still so much more we need to understand, but it is striking that back-boosting of immune responses to coronavirus OC43 was uniquely enriched in individuals with PASC.”

“In the study, individuals with PASC preferentially generated stronger responses to previously encountered cold-causing coronaviruses,” co–senior author Galit Alter, PhD, said.

“Instead of generating strong SARS-CoV-2 immunity, they bolstered a response to a different coronavirus, potentially making their response less effective in clearing SARS-CoV-2. Surprisingly, most of the individuals had been vaccinated – and they still maintained this unusual antibody response – pointing to new therapeutic pathways to treat PASC,” Dr. Alter said.
 

Humoral immunity offers a clue to long-COVID origins

One-fifth of COVID-19 patients progress to long COVID, but which patients develop PASC and why are not well understood, the authors write.

“Antibodies represent powerful biomarkers that have been used for decades to diagnose disease. However, antibodies also provide a powerful source of information on previous infections. The use of antibody profiling, here, pointed to the presence of incomplete antibody responses to SARS-CoV-2 in individuals with PASC,” Dr. Alter said.

The researchers reviewed the medical records of patients in the Mass General Brigham health care system in Boston, including referrals from rheumatologists of participants diagnosed with COVID-19 outside the MGB system, starting on March 1, 2020.

They focused on patients with systemic autoimmune rheumatic diseases (SARDs) because their tendency toward inflammation and autoantibody production may make them more susceptible to PASC and enrich for specific inflammatory-driven endotypes.

All 43 participants had COVID-19 without hospital admission and SARDs. Patients treated only for fibromyalgia, osteoarthritis, mechanical back pain, gout, or pseudogout without a SARD were excluded from the study.

Overall, 79% of participants were female, 35% had rheumatoid arthritis, 19% had psoriatic arthritis, and 95% had received a COVID-19 vaccine.

The researchers used systems serology to perform comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens.
 

Long-COVID patients had a distinct immune response

Overall, 17 patients developed PASC and 26 did not, and in those with PASC, they found a distinct humoral immune response. Patients with PASC:

• harbored less inflamed and weaker Fc-gamma receptor–binding anti–SARS-CoV-2 antibodies;
• showed a significantly expanded and more inflamed antibody response against endemic coronavirus OC43; and
• mounted more avid IgM responses and developed expanded inflammatory OC43 S2–specific Fc-receptor–binding responses, which were linked to cross reactivity across SARS-CoV-2 and common coronaviruses.

“Strengths of the study include the detailed phenotypes of cases after COVID-19, particularly to classify PASC presence or absence, as well as the depth and breadth of antibody profiling. This allowed us to identify a humoral immune signature of PASC,” said co–senior author Jeffrey A. Sparks, MD, MMSc.

“However, the study was limited in its size to investigate different types of PASC, such as fatigue or lung symptoms, that may have biologic differences. Also, all patients in the study had a preexisting rheumatic disease,” he acknowledged.

“A substantial portion of patients with COVID-19 will develop PASC, which can have substantial impact on health and quality of life,” said co–senior author Zachary S. Wallace, MD, MS. “Given the higher risk of COVID-19 in many patients with rheumatic disease, it is important to understand the etiology of PASC in this vulnerable population, to enable future diagnostic and therapeutic advances.”

Davey Smith, MD, professor of medicine and head of infectious diseases and global public health at the University of California, San Diego, in La Jolla, who was not involved in the study, called the findings interesting even though the results will not immediately affect patient care.

“There may be a link between previous non–SARS-CoV-2 coronavirus infection and PASC,” he added. “Perhaps, by understanding why some people do and do not get PASC, we can develop treatments for the condition.

“This paper is a preprint and will need to go through peer review,” Dr. Smith said. “There are many elements that need to be scrutinized. For example, there is no definition of PASC that is universally accepted, so how did that play into this study?”

Mark Cameron, PhD, associate professor in the department of population and quantitative health sciences at Case Western Reserve University, Cleveland, called this a strong study from a strong group, although it is a preprint prior to peer review.

“In this initial study, the scientists focused on people who had rheumatic disease before getting COVID-19, knowing they are at higher risk for lasting complications and hopefully are more immunologically similar when diagnosed with long COVID – a single ‘endotype’ or group of patients with similar clinical symptoms and background,” he noted.

“Our immune system’s memory sometimes fails to effectively fight a new virus that looks too much like a virus it saw before. This ineffective immune response can set up various problems, including the poor recoveries we see in people with long COVID,” he said.

“OC43 probably emerged in the late 1800s and probably caused a pandemic of severe respiratory illness between 1889 and 1890, previously thought to be a flu,” Dr. Cameron recalled. “OC43 is still around as an endemic coronavirus, usually causing mild or moderate upper-respiratory infections.”

COVID-19 immunity is complex, and previous SARS-CoV-2 infection doesn’t guarantee we won't get COVID-19 again, especially as new variants emerge, added Dr. Cameron, who also was not involved in the study.

“This study may help us better understand the risks and possible mechanisms associated with COVID-19 and long COVID in the face of previous coronavirus infections,” he said. “It may also help guide future COVID-19 therapies and vaccines.”

The authors plan further related research.

The study received grant support and an anonymous donation. Dr. Alter, Dr. Sparks, and Dr. Wallace report financial relationships with the pharmaceutical industry. All other authors, and Dr. Davey and Dr. Cameron, report no conflicts of interest with the study. All experts commented by email.

* This story was updated 10/12/2022.

People who develop long COVID may be responding more strongly to a non–SARS-CoV-2 virus they encountered in the past than to SARS-CoV-2, a study by researchers at Harvard Medical School suggests.

Long COVID, also called postacute sequelae of COVID-19 (PASC), causes various symptoms that persist at least 4 weeks after the initial SARS-CoV-2 infection, they write in the preprint server medRxiv. Four authors explained their research into possible mechanisms of long COVID in an interview.

“Immunity to non-COVID endemic coronaviruses may play a role in who develops PASC,” co–lead author Jonathan D. Herman, MD, PhD, said. “There’s still so much more we need to understand, but it is striking that back-boosting of immune responses to coronavirus OC43 was uniquely enriched in individuals with PASC.”

“In the study, individuals with PASC preferentially generated stronger responses to previously encountered cold-causing coronaviruses,” co–senior author Galit Alter, PhD, said.

“Instead of generating strong SARS-CoV-2 immunity, they bolstered a response to a different coronavirus, potentially making their response less effective in clearing SARS-CoV-2. Surprisingly, most of the individuals had been vaccinated – and they still maintained this unusual antibody response – pointing to new therapeutic pathways to treat PASC,” Dr. Alter said.
 

Humoral immunity offers a clue to long-COVID origins

One-fifth of COVID-19 patients progress to long COVID, but which patients develop PASC and why are not well understood, the authors write.

“Antibodies represent powerful biomarkers that have been used for decades to diagnose disease. However, antibodies also provide a powerful source of information on previous infections. The use of antibody profiling, here, pointed to the presence of incomplete antibody responses to SARS-CoV-2 in individuals with PASC,” Dr. Alter said.

The researchers reviewed the medical records of patients in the Mass General Brigham health care system in Boston, including referrals from rheumatologists of participants diagnosed with COVID-19 outside the MGB system, starting on March 1, 2020.

They focused on patients with systemic autoimmune rheumatic diseases (SARDs) because their tendency toward inflammation and autoantibody production may make them more susceptible to PASC and enrich for specific inflammatory-driven endotypes.

All 43 participants had COVID-19 without hospital admission and SARDs. Patients treated only for fibromyalgia, osteoarthritis, mechanical back pain, gout, or pseudogout without a SARD were excluded from the study.

Overall, 79% of participants were female, 35% had rheumatoid arthritis, 19% had psoriatic arthritis, and 95% had received a COVID-19 vaccine.

The researchers used systems serology to perform comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens.
 

Long-COVID patients had a distinct immune response

Overall, 17 patients developed PASC and 26 did not, and in those with PASC, they found a distinct humoral immune response. Patients with PASC:

• harbored less inflamed and weaker Fc-gamma receptor–binding anti–SARS-CoV-2 antibodies;
• showed a significantly expanded and more inflamed antibody response against endemic coronavirus OC43; and
• mounted more avid IgM responses and developed expanded inflammatory OC43 S2–specific Fc-receptor–binding responses, which were linked to cross reactivity across SARS-CoV-2 and common coronaviruses.

“Strengths of the study include the detailed phenotypes of cases after COVID-19, particularly to classify PASC presence or absence, as well as the depth and breadth of antibody profiling. This allowed us to identify a humoral immune signature of PASC,” said co–senior author Jeffrey A. Sparks, MD, MMSc.

“However, the study was limited in its size to investigate different types of PASC, such as fatigue or lung symptoms, that may have biologic differences. Also, all patients in the study had a preexisting rheumatic disease,” he acknowledged.

“A substantial portion of patients with COVID-19 will develop PASC, which can have substantial impact on health and quality of life,” said co–senior author Zachary S. Wallace, MD, MS. “Given the higher risk of COVID-19 in many patients with rheumatic disease, it is important to understand the etiology of PASC in this vulnerable population, to enable future diagnostic and therapeutic advances.”

Davey Smith, MD, professor of medicine and head of infectious diseases and global public health at the University of California, San Diego, in La Jolla, who was not involved in the study, called the findings interesting even though the results will not immediately affect patient care.

“There may be a link between previous non–SARS-CoV-2 coronavirus infection and PASC,” he added. “Perhaps, by understanding why some people do and do not get PASC, we can develop treatments for the condition.

“This paper is a preprint and will need to go through peer review,” Dr. Smith said. “There are many elements that need to be scrutinized. For example, there is no definition of PASC that is universally accepted, so how did that play into this study?”

Mark Cameron, PhD, associate professor in the department of population and quantitative health sciences at Case Western Reserve University, Cleveland, called this a strong study from a strong group, although it is a preprint prior to peer review.

“In this initial study, the scientists focused on people who had rheumatic disease before getting COVID-19, knowing they are at higher risk for lasting complications and hopefully are more immunologically similar when diagnosed with long COVID – a single ‘endotype’ or group of patients with similar clinical symptoms and background,” he noted.

“Our immune system’s memory sometimes fails to effectively fight a new virus that looks too much like a virus it saw before. This ineffective immune response can set up various problems, including the poor recoveries we see in people with long COVID,” he said.

“OC43 probably emerged in the late 1800s and probably caused a pandemic of severe respiratory illness between 1889 and 1890, previously thought to be a flu,” Dr. Cameron recalled. “OC43 is still around as an endemic coronavirus, usually causing mild or moderate upper-respiratory infections.”

COVID-19 immunity is complex, and previous SARS-CoV-2 infection doesn’t guarantee we won't get COVID-19 again, especially as new variants emerge, added Dr. Cameron, who also was not involved in the study.

“This study may help us better understand the risks and possible mechanisms associated with COVID-19 and long COVID in the face of previous coronavirus infections,” he said. “It may also help guide future COVID-19 therapies and vaccines.”

The authors plan further related research.

The study received grant support and an anonymous donation. Dr. Alter, Dr. Sparks, and Dr. Wallace report financial relationships with the pharmaceutical industry. All other authors, and Dr. Davey and Dr. Cameron, report no conflicts of interest with the study. All experts commented by email.

* This story was updated 10/12/2022.

People who develop long COVID may be responding more strongly to a non–SARS-CoV-2 virus they encountered in the past than to SARS-CoV-2, a study by researchers at Harvard Medical School suggests.

Long COVID, also called postacute sequelae of COVID-19 (PASC), causes various symptoms that persist at least 4 weeks after the initial SARS-CoV-2 infection, they write in the preprint server medRxiv. Four authors explained their research into possible mechanisms of long COVID in an interview.

“Immunity to non-COVID endemic coronaviruses may play a role in who develops PASC,” co–lead author Jonathan D. Herman, MD, PhD, said. “There’s still so much more we need to understand, but it is striking that back-boosting of immune responses to coronavirus OC43 was uniquely enriched in individuals with PASC.”

“In the study, individuals with PASC preferentially generated stronger responses to previously encountered cold-causing coronaviruses,” co–senior author Galit Alter, PhD, said.

“Instead of generating strong SARS-CoV-2 immunity, they bolstered a response to a different coronavirus, potentially making their response less effective in clearing SARS-CoV-2. Surprisingly, most of the individuals had been vaccinated – and they still maintained this unusual antibody response – pointing to new therapeutic pathways to treat PASC,” Dr. Alter said.
 

Humoral immunity offers a clue to long-COVID origins

One-fifth of COVID-19 patients progress to long COVID, but which patients develop PASC and why are not well understood, the authors write.

“Antibodies represent powerful biomarkers that have been used for decades to diagnose disease. However, antibodies also provide a powerful source of information on previous infections. The use of antibody profiling, here, pointed to the presence of incomplete antibody responses to SARS-CoV-2 in individuals with PASC,” Dr. Alter said.

The researchers reviewed the medical records of patients in the Mass General Brigham health care system in Boston, including referrals from rheumatologists of participants diagnosed with COVID-19 outside the MGB system, starting on March 1, 2020.

They focused on patients with systemic autoimmune rheumatic diseases (SARDs) because their tendency toward inflammation and autoantibody production may make them more susceptible to PASC and enrich for specific inflammatory-driven endotypes.

All 43 participants had COVID-19 without hospital admission and SARDs. Patients treated only for fibromyalgia, osteoarthritis, mechanical back pain, gout, or pseudogout without a SARD were excluded from the study.

Overall, 79% of participants were female, 35% had rheumatoid arthritis, 19% had psoriatic arthritis, and 95% had received a COVID-19 vaccine.

The researchers used systems serology to perform comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens.
 

Long-COVID patients had a distinct immune response

Overall, 17 patients developed PASC and 26 did not, and in those with PASC, they found a distinct humoral immune response. Patients with PASC:

• harbored less inflamed and weaker Fc-gamma receptor–binding anti–SARS-CoV-2 antibodies;
• showed a significantly expanded and more inflamed antibody response against endemic coronavirus OC43; and
• mounted more avid IgM responses and developed expanded inflammatory OC43 S2–specific Fc-receptor–binding responses, which were linked to cross reactivity across SARS-CoV-2 and common coronaviruses.

“Strengths of the study include the detailed phenotypes of cases after COVID-19, particularly to classify PASC presence or absence, as well as the depth and breadth of antibody profiling. This allowed us to identify a humoral immune signature of PASC,” said co–senior author Jeffrey A. Sparks, MD, MMSc.

“However, the study was limited in its size to investigate different types of PASC, such as fatigue or lung symptoms, that may have biologic differences. Also, all patients in the study had a preexisting rheumatic disease,” he acknowledged.

“A substantial portion of patients with COVID-19 will develop PASC, which can have substantial impact on health and quality of life,” said co–senior author Zachary S. Wallace, MD, MS. “Given the higher risk of COVID-19 in many patients with rheumatic disease, it is important to understand the etiology of PASC in this vulnerable population, to enable future diagnostic and therapeutic advances.”

Davey Smith, MD, professor of medicine and head of infectious diseases and global public health at the University of California, San Diego, in La Jolla, who was not involved in the study, called the findings interesting even though the results will not immediately affect patient care.

“There may be a link between previous non–SARS-CoV-2 coronavirus infection and PASC,” he added. “Perhaps, by understanding why some people do and do not get PASC, we can develop treatments for the condition.

“This paper is a preprint and will need to go through peer review,” Dr. Smith said. “There are many elements that need to be scrutinized. For example, there is no definition of PASC that is universally accepted, so how did that play into this study?”

Mark Cameron, PhD, associate professor in the department of population and quantitative health sciences at Case Western Reserve University, Cleveland, called this a strong study from a strong group, although it is a preprint prior to peer review.

“In this initial study, the scientists focused on people who had rheumatic disease before getting COVID-19, knowing they are at higher risk for lasting complications and hopefully are more immunologically similar when diagnosed with long COVID – a single ‘endotype’ or group of patients with similar clinical symptoms and background,” he noted.

“Our immune system’s memory sometimes fails to effectively fight a new virus that looks too much like a virus it saw before. This ineffective immune response can set up various problems, including the poor recoveries we see in people with long COVID,” he said.

“OC43 probably emerged in the late 1800s and probably caused a pandemic of severe respiratory illness between 1889 and 1890, previously thought to be a flu,” Dr. Cameron recalled. “OC43 is still around as an endemic coronavirus, usually causing mild or moderate upper-respiratory infections.”

COVID-19 immunity is complex, and previous SARS-CoV-2 infection doesn’t guarantee we won't get COVID-19 again, especially as new variants emerge, added Dr. Cameron, who also was not involved in the study.

“This study may help us better understand the risks and possible mechanisms associated with COVID-19 and long COVID in the face of previous coronavirus infections,” he said. “It may also help guide future COVID-19 therapies and vaccines.”

The authors plan further related research.

The study received grant support and an anonymous donation. Dr. Alter, Dr. Sparks, and Dr. Wallace report financial relationships with the pharmaceutical industry. All other authors, and Dr. Davey and Dr. Cameron, report no conflicts of interest with the study. All experts commented by email.

* This story was updated 10/12/2022.

Tixagevimab copackaged with cilgavimab (Evusheld) is a safe and effective preexposure prophylaxis (PrEP) in patients undergoing B-cell-depleting therapies who have poor immune response to COVID-19 vaccination and are at high risk for serious COVID-19 illness, a small, single-site study suggests.

Evusheld, the only COVID-19 PrEP option available, has Emergency Use Authorization (EUA) from the Food and Drug Administration for treatment of immunocompromised patients who may not respond sufficiently to COVID-19 vaccination and patients who’ve had a severe adverse reaction to COVID-19 vaccination.

“We report the largest real-world experience of Evusheld in this population, and our findings are encouraging,” lead study author Cassandra Calabrese, DO, rheumatologist and infectious disease specialist at Cleveland Clinic, said in an interview.

“Of 412 patients who received Evusheld, 12 [2.9%] developed breakthrough COVID-19, with 11 having mild courses and 1 who required hospitalization but recovered,” she added.

“Our data suggest that Evusheld PrEP, in combination with aggressive outpatient treatment of COVID-19, is likely effective in lowering risk of severe COVID in this vulnerable group.

“Practitioners who care for patients with immune-mediated inflammatory diseases should triage high-risk patients for Evusheld as well as rapid diagnosis and aggressive outpatient therapy if infected,” Dr. Calabrese advised.

For the study, Dr. Calabrese and colleagues at Cleveland Clinic searched the health care system pharmacy records for patients with immune‐mediated inflammatory diseases (IMIDs) or inborn errors of humoral immunity (IEI) who met the criteria to receive Evusheld. The researchers included patients on B-cell-depleting therapies or with humoral IEI who had received at least one dose of Evusheld and were later diagnosed with COVID-19, and they excluded those treated with B-cell-depleting therapies for cancer.
 

EVUSHELD was well tolerated

After extracting data on COVID-19 infection, vaccination status, and outcomes, they found that, between Jan. 18 and May 28, 2022, 412 patients with IMIDs or humoral IEI received Evusheld. No deaths occurred among these patients and, overall, they tolerated the medication well.

All 12 patients who experienced breakthrough COVID-19 infection were treated with B-cell-depleting therapies. Among the 12 patients:

• Six patients developed infection 13-84 (median 19) days after receiving 150 mg/150 mg tixagevimab/cilgavimab.
• Six patients developed infection 19-72 (median of 38.5) days after either a single dose of 300 mg/300 mg or a second dose of 150 mg/150 mg.
• Eleven patients had mild illness and recovered at home; one patient was hospitalized and treated with high-flow oxygen. All cases had been vaccinated against COVID-19 (five received two vaccinations, six received three, and one received four).
• One possible serious adverse event involved a patient with COVID-19 and immune-mediated thrombocytopenia (ITP) who was hospitalized soon after receiving Evusheld with ITP flare that resolved with intravenous immunoglobulin.

Dr. Calabrese acknowledged limitations to the study, including few patients, lack of a comparator group, and the study period falling during the Omicron wave.

“Also, nine of the breakthrough cases received additional COVID-19 therapy (oral antiviral or monoclonal antibody), which falls within standard of care for this high-risk group but prevents ascribing effectiveness to individual components of the regimen,” she added.

“Evusheld is authorized for PrEP against COVID-19 in patients at high risk for severe COVID due to suboptimal vaccine responses. This includes patients receiving B-cell-depleting drugs like rituximab, and patients with inborn errors of humoral immunity,” Dr. Calabrese explained.

“It is well known that this group of patients is at very high risk for severe COVID and death, even when fully vaccinated, and it has become clear that more strategies are needed to protect this vulnerable group, including use of Evusheld as well as aggressive treatment if infected,” she added.  
 

Evusheld not always easy to obtain

Although the medication has been available in the United States since January 2022, Dr. Calabrese said, patients may not receive it because of barriers including lack of both awareness and access.

Davey Smith, MD, professor of medicine and head of infectious diseases and global public health at the University of California San Diego, in La Jolla, said in an interview that he was not surprised by the results, but added that the study was conducted in too few patients to draw any strong conclusions or affect patient care.

“This small study that showed that breakthrough infections occurred but were generally mild, provides a small glimpse of real-world use of tixagevimab/cilgavimab as PrEP for immunocompromised persons,” said Dr. Smith, who was not involved in the study.

“In the setting of Omicron and vaccination, I would expect the same outcomes reported even without the treatment,” he added.

Dr. Smith recommends larger related randomized, controlled trials to provide clinicians with sufficient data to guide them in their patient care.

Graham Snyder, MD, associate professor in the division of infectious diseases at the University of Pittsburgh and medical director of infection prevention and hospital epidemiology at the University of Pittsburgh Medical Center, noted that the study “adds to a quickly growing literature on the real-world benefits of tixagevimab/cilgavimab to protect vulnerable individuals with weakened immune systems from the complications of COVID-19.

“This study provides a modest addition to our understanding of the role and benefit of Evusheld,” Dr. Snyder said in an interview. “By characterizing only patients who have received Evusheld without an untreated comparison group, we can’t draw any inference about the extent of benefit the agent provided to these patients.

“Substantial data already show that this agent is effective in preventing complications of COVID-19 infection in immunocompromised individuals,” added Dr. Snyder, who was not involved in the study.

“ ‘Immunocompromised’ represents a very diverse set of clinical conditions,” he said. “The research agenda should therefore focus on a more refined description of the effect in specific populations and a continued understanding of the effect of Evusheld in the context of updated vaccination strategies and changing virus ecology.”

Dr. Calabrese and her colleagues wrote that larger, controlled trials are underway.

 

FDA: Evusheld may not neutralize certain SARS-CoV-2 variants

“The biggest unanswered question is how Evusheld will hold up against new variants,” Dr. Calabrese said.

In an Oct. 3, 2022, update, the Food and Drug Administration released a statement about the risk of developing COVID-19 from SARS-CoV-2 variants that are not neutralized by Evusheld. The statement mentions an updated fact sheet that describes reduced protection from Evusheld against the Omicron subvariant BA.4.6, which accounted for nearly 13% of all new COVID-19 cases in the United States in the week ending Oct. 1.

There was no outside funding for the study. Dr. Smith reported no relevant financial conflicts of interest. Dr. Snyder said he is an unpaid adviser to an AstraZeneca observational study that’s assessing the real-world effectiveness of Evusheld.

Tixagevimab copackaged with cilgavimab (Evusheld) is a safe and effective preexposure prophylaxis (PrEP) in patients undergoing B-cell-depleting therapies who have poor immune response to COVID-19 vaccination and are at high risk for serious COVID-19 illness, a small, single-site study suggests.

Evusheld, the only COVID-19 PrEP option available, has Emergency Use Authorization (EUA) from the Food and Drug Administration for treatment of immunocompromised patients who may not respond sufficiently to COVID-19 vaccination and patients who’ve had a severe adverse reaction to COVID-19 vaccination.

“We report the largest real-world experience of Evusheld in this population, and our findings are encouraging,” lead study author Cassandra Calabrese, DO, rheumatologist and infectious disease specialist at Cleveland Clinic, said in an interview.

“Of 412 patients who received Evusheld, 12 [2.9%] developed breakthrough COVID-19, with 11 having mild courses and 1 who required hospitalization but recovered,” she added.

“Our data suggest that Evusheld PrEP, in combination with aggressive outpatient treatment of COVID-19, is likely effective in lowering risk of severe COVID in this vulnerable group.

“Practitioners who care for patients with immune-mediated inflammatory diseases should triage high-risk patients for Evusheld as well as rapid diagnosis and aggressive outpatient therapy if infected,” Dr. Calabrese advised.

For the study, Dr. Calabrese and colleagues at Cleveland Clinic searched the health care system pharmacy records for patients with immune‐mediated inflammatory diseases (IMIDs) or inborn errors of humoral immunity (IEI) who met the criteria to receive Evusheld. The researchers included patients on B-cell-depleting therapies or with humoral IEI who had received at least one dose of Evusheld and were later diagnosed with COVID-19, and they excluded those treated with B-cell-depleting therapies for cancer.
 

EVUSHELD was well tolerated

After extracting data on COVID-19 infection, vaccination status, and outcomes, they found that, between Jan. 18 and May 28, 2022, 412 patients with IMIDs or humoral IEI received Evusheld. No deaths occurred among these patients and, overall, they tolerated the medication well.

All 12 patients who experienced breakthrough COVID-19 infection were treated with B-cell-depleting therapies. Among the 12 patients:

• Six patients developed infection 13-84 (median 19) days after receiving 150 mg/150 mg tixagevimab/cilgavimab.
• Six patients developed infection 19-72 (median of 38.5) days after either a single dose of 300 mg/300 mg or a second dose of 150 mg/150 mg.
• Eleven patients had mild illness and recovered at home; one patient was hospitalized and treated with high-flow oxygen. All cases had been vaccinated against COVID-19 (five received two vaccinations, six received three, and one received four).
• One possible serious adverse event involved a patient with COVID-19 and immune-mediated thrombocytopenia (ITP) who was hospitalized soon after receiving Evusheld with ITP flare that resolved with intravenous immunoglobulin.

Dr. Calabrese acknowledged limitations to the study, including few patients, lack of a comparator group, and the study period falling during the Omicron wave.

“Also, nine of the breakthrough cases received additional COVID-19 therapy (oral antiviral or monoclonal antibody), which falls within standard of care for this high-risk group but prevents ascribing effectiveness to individual components of the regimen,” she added.

“Evusheld is authorized for PrEP against COVID-19 in patients at high risk for severe COVID due to suboptimal vaccine responses. This includes patients receiving B-cell-depleting drugs like rituximab, and patients with inborn errors of humoral immunity,” Dr. Calabrese explained.

“It is well known that this group of patients is at very high risk for severe COVID and death, even when fully vaccinated, and it has become clear that more strategies are needed to protect this vulnerable group, including use of Evusheld as well as aggressive treatment if infected,” she added.  
 

Evusheld not always easy to obtain

Although the medication has been available in the United States since January 2022, Dr. Calabrese said, patients may not receive it because of barriers including lack of both awareness and access.

Davey Smith, MD, professor of medicine and head of infectious diseases and global public health at the University of California San Diego, in La Jolla, said in an interview that he was not surprised by the results, but added that the study was conducted in too few patients to draw any strong conclusions or affect patient care.

“This small study that showed that breakthrough infections occurred but were generally mild, provides a small glimpse of real-world use of tixagevimab/cilgavimab as PrEP for immunocompromised persons,” said Dr. Smith, who was not involved in the study.

“In the setting of Omicron and vaccination, I would expect the same outcomes reported even without the treatment,” he added.

Dr. Smith recommends larger related randomized, controlled trials to provide clinicians with sufficient data to guide them in their patient care.

Graham Snyder, MD, associate professor in the division of infectious diseases at the University of Pittsburgh and medical director of infection prevention and hospital epidemiology at the University of Pittsburgh Medical Center, noted that the study “adds to a quickly growing literature on the real-world benefits of tixagevimab/cilgavimab to protect vulnerable individuals with weakened immune systems from the complications of COVID-19.

“This study provides a modest addition to our understanding of the role and benefit of Evusheld,” Dr. Snyder said in an interview. “By characterizing only patients who have received Evusheld without an untreated comparison group, we can’t draw any inference about the extent of benefit the agent provided to these patients.

“Substantial data already show that this agent is effective in preventing complications of COVID-19 infection in immunocompromised individuals,” added Dr. Snyder, who was not involved in the study.

“ ‘Immunocompromised’ represents a very diverse set of clinical conditions,” he said. “The research agenda should therefore focus on a more refined description of the effect in specific populations and a continued understanding of the effect of Evusheld in the context of updated vaccination strategies and changing virus ecology.”

Dr. Calabrese and her colleagues wrote that larger, controlled trials are underway.

 

FDA: Evusheld may not neutralize certain SARS-CoV-2 variants

“The biggest unanswered question is how Evusheld will hold up against new variants,” Dr. Calabrese said.

In an Oct. 3, 2022, update, the Food and Drug Administration released a statement about the risk of developing COVID-19 from SARS-CoV-2 variants that are not neutralized by Evusheld. The statement mentions an updated fact sheet that describes reduced protection from Evusheld against the Omicron subvariant BA.4.6, which accounted for nearly 13% of all new COVID-19 cases in the United States in the week ending Oct. 1.

There was no outside funding for the study. Dr. Smith reported no relevant financial conflicts of interest. Dr. Snyder said he is an unpaid adviser to an AstraZeneca observational study that’s assessing the real-world effectiveness of Evusheld.

Tixagevimab copackaged with cilgavimab (Evusheld) is a safe and effective preexposure prophylaxis (PrEP) in patients undergoing B-cell-depleting therapies who have poor immune response to COVID-19 vaccination and are at high risk for serious COVID-19 illness, a small, single-site study suggests.

Evusheld, the only COVID-19 PrEP option available, has Emergency Use Authorization (EUA) from the Food and Drug Administration for treatment of immunocompromised patients who may not respond sufficiently to COVID-19 vaccination and patients who’ve had a severe adverse reaction to COVID-19 vaccination.

“We report the largest real-world experience of Evusheld in this population, and our findings are encouraging,” lead study author Cassandra Calabrese, DO, rheumatologist and infectious disease specialist at Cleveland Clinic, said in an interview.

“Of 412 patients who received Evusheld, 12 [2.9%] developed breakthrough COVID-19, with 11 having mild courses and 1 who required hospitalization but recovered,” she added.

“Our data suggest that Evusheld PrEP, in combination with aggressive outpatient treatment of COVID-19, is likely effective in lowering risk of severe COVID in this vulnerable group.

“Practitioners who care for patients with immune-mediated inflammatory diseases should triage high-risk patients for Evusheld as well as rapid diagnosis and aggressive outpatient therapy if infected,” Dr. Calabrese advised.

For the study, Dr. Calabrese and colleagues at Cleveland Clinic searched the health care system pharmacy records for patients with immune‐mediated inflammatory diseases (IMIDs) or inborn errors of humoral immunity (IEI) who met the criteria to receive Evusheld. The researchers included patients on B-cell-depleting therapies or with humoral IEI who had received at least one dose of Evusheld and were later diagnosed with COVID-19, and they excluded those treated with B-cell-depleting therapies for cancer.
 

EVUSHELD was well tolerated

After extracting data on COVID-19 infection, vaccination status, and outcomes, they found that, between Jan. 18 and May 28, 2022, 412 patients with IMIDs or humoral IEI received Evusheld. No deaths occurred among these patients and, overall, they tolerated the medication well.

All 12 patients who experienced breakthrough COVID-19 infection were treated with B-cell-depleting therapies. Among the 12 patients:

• Six patients developed infection 13-84 (median 19) days after receiving 150 mg/150 mg tixagevimab/cilgavimab.
• Six patients developed infection 19-72 (median of 38.5) days after either a single dose of 300 mg/300 mg or a second dose of 150 mg/150 mg.
• Eleven patients had mild illness and recovered at home; one patient was hospitalized and treated with high-flow oxygen. All cases had been vaccinated against COVID-19 (five received two vaccinations, six received three, and one received four).
• One possible serious adverse event involved a patient with COVID-19 and immune-mediated thrombocytopenia (ITP) who was hospitalized soon after receiving Evusheld with ITP flare that resolved with intravenous immunoglobulin.

Dr. Calabrese acknowledged limitations to the study, including few patients, lack of a comparator group, and the study period falling during the Omicron wave.

“Also, nine of the breakthrough cases received additional COVID-19 therapy (oral antiviral or monoclonal antibody), which falls within standard of care for this high-risk group but prevents ascribing effectiveness to individual components of the regimen,” she added.

“Evusheld is authorized for PrEP against COVID-19 in patients at high risk for severe COVID due to suboptimal vaccine responses. This includes patients receiving B-cell-depleting drugs like rituximab, and patients with inborn errors of humoral immunity,” Dr. Calabrese explained.

“It is well known that this group of patients is at very high risk for severe COVID and death, even when fully vaccinated, and it has become clear that more strategies are needed to protect this vulnerable group, including use of Evusheld as well as aggressive treatment if infected,” she added.  
 

Evusheld not always easy to obtain

Although the medication has been available in the United States since January 2022, Dr. Calabrese said, patients may not receive it because of barriers including lack of both awareness and access.

Davey Smith, MD, professor of medicine and head of infectious diseases and global public health at the University of California San Diego, in La Jolla, said in an interview that he was not surprised by the results, but added that the study was conducted in too few patients to draw any strong conclusions or affect patient care.

“This small study that showed that breakthrough infections occurred but were generally mild, provides a small glimpse of real-world use of tixagevimab/cilgavimab as PrEP for immunocompromised persons,” said Dr. Smith, who was not involved in the study.

“In the setting of Omicron and vaccination, I would expect the same outcomes reported even without the treatment,” he added.

Dr. Smith recommends larger related randomized, controlled trials to provide clinicians with sufficient data to guide them in their patient care.

Graham Snyder, MD, associate professor in the division of infectious diseases at the University of Pittsburgh and medical director of infection prevention and hospital epidemiology at the University of Pittsburgh Medical Center, noted that the study “adds to a quickly growing literature on the real-world benefits of tixagevimab/cilgavimab to protect vulnerable individuals with weakened immune systems from the complications of COVID-19.

“This study provides a modest addition to our understanding of the role and benefit of Evusheld,” Dr. Snyder said in an interview. “By characterizing only patients who have received Evusheld without an untreated comparison group, we can’t draw any inference about the extent of benefit the agent provided to these patients.

“Substantial data already show that this agent is effective in preventing complications of COVID-19 infection in immunocompromised individuals,” added Dr. Snyder, who was not involved in the study.

“ ‘Immunocompromised’ represents a very diverse set of clinical conditions,” he said. “The research agenda should therefore focus on a more refined description of the effect in specific populations and a continued understanding of the effect of Evusheld in the context of updated vaccination strategies and changing virus ecology.”

Dr. Calabrese and her colleagues wrote that larger, controlled trials are underway.

 

FDA: Evusheld may not neutralize certain SARS-CoV-2 variants

“The biggest unanswered question is how Evusheld will hold up against new variants,” Dr. Calabrese said.

In an Oct. 3, 2022, update, the Food and Drug Administration released a statement about the risk of developing COVID-19 from SARS-CoV-2 variants that are not neutralized by Evusheld. The statement mentions an updated fact sheet that describes reduced protection from Evusheld against the Omicron subvariant BA.4.6, which accounted for nearly 13% of all new COVID-19 cases in the United States in the week ending Oct. 1.

There was no outside funding for the study. Dr. Smith reported no relevant financial conflicts of interest. Dr. Snyder said he is an unpaid adviser to an AstraZeneca observational study that’s assessing the real-world effectiveness of Evusheld.

People with immune-mediated inflammatory diseases who are taking immunosuppressants don’t mount as strong of an immune defense against the Omicron variant as they did against the original SARS-CoV-2 wild-type virus, according to two studies published in Annals of the Rheumatic Diseases. One of the studies further showed that vaccinated individuals taking immunosuppressants have poorer cross-neutralizing responses to Omicron than do healthy vaccinated individuals, even after three doses of the COVID-19 mRNA vaccines.

filadendron/E+/Getty Images

“We carefully suggest that if Omicron-specific vaccination can be administered, it may be an effective way to reduce the risk of breakthrough infections in patients with autoimmune rheumatic disease,” Sang Tae Choi, MD, PhD, of the University College of Medicine, Seoul, Korea, and one of the authors of the study on cross-neutralizing protection, told this news organization. “However, further research is needed on Omicron-specific vaccine effectiveness in patients with immune dysfunctions. We believe that these study results can be of great benefit in determining the strategy of vaccination in the future.”

The earlier study, published in July, examined the ability of COVID-19 vaccines to induce cross-reactive antibody responses against Omicron infections in patients with autoimmune rheumatic diseases (ARDs). The observational study involved 149 patients with ARDs and 94 health care workers as controls, all of whom provided blood samples a median 15 weeks after their second COVID vaccine dose or a median 8 weeks after their third dose. A little more than two-thirds of the patients (68.5%) had received a third mRNA vaccine dose. None of the participants previously had COVID-19.

The researchers compared the rate of breakthrough infections with the Omicron variant to the neutralizing responses in patients’ blood, specifically the cross-neutralizing antibody responses because the original mRNA vaccines targeted a different variant than Omicron. Breakthrough infections were assessed by survey questions.

“Our findings suggested that neither primary series vaccinations nor booster doses are sufficient to induce Omicron-neutralizing responses above the threshold in patients with ARDs, although responses were noticeably increased following the third dose of an mRNA vaccine,” write Woo-Joong Kim, of the Chung-Ang University College of Medicine, Seoul, Korea, and his colleagues. “This impairment of cross-neutralization responses across most of our patients contrasts starkly with a potent elicitation of the Omicron-neutralizing responses after the third vaccination in healthy recipients.”

The average neutralizing responses against the original SARS-CoV-2 strain were similar in both groups: 76% in patients with ARDs and 72% in health care workers after the second dose. The mean response after a third dose was 97% in health care workers and 88% in patients.

The average cross-neutralizing response against the Omicron variant was far lower, particularly in those with rheumatic disease: only 11.5%, which rose to 27% after the third dose. Only 39% of the patient sera showed neutralization of Omicron, even after the third dose. Meanwhile, the mean cross-neutralizing response in health care workers was 18% after the second dose and 50% after the third.

When the researchers compared seropositivity rates against the original virus to neutralizing responses against Omicron, the association between these was stronger in health care workers than in those with ARDs. In fact, among patients with ARDs who seroconverted, only 41% showed any response against Omicron. Among all the patients, most of those who didn’t respond to Omicron (93.5%) had initially seroconverted.

The researchers also looked at the ability to neutralize Omicron on the basis of disease in those who received three doses of the vaccine. About half of those with lupus (52%) showed any neutralization against Omicron, compared with 25% of those with rheumatoid arthritis, 37.5% of those with ankylosing spondylitis, 33% of those with Behçet snydrome, and all of those with adult-onset Still’s disease.

The rate of breakthrough infections was lower in patients (19%) than in health care workers (33%). A similar pattern was seen in the more recent study published Sept. 5. Researchers used data from a prospective cohort study in the Netherlands to examine incidence and severity of Omicron breakthrough infections in patients with immune-mediated inflammatory diseases. The researchers compared infection rates and severity among 1,593 vaccinated patients with inflammatory disease who were taking immunosuppressants and 579 vaccinated controls (418 patients with inflammatory disease not on immunosuppressants and 161 healthy controls).

One in five patients with inflammatory disease (21%) were taking immunosuppressants that substantially impair antibodies, such as anti-CD20 therapy, S1P modulators, or mycophenolate mofetil combination therapy, and 48% of these patients seroconverted after primary vaccination, compared with 96% of patients taking other immunosuppressants and 98% of controls.

Breakthrough infection rates were similar between the control group (31%) and those taking immunosuppressants (30%). Only three participants had severe disease requiring hospitalization: one control and two patients taking immunosuppressants.

“In both studies, the controls had similar or higher rates of breakthrough infections, compared with the immunosuppressed,” noted Alfred Kim, MD, an assistant professor of medicine at Washington University, St Louis, but he added, “one has to consider differences in mitigation strategies, such as masking, that may explain these findings.” That is, patients taking immunosuppressants may be taking fewer risks in the community or have fewer potential exposures, especially in the Korean study, wherein the controls were health care workers.

A greater disparity in infections occurred when considering seroconversion rates. Breakthrough incidence was 38% among those taking immunosuppressants who did not seroconvert, compared with 29% among those who did. A similar trend was seen in breakthrough incidence between those taking strongly antibody-impairing immunosuppressants (36% breakthrough rate) and those taking other immunosuppressants (28%).

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

People with immune-mediated inflammatory diseases who are taking immunosuppressants don’t mount as strong of an immune defense against the Omicron variant as they did against the original SARS-CoV-2 wild-type virus, according to two studies published in Annals of the Rheumatic Diseases. One of the studies further showed that vaccinated individuals taking immunosuppressants have poorer cross-neutralizing responses to Omicron than do healthy vaccinated individuals, even after three doses of the COVID-19 mRNA vaccines.

filadendron/E+/Getty Images

“We carefully suggest that if Omicron-specific vaccination can be administered, it may be an effective way to reduce the risk of breakthrough infections in patients with autoimmune rheumatic disease,” Sang Tae Choi, MD, PhD, of the University College of Medicine, Seoul, Korea, and one of the authors of the study on cross-neutralizing protection, told this news organization. “However, further research is needed on Omicron-specific vaccine effectiveness in patients with immune dysfunctions. We believe that these study results can be of great benefit in determining the strategy of vaccination in the future.”

The earlier study, published in July, examined the ability of COVID-19 vaccines to induce cross-reactive antibody responses against Omicron infections in patients with autoimmune rheumatic diseases (ARDs). The observational study involved 149 patients with ARDs and 94 health care workers as controls, all of whom provided blood samples a median 15 weeks after their second COVID vaccine dose or a median 8 weeks after their third dose. A little more than two-thirds of the patients (68.5%) had received a third mRNA vaccine dose. None of the participants previously had COVID-19.

The researchers compared the rate of breakthrough infections with the Omicron variant to the neutralizing responses in patients’ blood, specifically the cross-neutralizing antibody responses because the original mRNA vaccines targeted a different variant than Omicron. Breakthrough infections were assessed by survey questions.

“Our findings suggested that neither primary series vaccinations nor booster doses are sufficient to induce Omicron-neutralizing responses above the threshold in patients with ARDs, although responses were noticeably increased following the third dose of an mRNA vaccine,” write Woo-Joong Kim, of the Chung-Ang University College of Medicine, Seoul, Korea, and his colleagues. “This impairment of cross-neutralization responses across most of our patients contrasts starkly with a potent elicitation of the Omicron-neutralizing responses after the third vaccination in healthy recipients.”

The average neutralizing responses against the original SARS-CoV-2 strain were similar in both groups: 76% in patients with ARDs and 72% in health care workers after the second dose. The mean response after a third dose was 97% in health care workers and 88% in patients.

The average cross-neutralizing response against the Omicron variant was far lower, particularly in those with rheumatic disease: only 11.5%, which rose to 27% after the third dose. Only 39% of the patient sera showed neutralization of Omicron, even after the third dose. Meanwhile, the mean cross-neutralizing response in health care workers was 18% after the second dose and 50% after the third.

When the researchers compared seropositivity rates against the original virus to neutralizing responses against Omicron, the association between these was stronger in health care workers than in those with ARDs. In fact, among patients with ARDs who seroconverted, only 41% showed any response against Omicron. Among all the patients, most of those who didn’t respond to Omicron (93.5%) had initially seroconverted.

The researchers also looked at the ability to neutralize Omicron on the basis of disease in those who received three doses of the vaccine. About half of those with lupus (52%) showed any neutralization against Omicron, compared with 25% of those with rheumatoid arthritis, 37.5% of those with ankylosing spondylitis, 33% of those with Behçet snydrome, and all of those with adult-onset Still’s disease.

The rate of breakthrough infections was lower in patients (19%) than in health care workers (33%). A similar pattern was seen in the more recent study published Sept. 5. Researchers used data from a prospective cohort study in the Netherlands to examine incidence and severity of Omicron breakthrough infections in patients with immune-mediated inflammatory diseases. The researchers compared infection rates and severity among 1,593 vaccinated patients with inflammatory disease who were taking immunosuppressants and 579 vaccinated controls (418 patients with inflammatory disease not on immunosuppressants and 161 healthy controls).

One in five patients with inflammatory disease (21%) were taking immunosuppressants that substantially impair antibodies, such as anti-CD20 therapy, S1P modulators, or mycophenolate mofetil combination therapy, and 48% of these patients seroconverted after primary vaccination, compared with 96% of patients taking other immunosuppressants and 98% of controls.

Breakthrough infection rates were similar between the control group (31%) and those taking immunosuppressants (30%). Only three participants had severe disease requiring hospitalization: one control and two patients taking immunosuppressants.

“In both studies, the controls had similar or higher rates of breakthrough infections, compared with the immunosuppressed,” noted Alfred Kim, MD, an assistant professor of medicine at Washington University, St Louis, but he added, “one has to consider differences in mitigation strategies, such as masking, that may explain these findings.” That is, patients taking immunosuppressants may be taking fewer risks in the community or have fewer potential exposures, especially in the Korean study, wherein the controls were health care workers.

A greater disparity in infections occurred when considering seroconversion rates. Breakthrough incidence was 38% among those taking immunosuppressants who did not seroconvert, compared with 29% among those who did. A similar trend was seen in breakthrough incidence between those taking strongly antibody-impairing immunosuppressants (36% breakthrough rate) and those taking other immunosuppressants (28%).

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

People with immune-mediated inflammatory diseases who are taking immunosuppressants don’t mount as strong of an immune defense against the Omicron variant as they did against the original SARS-CoV-2 wild-type virus, according to two studies published in Annals of the Rheumatic Diseases. One of the studies further showed that vaccinated individuals taking immunosuppressants have poorer cross-neutralizing responses to Omicron than do healthy vaccinated individuals, even after three doses of the COVID-19 mRNA vaccines.

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“We carefully suggest that if Omicron-specific vaccination can be administered, it may be an effective way to reduce the risk of breakthrough infections in patients with autoimmune rheumatic disease,” Sang Tae Choi, MD, PhD, of the University College of Medicine, Seoul, Korea, and one of the authors of the study on cross-neutralizing protection, told this news organization. “However, further research is needed on Omicron-specific vaccine effectiveness in patients with immune dysfunctions. We believe that these study results can be of great benefit in determining the strategy of vaccination in the future.”

The earlier study, published in July, examined the ability of COVID-19 vaccines to induce cross-reactive antibody responses against Omicron infections in patients with autoimmune rheumatic diseases (ARDs). The observational study involved 149 patients with ARDs and 94 health care workers as controls, all of whom provided blood samples a median 15 weeks after their second COVID vaccine dose or a median 8 weeks after their third dose. A little more than two-thirds of the patients (68.5%) had received a third mRNA vaccine dose. None of the participants previously had COVID-19.

The researchers compared the rate of breakthrough infections with the Omicron variant to the neutralizing responses in patients’ blood, specifically the cross-neutralizing antibody responses because the original mRNA vaccines targeted a different variant than Omicron. Breakthrough infections were assessed by survey questions.

“Our findings suggested that neither primary series vaccinations nor booster doses are sufficient to induce Omicron-neutralizing responses above the threshold in patients with ARDs, although responses were noticeably increased following the third dose of an mRNA vaccine,” write Woo-Joong Kim, of the Chung-Ang University College of Medicine, Seoul, Korea, and his colleagues. “This impairment of cross-neutralization responses across most of our patients contrasts starkly with a potent elicitation of the Omicron-neutralizing responses after the third vaccination in healthy recipients.”

The average neutralizing responses against the original SARS-CoV-2 strain were similar in both groups: 76% in patients with ARDs and 72% in health care workers after the second dose. The mean response after a third dose was 97% in health care workers and 88% in patients.

The average cross-neutralizing response against the Omicron variant was far lower, particularly in those with rheumatic disease: only 11.5%, which rose to 27% after the third dose. Only 39% of the patient sera showed neutralization of Omicron, even after the third dose. Meanwhile, the mean cross-neutralizing response in health care workers was 18% after the second dose and 50% after the third.

When the researchers compared seropositivity rates against the original virus to neutralizing responses against Omicron, the association between these was stronger in health care workers than in those with ARDs. In fact, among patients with ARDs who seroconverted, only 41% showed any response against Omicron. Among all the patients, most of those who didn’t respond to Omicron (93.5%) had initially seroconverted.

The researchers also looked at the ability to neutralize Omicron on the basis of disease in those who received three doses of the vaccine. About half of those with lupus (52%) showed any neutralization against Omicron, compared with 25% of those with rheumatoid arthritis, 37.5% of those with ankylosing spondylitis, 33% of those with Behçet snydrome, and all of those with adult-onset Still’s disease.

The rate of breakthrough infections was lower in patients (19%) than in health care workers (33%). A similar pattern was seen in the more recent study published Sept. 5. Researchers used data from a prospective cohort study in the Netherlands to examine incidence and severity of Omicron breakthrough infections in patients with immune-mediated inflammatory diseases. The researchers compared infection rates and severity among 1,593 vaccinated patients with inflammatory disease who were taking immunosuppressants and 579 vaccinated controls (418 patients with inflammatory disease not on immunosuppressants and 161 healthy controls).

One in five patients with inflammatory disease (21%) were taking immunosuppressants that substantially impair antibodies, such as anti-CD20 therapy, S1P modulators, or mycophenolate mofetil combination therapy, and 48% of these patients seroconverted after primary vaccination, compared with 96% of patients taking other immunosuppressants and 98% of controls.

Breakthrough infection rates were similar between the control group (31%) and those taking immunosuppressants (30%). Only three participants had severe disease requiring hospitalization: one control and two patients taking immunosuppressants.

“In both studies, the controls had similar or higher rates of breakthrough infections, compared with the immunosuppressed,” noted Alfred Kim, MD, an assistant professor of medicine at Washington University, St Louis, but he added, “one has to consider differences in mitigation strategies, such as masking, that may explain these findings.” That is, patients taking immunosuppressants may be taking fewer risks in the community or have fewer potential exposures, especially in the Korean study, wherein the controls were health care workers.

A greater disparity in infections occurred when considering seroconversion rates. Breakthrough incidence was 38% among those taking immunosuppressants who did not seroconvert, compared with 29% among those who did. A similar trend was seen in breakthrough incidence between those taking strongly antibody-impairing immunosuppressants (36% breakthrough rate) and those taking other immunosuppressants (28%).

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

The antifibrotic pirfenidone (Esbriet) did not change the decline in forced vital capacity percentage (FVC%) from baseline of 10% or more or the risk of death compared with placebo in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the drug appeared to slow the rate of decline in lung function, a phase 2 study indicated.

“This is the first randomized double-blind, placebo-controlled trial focused only on patients with RA-ILD,” observed Joshua Solomon, MD, National Jewish Health, Denver, and fellow TRAIL1 Network investigators.

“Although we did not meet our composite primary endpoint, key secondary endpoints showed a safe and beneficial effect of pirfenidone in patients with rheumatoid arthritis and evidence of fibrotic interstitial lung disease and the totality of the evidence suggests that pirfenidone is effective in the treatment of RA-ILD,” they suggest.

The study was published online in the Lancet Respiratory Medicine.


 

TRAIL1

The treatment for Rheumatoid Arthritis and Interstitial Lung Disease 1 (TRAIL1) was carried out in 34 academic centers specializing in ILD. Patients had RA and the presence of ILD on high-resolution CT scan and, where possible, lung biopsy. A total of 231 patients were randomly assigned to the pirfenidone group and the remainder to placebo. The mean age of patients was 66 (interquartile range (IQR, 61.0-74.0) in the pirfenidone group and 69.56 (IQR, 63.-74.5) among placebo controls.

Patients received pirfenidone at a dose of 2,403 mg per day, given in divided doses of three 267-mg tablets, three times a day, titrated to full dose over the course of 2 weeks. High-resolution CT scans were done at the beginning and the end of the study interval. Several disease-modifying antirheumatic drugs (DMARDS) were used for the treatment of RA but no differences were observed between treatment groups accounting for the DMARD classes.

“The primary endpoint was the incidence of the composite endpoint of a decline from baseline in [FVC%] of 10% or more or death during the 52-week treatment period,” Dr. Solomon and colleagues observed. The primary outcome was measured in the intent-to-treat (ITT) population.

Some 11% of patients in the active treatment group vs. 15% of patients in the placebo group met the composite primary endpoint, as investigators reported. For the secondary endpoint of the change in FVC over 52 weeks, patients treated with pirfenidone had a slow rate of decline in lung function compared with placebo patients as measured by estimated annual change in absolute FVC (–66 ml vs. –146 mL; P = .0082).

Moreover, in a post hoc analysis by CT pattern, the effect of the antifibrotic therapy on decline in FVC was more pronounced in those with usual interstitial pneumonia pattern on imaging compared with those with any pattern of ILD, the investigators observed. Indeed, approximately half of patients with the usual interstitial pneumonia in the pirfenidone group had a significantly smaller reduction in annual change in FVC at 52 weeks compared with over three-quarters of patients with usual interstitial pneumonia treated with placebo.

In contrast, the two groups were similar with regard to the decline in FVC% by 10% more or the frequency of progression. All-cause mortality rates were similar between the two groups. Adverse events thought to be related to treatment were more frequently reported in the pirfenidone group at 44% vs. 30% of placebo patients, the most frequent of which were nausea, fatigue, and diarrhea.

“These adverse events were generally grade 1 and were not clinically significant,” as the authors emphasized, although 24% of patients receiving pirfenidone discontinued treatment because of AEs vs. only 10% of placebo patients.

Limitations of the trial included early termination because of slow recruitment and the COVID-19 pandemic. This led to underpowering of the study.

Wrong endpoint?

In an accompanying editorial, Marco Sebastiani and Andreina Manfredi, MD, said that the choice of the primary outcome of an FVC decline from a baseline of 10% or more could have negatively influenced results because an FVC decline of 10% or more was probably too challenging to show a difference between the two groups. Indeed, the updated 2022 guidelines proposed a decline of 5% or more in FVC as a “significant threshold” for disease progression in patients with progressive pulmonary fibrosis, as the editorialists pointed out.

Nevertheless, the editorialists felt that the effect of pirfenidone on the decline in FVC seems to be significant, particularly when patients with usual interstitial pneumonia are considered. ”The magnitude of the effect of pirfenidone in patients with usual interstitial pneumonia-rheumatoid arthritis-interstitial lung disease and idiopathic pulmonary fibrosis [enrolled in a different study] was very similar,” they noted, “suggesting that a careful identification of usual interstitial pneumonia pattern at HRCT [high resolution CT] could be relevant in patients with RA-ILD. Moreover, given that pirfenidone did not modify its safety in these patients, the fact that pirfenidone can be safely used with DMARD therapy is important in clinical practice.

Dr. Solomon had no conflicts of interest to declare. Dr. Sebastiani disclosed ties with Bristol Myers Squibb, Pfizer, Boehringer-Ingelheim, Lilly, Amgen, Janssen, and Celltrion. Dr. Manfredi disclosed ties with Bristol Myers Squibb, Lilly, and Boehringer-Ingelheim. The study was funded by Genentech.

The antifibrotic pirfenidone (Esbriet) did not change the decline in forced vital capacity percentage (FVC%) from baseline of 10% or more or the risk of death compared with placebo in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the drug appeared to slow the rate of decline in lung function, a phase 2 study indicated.

“This is the first randomized double-blind, placebo-controlled trial focused only on patients with RA-ILD,” observed Joshua Solomon, MD, National Jewish Health, Denver, and fellow TRAIL1 Network investigators.

“Although we did not meet our composite primary endpoint, key secondary endpoints showed a safe and beneficial effect of pirfenidone in patients with rheumatoid arthritis and evidence of fibrotic interstitial lung disease and the totality of the evidence suggests that pirfenidone is effective in the treatment of RA-ILD,” they suggest.

The study was published online in the Lancet Respiratory Medicine.


 

TRAIL1

The treatment for Rheumatoid Arthritis and Interstitial Lung Disease 1 (TRAIL1) was carried out in 34 academic centers specializing in ILD. Patients had RA and the presence of ILD on high-resolution CT scan and, where possible, lung biopsy. A total of 231 patients were randomly assigned to the pirfenidone group and the remainder to placebo. The mean age of patients was 66 (interquartile range (IQR, 61.0-74.0) in the pirfenidone group and 69.56 (IQR, 63.-74.5) among placebo controls.

Patients received pirfenidone at a dose of 2,403 mg per day, given in divided doses of three 267-mg tablets, three times a day, titrated to full dose over the course of 2 weeks. High-resolution CT scans were done at the beginning and the end of the study interval. Several disease-modifying antirheumatic drugs (DMARDS) were used for the treatment of RA but no differences were observed between treatment groups accounting for the DMARD classes.

“The primary endpoint was the incidence of the composite endpoint of a decline from baseline in [FVC%] of 10% or more or death during the 52-week treatment period,” Dr. Solomon and colleagues observed. The primary outcome was measured in the intent-to-treat (ITT) population.

Some 11% of patients in the active treatment group vs. 15% of patients in the placebo group met the composite primary endpoint, as investigators reported. For the secondary endpoint of the change in FVC over 52 weeks, patients treated with pirfenidone had a slow rate of decline in lung function compared with placebo patients as measured by estimated annual change in absolute FVC (–66 ml vs. –146 mL; P = .0082).

Moreover, in a post hoc analysis by CT pattern, the effect of the antifibrotic therapy on decline in FVC was more pronounced in those with usual interstitial pneumonia pattern on imaging compared with those with any pattern of ILD, the investigators observed. Indeed, approximately half of patients with the usual interstitial pneumonia in the pirfenidone group had a significantly smaller reduction in annual change in FVC at 52 weeks compared with over three-quarters of patients with usual interstitial pneumonia treated with placebo.

In contrast, the two groups were similar with regard to the decline in FVC% by 10% more or the frequency of progression. All-cause mortality rates were similar between the two groups. Adverse events thought to be related to treatment were more frequently reported in the pirfenidone group at 44% vs. 30% of placebo patients, the most frequent of which were nausea, fatigue, and diarrhea.

“These adverse events were generally grade 1 and were not clinically significant,” as the authors emphasized, although 24% of patients receiving pirfenidone discontinued treatment because of AEs vs. only 10% of placebo patients.

Limitations of the trial included early termination because of slow recruitment and the COVID-19 pandemic. This led to underpowering of the study.

Wrong endpoint?

In an accompanying editorial, Marco Sebastiani and Andreina Manfredi, MD, said that the choice of the primary outcome of an FVC decline from a baseline of 10% or more could have negatively influenced results because an FVC decline of 10% or more was probably too challenging to show a difference between the two groups. Indeed, the updated 2022 guidelines proposed a decline of 5% or more in FVC as a “significant threshold” for disease progression in patients with progressive pulmonary fibrosis, as the editorialists pointed out.

Nevertheless, the editorialists felt that the effect of pirfenidone on the decline in FVC seems to be significant, particularly when patients with usual interstitial pneumonia are considered. ”The magnitude of the effect of pirfenidone in patients with usual interstitial pneumonia-rheumatoid arthritis-interstitial lung disease and idiopathic pulmonary fibrosis [enrolled in a different study] was very similar,” they noted, “suggesting that a careful identification of usual interstitial pneumonia pattern at HRCT [high resolution CT] could be relevant in patients with RA-ILD. Moreover, given that pirfenidone did not modify its safety in these patients, the fact that pirfenidone can be safely used with DMARD therapy is important in clinical practice.

Dr. Solomon had no conflicts of interest to declare. Dr. Sebastiani disclosed ties with Bristol Myers Squibb, Pfizer, Boehringer-Ingelheim, Lilly, Amgen, Janssen, and Celltrion. Dr. Manfredi disclosed ties with Bristol Myers Squibb, Lilly, and Boehringer-Ingelheim. The study was funded by Genentech.

The antifibrotic pirfenidone (Esbriet) did not change the decline in forced vital capacity percentage (FVC%) from baseline of 10% or more or the risk of death compared with placebo in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the drug appeared to slow the rate of decline in lung function, a phase 2 study indicated.

“This is the first randomized double-blind, placebo-controlled trial focused only on patients with RA-ILD,” observed Joshua Solomon, MD, National Jewish Health, Denver, and fellow TRAIL1 Network investigators.

“Although we did not meet our composite primary endpoint, key secondary endpoints showed a safe and beneficial effect of pirfenidone in patients with rheumatoid arthritis and evidence of fibrotic interstitial lung disease and the totality of the evidence suggests that pirfenidone is effective in the treatment of RA-ILD,” they suggest.

The study was published online in the Lancet Respiratory Medicine.


 

TRAIL1

The treatment for Rheumatoid Arthritis and Interstitial Lung Disease 1 (TRAIL1) was carried out in 34 academic centers specializing in ILD. Patients had RA and the presence of ILD on high-resolution CT scan and, where possible, lung biopsy. A total of 231 patients were randomly assigned to the pirfenidone group and the remainder to placebo. The mean age of patients was 66 (interquartile range (IQR, 61.0-74.0) in the pirfenidone group and 69.56 (IQR, 63.-74.5) among placebo controls.

Patients received pirfenidone at a dose of 2,403 mg per day, given in divided doses of three 267-mg tablets, three times a day, titrated to full dose over the course of 2 weeks. High-resolution CT scans were done at the beginning and the end of the study interval. Several disease-modifying antirheumatic drugs (DMARDS) were used for the treatment of RA but no differences were observed between treatment groups accounting for the DMARD classes.

“The primary endpoint was the incidence of the composite endpoint of a decline from baseline in [FVC%] of 10% or more or death during the 52-week treatment period,” Dr. Solomon and colleagues observed. The primary outcome was measured in the intent-to-treat (ITT) population.

Some 11% of patients in the active treatment group vs. 15% of patients in the placebo group met the composite primary endpoint, as investigators reported. For the secondary endpoint of the change in FVC over 52 weeks, patients treated with pirfenidone had a slow rate of decline in lung function compared with placebo patients as measured by estimated annual change in absolute FVC (–66 ml vs. –146 mL; P = .0082).

Moreover, in a post hoc analysis by CT pattern, the effect of the antifibrotic therapy on decline in FVC was more pronounced in those with usual interstitial pneumonia pattern on imaging compared with those with any pattern of ILD, the investigators observed. Indeed, approximately half of patients with the usual interstitial pneumonia in the pirfenidone group had a significantly smaller reduction in annual change in FVC at 52 weeks compared with over three-quarters of patients with usual interstitial pneumonia treated with placebo.

In contrast, the two groups were similar with regard to the decline in FVC% by 10% more or the frequency of progression. All-cause mortality rates were similar between the two groups. Adverse events thought to be related to treatment were more frequently reported in the pirfenidone group at 44% vs. 30% of placebo patients, the most frequent of which were nausea, fatigue, and diarrhea.

“These adverse events were generally grade 1 and were not clinically significant,” as the authors emphasized, although 24% of patients receiving pirfenidone discontinued treatment because of AEs vs. only 10% of placebo patients.

Limitations of the trial included early termination because of slow recruitment and the COVID-19 pandemic. This led to underpowering of the study.

Wrong endpoint?

In an accompanying editorial, Marco Sebastiani and Andreina Manfredi, MD, said that the choice of the primary outcome of an FVC decline from a baseline of 10% or more could have negatively influenced results because an FVC decline of 10% or more was probably too challenging to show a difference between the two groups. Indeed, the updated 2022 guidelines proposed a decline of 5% or more in FVC as a “significant threshold” for disease progression in patients with progressive pulmonary fibrosis, as the editorialists pointed out.

Nevertheless, the editorialists felt that the effect of pirfenidone on the decline in FVC seems to be significant, particularly when patients with usual interstitial pneumonia are considered. ”The magnitude of the effect of pirfenidone in patients with usual interstitial pneumonia-rheumatoid arthritis-interstitial lung disease and idiopathic pulmonary fibrosis [enrolled in a different study] was very similar,” they noted, “suggesting that a careful identification of usual interstitial pneumonia pattern at HRCT [high resolution CT] could be relevant in patients with RA-ILD. Moreover, given that pirfenidone did not modify its safety in these patients, the fact that pirfenidone can be safely used with DMARD therapy is important in clinical practice.

Dr. Solomon had no conflicts of interest to declare. Dr. Sebastiani disclosed ties with Bristol Myers Squibb, Pfizer, Boehringer-Ingelheim, Lilly, Amgen, Janssen, and Celltrion. Dr. Manfredi disclosed ties with Bristol Myers Squibb, Lilly, and Boehringer-Ingelheim. The study was funded by Genentech.