Rheumatoid Arthritis

Key clinical point: Patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (methotrexate-IR) who initiated upadacitinib vs adalimumab spent a longer time in improved disease states and reported faster achievement of treatment targets.

Major finding: Patients initially receiving upadacitinib vs adalimumab spent 19% vs 14% of the time over 48 weeks in clinical disease activity index remission (nominal P  =  .012) and achieved the 28-joint disease activity score using C-reactive protein of <2.6/≤3.2 approximately 6-8 weeks (median time) earlier.

Study details: Findings are from a post hoc analysis including patients with RA and methotrexate-IR from the phase 3 SELECT-COMPARE trial who were randomly assigned to receive upadacitinib (n = 651) or adalimumab (n = 327) with background methotrexate.

Disclosures: The trial was funded by AbbVie, Inc. Five authors declared being employees of and may own stocks or options in AbbVie. The other authors reported ties with various sources, including AbbVie.

Source: Mysler E et al. Impact of initial therapy with upadacitinib or adalimumab on achievement of 48-week treatment goals in patients with rheumatoid arthritis: Post hoc analysis of SELECT-COMPARE. Rheumatology (Oxford). 2022 (Aug 26). Doi:  10.1093/rheumatology/keac477

Key clinical point: Patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (methotrexate-IR) who initiated upadacitinib vs adalimumab spent a longer time in improved disease states and reported faster achievement of treatment targets.

Major finding: Patients initially receiving upadacitinib vs adalimumab spent 19% vs 14% of the time over 48 weeks in clinical disease activity index remission (nominal P  =  .012) and achieved the 28-joint disease activity score using C-reactive protein of <2.6/≤3.2 approximately 6-8 weeks (median time) earlier.

Study details: Findings are from a post hoc analysis including patients with RA and methotrexate-IR from the phase 3 SELECT-COMPARE trial who were randomly assigned to receive upadacitinib (n = 651) or adalimumab (n = 327) with background methotrexate.

Disclosures: The trial was funded by AbbVie, Inc. Five authors declared being employees of and may own stocks or options in AbbVie. The other authors reported ties with various sources, including AbbVie.

Source: Mysler E et al. Impact of initial therapy with upadacitinib or adalimumab on achievement of 48-week treatment goals in patients with rheumatoid arthritis: Post hoc analysis of SELECT-COMPARE. Rheumatology (Oxford). 2022 (Aug 26). Doi:  10.1093/rheumatology/keac477

Key clinical point: Patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (methotrexate-IR) who initiated upadacitinib vs adalimumab spent a longer time in improved disease states and reported faster achievement of treatment targets.

Major finding: Patients initially receiving upadacitinib vs adalimumab spent 19% vs 14% of the time over 48 weeks in clinical disease activity index remission (nominal P  =  .012) and achieved the 28-joint disease activity score using C-reactive protein of <2.6/≤3.2 approximately 6-8 weeks (median time) earlier.

Study details: Findings are from a post hoc analysis including patients with RA and methotrexate-IR from the phase 3 SELECT-COMPARE trial who were randomly assigned to receive upadacitinib (n = 651) or adalimumab (n = 327) with background methotrexate.

Disclosures: The trial was funded by AbbVie, Inc. Five authors declared being employees of and may own stocks or options in AbbVie. The other authors reported ties with various sources, including AbbVie.

Source: Mysler E et al. Impact of initial therapy with upadacitinib or adalimumab on achievement of 48-week treatment goals in patients with rheumatoid arthritis: Post hoc analysis of SELECT-COMPARE. Rheumatology (Oxford). 2022 (Aug 26). Doi:  10.1093/rheumatology/keac477

Key clinical point: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) were at an increased risk for mortality, with age, chronic obstructive pulmonary disease (COPD), diabetes mellitus with end-organ damage (DM-EOD), and corticosteroid dose being the major risk factors.

Major finding: Risk for mortality was higher in patients with RA-ILD vs RA without ILD (adjusted hazard ratio [aHR] 4.38; 95% CI 2.03-9.43). Age at ILD diagnosis (aHR 1.05; P < .001), comorbidities, such as COPD (aHR 2.12; P  =  .005) and DM-EOD (aHR 33.85; P  =  .002), and average daily prednisolone dose (aHR 1.09; P < .001) were associated with an increased risk for mortality in patients with RA-ILD.

Study details: Findings are from a population-based cohort study including patients with RA-ILD (n = 214) and RA without ILD (n = 30,882) who were propensity-matched (1:1) for selected comorbidities.

Disclosures: This study did not receive any funding. No conflicts of interest were declared.

Source: Ng K-H et al. Analysis of risk factors of mortality in rheumatoid arthritis patients with interstitial lung disease: A nationwide, population-based cohort study in Taiwan. RMD Open. 2022;8(2):e002343 (Aug 22). Doi: 10.1136/rmdopen-2022-002343

Key clinical point: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) were at an increased risk for mortality, with age, chronic obstructive pulmonary disease (COPD), diabetes mellitus with end-organ damage (DM-EOD), and corticosteroid dose being the major risk factors.

Major finding: Risk for mortality was higher in patients with RA-ILD vs RA without ILD (adjusted hazard ratio [aHR] 4.38; 95% CI 2.03-9.43). Age at ILD diagnosis (aHR 1.05; P < .001), comorbidities, such as COPD (aHR 2.12; P  =  .005) and DM-EOD (aHR 33.85; P  =  .002), and average daily prednisolone dose (aHR 1.09; P < .001) were associated with an increased risk for mortality in patients with RA-ILD.

Study details: Findings are from a population-based cohort study including patients with RA-ILD (n = 214) and RA without ILD (n = 30,882) who were propensity-matched (1:1) for selected comorbidities.

Disclosures: This study did not receive any funding. No conflicts of interest were declared.

Source: Ng K-H et al. Analysis of risk factors of mortality in rheumatoid arthritis patients with interstitial lung disease: A nationwide, population-based cohort study in Taiwan. RMD Open. 2022;8(2):e002343 (Aug 22). Doi: 10.1136/rmdopen-2022-002343

Key clinical point: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) were at an increased risk for mortality, with age, chronic obstructive pulmonary disease (COPD), diabetes mellitus with end-organ damage (DM-EOD), and corticosteroid dose being the major risk factors.

Major finding: Risk for mortality was higher in patients with RA-ILD vs RA without ILD (adjusted hazard ratio [aHR] 4.38; 95% CI 2.03-9.43). Age at ILD diagnosis (aHR 1.05; P < .001), comorbidities, such as COPD (aHR 2.12; P  =  .005) and DM-EOD (aHR 33.85; P  =  .002), and average daily prednisolone dose (aHR 1.09; P < .001) were associated with an increased risk for mortality in patients with RA-ILD.

Study details: Findings are from a population-based cohort study including patients with RA-ILD (n = 214) and RA without ILD (n = 30,882) who were propensity-matched (1:1) for selected comorbidities.

Disclosures: This study did not receive any funding. No conflicts of interest were declared.

Source: Ng K-H et al. Analysis of risk factors of mortality in rheumatoid arthritis patients with interstitial lung disease: A nationwide, population-based cohort study in Taiwan. RMD Open. 2022;8(2):e002343 (Aug 22). Doi: 10.1136/rmdopen-2022-002343

Key clinical point: Ultra-low dosing and repeated COVID-19 vaccination as late as possible after the latest rituximab infusion seems to be the best vaccination strategy in rituximab-treated patients with rheumatoid arthritis (RA).

Major finding: Humoral response after the third COVID-19 vaccination was numerically higher with 200 vs 1000 mg as the latest rituximab dose for the first vaccination (38% vs 15%; P  =  .06), with a trend toward improved response observed with a longer time between rituximab infusion and vaccination (odds ratio 1.16 per month increased time; P  =  .10). Overall, the humoral response persisted in 96% of patients, with response being persistent in 89% of patients despite intercurrent rituximab infusion.

Study details: Findings are from a follow-up study of the RTX-COVAC cohort including 121 rituximab-treated patients with RA who received a third COVID-19 vaccination.

Disclosures: This study did not receive any funding. AA den Broeder reported receiving grants outside the submitted work from various sources. The other authors declared no conflicts of interest.

Source: van der Togt CJT et al. Seroconversion after a third COVID-19 vaccine is affected by rituximab dose but persistence is not in patients with rheumatoid arthritis. Rheumatology (Oxford). 2022 (Aug 24). Doi: 10.1093/rheumatology/keac486

Key clinical point: Ultra-low dosing and repeated COVID-19 vaccination as late as possible after the latest rituximab infusion seems to be the best vaccination strategy in rituximab-treated patients with rheumatoid arthritis (RA).

Major finding: Humoral response after the third COVID-19 vaccination was numerically higher with 200 vs 1000 mg as the latest rituximab dose for the first vaccination (38% vs 15%; P  =  .06), with a trend toward improved response observed with a longer time between rituximab infusion and vaccination (odds ratio 1.16 per month increased time; P  =  .10). Overall, the humoral response persisted in 96% of patients, with response being persistent in 89% of patients despite intercurrent rituximab infusion.

Study details: Findings are from a follow-up study of the RTX-COVAC cohort including 121 rituximab-treated patients with RA who received a third COVID-19 vaccination.

Disclosures: This study did not receive any funding. AA den Broeder reported receiving grants outside the submitted work from various sources. The other authors declared no conflicts of interest.

Source: van der Togt CJT et al. Seroconversion after a third COVID-19 vaccine is affected by rituximab dose but persistence is not in patients with rheumatoid arthritis. Rheumatology (Oxford). 2022 (Aug 24). Doi: 10.1093/rheumatology/keac486

Key clinical point: Ultra-low dosing and repeated COVID-19 vaccination as late as possible after the latest rituximab infusion seems to be the best vaccination strategy in rituximab-treated patients with rheumatoid arthritis (RA).

Major finding: Humoral response after the third COVID-19 vaccination was numerically higher with 200 vs 1000 mg as the latest rituximab dose for the first vaccination (38% vs 15%; P  =  .06), with a trend toward improved response observed with a longer time between rituximab infusion and vaccination (odds ratio 1.16 per month increased time; P  =  .10). Overall, the humoral response persisted in 96% of patients, with response being persistent in 89% of patients despite intercurrent rituximab infusion.

Study details: Findings are from a follow-up study of the RTX-COVAC cohort including 121 rituximab-treated patients with RA who received a third COVID-19 vaccination.

Disclosures: This study did not receive any funding. AA den Broeder reported receiving grants outside the submitted work from various sources. The other authors declared no conflicts of interest.

Source: van der Togt CJT et al. Seroconversion after a third COVID-19 vaccine is affected by rituximab dose but persistence is not in patients with rheumatoid arthritis. Rheumatology (Oxford). 2022 (Aug 24). Doi: 10.1093/rheumatology/keac486

Key clinical point: Despite no significant treatment difference between the sexes, the time-averaged difference in remission rates between men and women with early rheumatoid arthritis (RA) was significantly greater with tocilizumab than with active conventional treatment.

Major finding: The remission rates were only numerically higher in men vs women. However, when averaged over time, tocilizumab vs active conventional therapy was associated with a higher probability of Clinical Disease Activity Index (CDAI) remission in men (risk difference [RD] 0.12; P  =  .04) but with a lower probability of CDAI remission in women (RD −0.05; P  =  .17).

Study details: This was a post hoc analysis of the phase 4 trial, NORD-STAR, including 812 treatment-naive patients with early RA who were randomly assigned to receive active conventional treatment or certolizumab-pegol or abatacept or tocilizumab in combination with methotrexate.

Disclosures: This study did not receive any funding. Several authors reported receiving institutional grants, honoraria, consulting or personal fees, travel support, or personal data safety monitoring or advisory board fees from various sources.

Source: Lend K et al. Sex differences in remission rates over 24 weeks among three different biological treatments compared to conventional therapy in patients with early rheumatoid arthritis (NORD-STAR): A post-hoc analysis of a randomised controlled trial. Lancet Rheumatol. 2022 (Aug 23). Doi: 10.1016/S2665-9913(22)00186-2

Key clinical point: Despite no significant treatment difference between the sexes, the time-averaged difference in remission rates between men and women with early rheumatoid arthritis (RA) was significantly greater with tocilizumab than with active conventional treatment.

Major finding: The remission rates were only numerically higher in men vs women. However, when averaged over time, tocilizumab vs active conventional therapy was associated with a higher probability of Clinical Disease Activity Index (CDAI) remission in men (risk difference [RD] 0.12; P  =  .04) but with a lower probability of CDAI remission in women (RD −0.05; P  =  .17).

Study details: This was a post hoc analysis of the phase 4 trial, NORD-STAR, including 812 treatment-naive patients with early RA who were randomly assigned to receive active conventional treatment or certolizumab-pegol or abatacept or tocilizumab in combination with methotrexate.

Disclosures: This study did not receive any funding. Several authors reported receiving institutional grants, honoraria, consulting or personal fees, travel support, or personal data safety monitoring or advisory board fees from various sources.

Source: Lend K et al. Sex differences in remission rates over 24 weeks among three different biological treatments compared to conventional therapy in patients with early rheumatoid arthritis (NORD-STAR): A post-hoc analysis of a randomised controlled trial. Lancet Rheumatol. 2022 (Aug 23). Doi: 10.1016/S2665-9913(22)00186-2

Key clinical point: Despite no significant treatment difference between the sexes, the time-averaged difference in remission rates between men and women with early rheumatoid arthritis (RA) was significantly greater with tocilizumab than with active conventional treatment.

Major finding: The remission rates were only numerically higher in men vs women. However, when averaged over time, tocilizumab vs active conventional therapy was associated with a higher probability of Clinical Disease Activity Index (CDAI) remission in men (risk difference [RD] 0.12; P  =  .04) but with a lower probability of CDAI remission in women (RD −0.05; P  =  .17).

Study details: This was a post hoc analysis of the phase 4 trial, NORD-STAR, including 812 treatment-naive patients with early RA who were randomly assigned to receive active conventional treatment or certolizumab-pegol or abatacept or tocilizumab in combination with methotrexate.

Disclosures: This study did not receive any funding. Several authors reported receiving institutional grants, honoraria, consulting or personal fees, travel support, or personal data safety monitoring or advisory board fees from various sources.

Source: Lend K et al. Sex differences in remission rates over 24 weeks among three different biological treatments compared to conventional therapy in patients with early rheumatoid arthritis (NORD-STAR): A post-hoc analysis of a randomised controlled trial. Lancet Rheumatol. 2022 (Aug 23). Doi: 10.1016/S2665-9913(22)00186-2

Key clinical point: In patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (methotrexate-IR), olokizumab fared better than placebo and was noninferior to adalimumab in improving the American College of Rheumatology (ACR20) response by ≥ 20%.

Major finding: Olokizumab once every 2 (q2w) or 4 weeks (q4w) was superior to placebo (P < .001 for superiority) for ACR20. However, a similar proportion of patients receiving olokizumab q2w (difference 3.4 percentage points; 97.5% CI −3.5 to 10.2) and q4w (difference 4.5 percentage points; 97.5% CI −2.2 to 11.2) vs adalimumab achieved ACR20 at week 12, with the incidence of serious adverse events being similar.

Study details: Findings are from the CREDO2  phase 3 trial, including 1648 patients with RA who were taking methotrexate-IR who were randomly assigned to receive 64 mg olokizumab (q2w/q4w), 40 mg adalimumab (q2w), or placebo (q2w) while continuing methotrexate.

Disclosures: This study was supported by R-Pharm. Three authors declared being employees of R-Pharm. Several authors served as consultants or received grants or contracts from various sources, including R-Pharm.

Source: Smolen JS et al. Olokizumab versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2022;387(8):715-726 (Aug 25). Doi: 10.1056/NEJMoa2201302

Key clinical point: In patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (methotrexate-IR), olokizumab fared better than placebo and was noninferior to adalimumab in improving the American College of Rheumatology (ACR20) response by ≥ 20%.

Major finding: Olokizumab once every 2 (q2w) or 4 weeks (q4w) was superior to placebo (P < .001 for superiority) for ACR20. However, a similar proportion of patients receiving olokizumab q2w (difference 3.4 percentage points; 97.5% CI −3.5 to 10.2) and q4w (difference 4.5 percentage points; 97.5% CI −2.2 to 11.2) vs adalimumab achieved ACR20 at week 12, with the incidence of serious adverse events being similar.

Study details: Findings are from the CREDO2  phase 3 trial, including 1648 patients with RA who were taking methotrexate-IR who were randomly assigned to receive 64 mg olokizumab (q2w/q4w), 40 mg adalimumab (q2w), or placebo (q2w) while continuing methotrexate.

Disclosures: This study was supported by R-Pharm. Three authors declared being employees of R-Pharm. Several authors served as consultants or received grants or contracts from various sources, including R-Pharm.

Source: Smolen JS et al. Olokizumab versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2022;387(8):715-726 (Aug 25). Doi: 10.1056/NEJMoa2201302

Key clinical point: In patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (methotrexate-IR), olokizumab fared better than placebo and was noninferior to adalimumab in improving the American College of Rheumatology (ACR20) response by ≥ 20%.

Major finding: Olokizumab once every 2 (q2w) or 4 weeks (q4w) was superior to placebo (P < .001 for superiority) for ACR20. However, a similar proportion of patients receiving olokizumab q2w (difference 3.4 percentage points; 97.5% CI −3.5 to 10.2) and q4w (difference 4.5 percentage points; 97.5% CI −2.2 to 11.2) vs adalimumab achieved ACR20 at week 12, with the incidence of serious adverse events being similar.

Study details: Findings are from the CREDO2  phase 3 trial, including 1648 patients with RA who were taking methotrexate-IR who were randomly assigned to receive 64 mg olokizumab (q2w/q4w), 40 mg adalimumab (q2w), or placebo (q2w) while continuing methotrexate.

Disclosures: This study was supported by R-Pharm. Three authors declared being employees of R-Pharm. Several authors served as consultants or received grants or contracts from various sources, including R-Pharm.

Source: Smolen JS et al. Olokizumab versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2022;387(8):715-726 (Aug 25). Doi: 10.1056/NEJMoa2201302

Patients with a rheumatic immune-mediated inflammatory disease (IMID) had worse outcomes, especially for mortality, after a myocardial infarction than those without an IMID, in a large propensity-matched analysis.

At a median of 2 years after their MI, Medicare beneficiaries with an IMID had adjusted risks that were:

• 15% higher for all-cause death (hazard ratio, 1.15);
• 12% higher for heart failure (HR, 1.12);
• 8% higher for recurrent MI (HR, 1.08); and
• 6% higher risk for coronary reintervention (HR, 1.06; P < .05 for all).

In addition, interventions known to improve outcomes in this context, such as coronary revascularization, were less common in patients with IMID.

“This could be because they usually are sicker and have more risk factors when they present, like kidney disease, so maybe they’re not eligible for the therapy. But by itself, it was surprising they’re not offered these interventions as common[ly] as people who don’t have the disease,” Amgad Mentias, MD, a clinical cardiologist at the Cleveland Clinic, said in an interview.

The study was published Sept. 14 in the Journal of the American Heart Association, with Dr. Mentias as senior author and Heba Wassif, MD, MPH, also with Cleveland Clinic, as first author.

IMIDs, such as rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease, are known to be associated with significantly higher cardiovascular disease (CVD) risk due to a greater prevalence of traditional CVD risk factors and chronic systemic inflammation.

Certain disease-modifying agents may also increase patients’ cardiovascular risk. This has been a long-simmering issue for the arthritis and ulcerative colitis drug tofacitinib (Xeljanz, Xeljanz XR), resulting in an updated boxed warning in 2021.

Many of these patients also have joint disease, pain, and fatigue, which can limit physical activity, Dr. Mentias said. “So these small nuances of how to manage these patients, or balance between controlling the inflammation but also improv[ing] cardiac risk factors, is not an easy task.”

Evidence regarding post-MI events has been inconsistent and limited to smaller single-center studies, he said. After propensity-score matching, the present study included 59,820 patients with and 178,547 patients without rheumatic IMIDs followed for a maximum of 6 years.

They were drawn from a cohort of 1.6 million persons aged 65 or older in the Medicare Provider Analysis and Review (MedPAR) file who had been admitted for an MI between 2014 and 2019. Of these, 60,072 had a prior history of rheumatic IMIDs, most commonly rheumatoid arthritis (77.8%), followed by systemic lupus erythematosus (12.2%), psoriasis (5.1%), systemic sclerosis (2.8%), and myositis/dermatomyositis (1.8%).

Patients with an IMID were more often women; had a higher prevalence of valve disease, pulmonary hypertension, hypothyroidism, and anemia; and were more likely to present with non–ST-segment MI (NSTEMI).

Rates of coronary angiography (46.1% vs. 51.5%), percutaneous coronary intervention (31.6% vs. 33.6%), and coronary artery bypass grafting (7.7% vs. 10.7%) were significantly lower in patients with IMIDs who had NSTEMI, compared with patients without an IMID who had NSTEMI. Rates of these interventions were also lower in patients with IMIDs who presented with STEMI versus their peers without an IMID, at 78.2% vs. 80.7%, 70.2% vs. 71.5%, and 4.9% vs. 6.4%, respectively.

Dr. Mentias pointed out that the emerging subspecialty of cardiorheumatology is gaining traction, especially at large hospitals and academic centers, but that less than one-third of persons in the United States with an IMID are likely to be under the care of such specialists.

“It’s important before developing an MI to try and control the different risk factors and improve the risk profile for these patients as much as possible by both specialties, and then, after an unfortunate event like MI happens, it’s important to make sure we offer therapies and treatments that are known to improve outcomes,” he said.

Commenting for this article, Jon Tyler Giles, MD, a clinical researcher who focuses on cardiovascular diseases in rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York, said that “at least for rheumatoid arthritis, this is something that we already knew. People with rheumatic arthritis, when they have a heart attack, are less likely to get the standard kind of treatments and have worse outcomes. This is a little larger sample, but it’s not a surprise, not a surprise at all.”

He noted that the study could have answered questions regarding potential drivers, but “they didn’t dig down into any of the factors that were associated with the poorer outcomes in the patients with rheumatoid arthritis and lupus and scleroderma.”

Indeed, the investigators acknowledge that the study lacked information on coronary anatomy, duration and severity of the autoimmune disease, imaging data, and medications such as anti-inflammatory or immune-targeted therapies.

Dr. Giles highlighted several factors that can contribute to a poorer post-MI prognosis in patients with rheumatic diseases; these include frailty, being more hypercoaguable, increased rates of myocardial dysfunction and other heart and blood vessel diseases, and chronic treatment with steroids and nonsteroidal anti-inflammatory drugs that often interferes with anticoagulation after a MI or when putting in a stent. “So, there’s lot of moving parts, and not one single thing that is likely the answer.”

In addition, he said, “there’s always going to be a portion of these patients who, despite doing the best that we can with treatment, are going to have very severe disease. That may or may not be the subset of patients that did the worst, but likely they’re overrepresented in those patients.”

Finally, the inability to move the needle may lie with the lack of evidence-based screening and management guidelines for cardiovascular disease in any rheumatic disease, Dr. Giles observed. “There’s no guideline for us to use to decide who needs screening over and above what’s recommended for the general population, and then, even if you do screen, what do you do other than what you would normally?”

Rheumatologists are often reluctant to take up the cardiovascular screening side of things because visits are short, and a lot of that time is spent trying to manage the inflammatory components of a patient’s disease, he said. There’s also a barrier in getting some patients to add a cardiologist to the mix of physicians they already see, especially if they don’t have any symptoms.

“If someone has had an event, it’s a lot easier for people to be convinced to go see the cardiologist, obviously, but prior to having an event, the preventative side of things is something that often gets missed or goes to the wayside,” Dr. Giles said.

The study was partly funded by philanthropic gifts by the Haslam family, Bailey family, and Khouri family to the Cleveland Clinic for coauthor Dr. Milind Desai’s research. Dr. Desai is a consultant for Medtronic and Bristol Myers Squibb and serves on an executive steering committee of a BMS-sponsored trial. The remaining authors report having no relevant disclosures. Dr. Giles is a consultant on drug cardiovascular safety for Pfizer, AbbVie, and Eli Lilly.

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

Patients with a rheumatic immune-mediated inflammatory disease (IMID) had worse outcomes, especially for mortality, after a myocardial infarction than those without an IMID, in a large propensity-matched analysis.

At a median of 2 years after their MI, Medicare beneficiaries with an IMID had adjusted risks that were:

• 15% higher for all-cause death (hazard ratio, 1.15);
• 12% higher for heart failure (HR, 1.12);
• 8% higher for recurrent MI (HR, 1.08); and
• 6% higher risk for coronary reintervention (HR, 1.06; P < .05 for all).

In addition, interventions known to improve outcomes in this context, such as coronary revascularization, were less common in patients with IMID.

“This could be because they usually are sicker and have more risk factors when they present, like kidney disease, so maybe they’re not eligible for the therapy. But by itself, it was surprising they’re not offered these interventions as common[ly] as people who don’t have the disease,” Amgad Mentias, MD, a clinical cardiologist at the Cleveland Clinic, said in an interview.

The study was published Sept. 14 in the Journal of the American Heart Association, with Dr. Mentias as senior author and Heba Wassif, MD, MPH, also with Cleveland Clinic, as first author.

IMIDs, such as rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease, are known to be associated with significantly higher cardiovascular disease (CVD) risk due to a greater prevalence of traditional CVD risk factors and chronic systemic inflammation.

Certain disease-modifying agents may also increase patients’ cardiovascular risk. This has been a long-simmering issue for the arthritis and ulcerative colitis drug tofacitinib (Xeljanz, Xeljanz XR), resulting in an updated boxed warning in 2021.

Many of these patients also have joint disease, pain, and fatigue, which can limit physical activity, Dr. Mentias said. “So these small nuances of how to manage these patients, or balance between controlling the inflammation but also improv[ing] cardiac risk factors, is not an easy task.”

Evidence regarding post-MI events has been inconsistent and limited to smaller single-center studies, he said. After propensity-score matching, the present study included 59,820 patients with and 178,547 patients without rheumatic IMIDs followed for a maximum of 6 years.

They were drawn from a cohort of 1.6 million persons aged 65 or older in the Medicare Provider Analysis and Review (MedPAR) file who had been admitted for an MI between 2014 and 2019. Of these, 60,072 had a prior history of rheumatic IMIDs, most commonly rheumatoid arthritis (77.8%), followed by systemic lupus erythematosus (12.2%), psoriasis (5.1%), systemic sclerosis (2.8%), and myositis/dermatomyositis (1.8%).

Patients with an IMID were more often women; had a higher prevalence of valve disease, pulmonary hypertension, hypothyroidism, and anemia; and were more likely to present with non–ST-segment MI (NSTEMI).

Rates of coronary angiography (46.1% vs. 51.5%), percutaneous coronary intervention (31.6% vs. 33.6%), and coronary artery bypass grafting (7.7% vs. 10.7%) were significantly lower in patients with IMIDs who had NSTEMI, compared with patients without an IMID who had NSTEMI. Rates of these interventions were also lower in patients with IMIDs who presented with STEMI versus their peers without an IMID, at 78.2% vs. 80.7%, 70.2% vs. 71.5%, and 4.9% vs. 6.4%, respectively.

Dr. Mentias pointed out that the emerging subspecialty of cardiorheumatology is gaining traction, especially at large hospitals and academic centers, but that less than one-third of persons in the United States with an IMID are likely to be under the care of such specialists.

“It’s important before developing an MI to try and control the different risk factors and improve the risk profile for these patients as much as possible by both specialties, and then, after an unfortunate event like MI happens, it’s important to make sure we offer therapies and treatments that are known to improve outcomes,” he said.

Commenting for this article, Jon Tyler Giles, MD, a clinical researcher who focuses on cardiovascular diseases in rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York, said that “at least for rheumatoid arthritis, this is something that we already knew. People with rheumatic arthritis, when they have a heart attack, are less likely to get the standard kind of treatments and have worse outcomes. This is a little larger sample, but it’s not a surprise, not a surprise at all.”

He noted that the study could have answered questions regarding potential drivers, but “they didn’t dig down into any of the factors that were associated with the poorer outcomes in the patients with rheumatoid arthritis and lupus and scleroderma.”

Indeed, the investigators acknowledge that the study lacked information on coronary anatomy, duration and severity of the autoimmune disease, imaging data, and medications such as anti-inflammatory or immune-targeted therapies.

Dr. Giles highlighted several factors that can contribute to a poorer post-MI prognosis in patients with rheumatic diseases; these include frailty, being more hypercoaguable, increased rates of myocardial dysfunction and other heart and blood vessel diseases, and chronic treatment with steroids and nonsteroidal anti-inflammatory drugs that often interferes with anticoagulation after a MI or when putting in a stent. “So, there’s lot of moving parts, and not one single thing that is likely the answer.”

In addition, he said, “there’s always going to be a portion of these patients who, despite doing the best that we can with treatment, are going to have very severe disease. That may or may not be the subset of patients that did the worst, but likely they’re overrepresented in those patients.”

Finally, the inability to move the needle may lie with the lack of evidence-based screening and management guidelines for cardiovascular disease in any rheumatic disease, Dr. Giles observed. “There’s no guideline for us to use to decide who needs screening over and above what’s recommended for the general population, and then, even if you do screen, what do you do other than what you would normally?”

Rheumatologists are often reluctant to take up the cardiovascular screening side of things because visits are short, and a lot of that time is spent trying to manage the inflammatory components of a patient’s disease, he said. There’s also a barrier in getting some patients to add a cardiologist to the mix of physicians they already see, especially if they don’t have any symptoms.

“If someone has had an event, it’s a lot easier for people to be convinced to go see the cardiologist, obviously, but prior to having an event, the preventative side of things is something that often gets missed or goes to the wayside,” Dr. Giles said.

The study was partly funded by philanthropic gifts by the Haslam family, Bailey family, and Khouri family to the Cleveland Clinic for coauthor Dr. Milind Desai’s research. Dr. Desai is a consultant for Medtronic and Bristol Myers Squibb and serves on an executive steering committee of a BMS-sponsored trial. The remaining authors report having no relevant disclosures. Dr. Giles is a consultant on drug cardiovascular safety for Pfizer, AbbVie, and Eli Lilly.

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

Patients with a rheumatic immune-mediated inflammatory disease (IMID) had worse outcomes, especially for mortality, after a myocardial infarction than those without an IMID, in a large propensity-matched analysis.

At a median of 2 years after their MI, Medicare beneficiaries with an IMID had adjusted risks that were:

• 15% higher for all-cause death (hazard ratio, 1.15);
• 12% higher for heart failure (HR, 1.12);
• 8% higher for recurrent MI (HR, 1.08); and
• 6% higher risk for coronary reintervention (HR, 1.06; P < .05 for all).

In addition, interventions known to improve outcomes in this context, such as coronary revascularization, were less common in patients with IMID.

“This could be because they usually are sicker and have more risk factors when they present, like kidney disease, so maybe they’re not eligible for the therapy. But by itself, it was surprising they’re not offered these interventions as common[ly] as people who don’t have the disease,” Amgad Mentias, MD, a clinical cardiologist at the Cleveland Clinic, said in an interview.

The study was published Sept. 14 in the Journal of the American Heart Association, with Dr. Mentias as senior author and Heba Wassif, MD, MPH, also with Cleveland Clinic, as first author.

IMIDs, such as rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease, are known to be associated with significantly higher cardiovascular disease (CVD) risk due to a greater prevalence of traditional CVD risk factors and chronic systemic inflammation.

Certain disease-modifying agents may also increase patients’ cardiovascular risk. This has been a long-simmering issue for the arthritis and ulcerative colitis drug tofacitinib (Xeljanz, Xeljanz XR), resulting in an updated boxed warning in 2021.

Many of these patients also have joint disease, pain, and fatigue, which can limit physical activity, Dr. Mentias said. “So these small nuances of how to manage these patients, or balance between controlling the inflammation but also improv[ing] cardiac risk factors, is not an easy task.”

Evidence regarding post-MI events has been inconsistent and limited to smaller single-center studies, he said. After propensity-score matching, the present study included 59,820 patients with and 178,547 patients without rheumatic IMIDs followed for a maximum of 6 years.

They were drawn from a cohort of 1.6 million persons aged 65 or older in the Medicare Provider Analysis and Review (MedPAR) file who had been admitted for an MI between 2014 and 2019. Of these, 60,072 had a prior history of rheumatic IMIDs, most commonly rheumatoid arthritis (77.8%), followed by systemic lupus erythematosus (12.2%), psoriasis (5.1%), systemic sclerosis (2.8%), and myositis/dermatomyositis (1.8%).

Patients with an IMID were more often women; had a higher prevalence of valve disease, pulmonary hypertension, hypothyroidism, and anemia; and were more likely to present with non–ST-segment MI (NSTEMI).

Rates of coronary angiography (46.1% vs. 51.5%), percutaneous coronary intervention (31.6% vs. 33.6%), and coronary artery bypass grafting (7.7% vs. 10.7%) were significantly lower in patients with IMIDs who had NSTEMI, compared with patients without an IMID who had NSTEMI. Rates of these interventions were also lower in patients with IMIDs who presented with STEMI versus their peers without an IMID, at 78.2% vs. 80.7%, 70.2% vs. 71.5%, and 4.9% vs. 6.4%, respectively.

Dr. Mentias pointed out that the emerging subspecialty of cardiorheumatology is gaining traction, especially at large hospitals and academic centers, but that less than one-third of persons in the United States with an IMID are likely to be under the care of such specialists.

“It’s important before developing an MI to try and control the different risk factors and improve the risk profile for these patients as much as possible by both specialties, and then, after an unfortunate event like MI happens, it’s important to make sure we offer therapies and treatments that are known to improve outcomes,” he said.

Commenting for this article, Jon Tyler Giles, MD, a clinical researcher who focuses on cardiovascular diseases in rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York, said that “at least for rheumatoid arthritis, this is something that we already knew. People with rheumatic arthritis, when they have a heart attack, are less likely to get the standard kind of treatments and have worse outcomes. This is a little larger sample, but it’s not a surprise, not a surprise at all.”

He noted that the study could have answered questions regarding potential drivers, but “they didn’t dig down into any of the factors that were associated with the poorer outcomes in the patients with rheumatoid arthritis and lupus and scleroderma.”

Indeed, the investigators acknowledge that the study lacked information on coronary anatomy, duration and severity of the autoimmune disease, imaging data, and medications such as anti-inflammatory or immune-targeted therapies.

Dr. Giles highlighted several factors that can contribute to a poorer post-MI prognosis in patients with rheumatic diseases; these include frailty, being more hypercoaguable, increased rates of myocardial dysfunction and other heart and blood vessel diseases, and chronic treatment with steroids and nonsteroidal anti-inflammatory drugs that often interferes with anticoagulation after a MI or when putting in a stent. “So, there’s lot of moving parts, and not one single thing that is likely the answer.”

In addition, he said, “there’s always going to be a portion of these patients who, despite doing the best that we can with treatment, are going to have very severe disease. That may or may not be the subset of patients that did the worst, but likely they’re overrepresented in those patients.”

Finally, the inability to move the needle may lie with the lack of evidence-based screening and management guidelines for cardiovascular disease in any rheumatic disease, Dr. Giles observed. “There’s no guideline for us to use to decide who needs screening over and above what’s recommended for the general population, and then, even if you do screen, what do you do other than what you would normally?”

Rheumatologists are often reluctant to take up the cardiovascular screening side of things because visits are short, and a lot of that time is spent trying to manage the inflammatory components of a patient’s disease, he said. There’s also a barrier in getting some patients to add a cardiologist to the mix of physicians they already see, especially if they don’t have any symptoms.

“If someone has had an event, it’s a lot easier for people to be convinced to go see the cardiologist, obviously, but prior to having an event, the preventative side of things is something that often gets missed or goes to the wayside,” Dr. Giles said.

The study was partly funded by philanthropic gifts by the Haslam family, Bailey family, and Khouri family to the Cleveland Clinic for coauthor Dr. Milind Desai’s research. Dr. Desai is a consultant for Medtronic and Bristol Myers Squibb and serves on an executive steering committee of a BMS-sponsored trial. The remaining authors report having no relevant disclosures. Dr. Giles is a consultant on drug cardiovascular safety for Pfizer, AbbVie, and Eli Lilly.

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

Men with early rheumatoid arthritis who had previously never been treated with disease-modifying antirheumatic drugs (DMARDs) achieved remission significantly more often than women when given the interleukin (IL)-6 inhibitor tocilizumab (Actemra), according to new findings published in The Lancet Rheumatology.

Researchers also found that men had higher rates of remission than women when treated with certolizumab pegol (Cimzia), abatacept (Orencia), or conventional synthetic DMARDs, but the differences were not statistically significant.

The findings are based on a post-hoc analysis of data from the randomized, controlled, phase 4 NORD-STAR trial performed across Scandinavia, Iceland, and the Netherlands that is believed to be the first study on treatment-naive patients to specifically analyze the interaction between sex and treatment using interaction terms. In the study, outcomes for men versus women were compared within each treatment group and also to the conventional treatment arm used as the reference group.

“Our findings could provide guidance about the optimal treatment choice for DMARD-naive men and women with early RA,” said first author Kristina Lend, MSc, research assistant at the Karolinska Institute, Stockholm, and PhD student at Amsterdam University Medical Center.

Researchers enrolled 812 patients between 2012 and 2018 and randomly assigned them to receive:

• Conventional treatment involving methotrexate plus prednisolone tapered from 20 mg per day to 5 mg per day within 9 weeks or methotrexate plus sulfasalazine (2 g per day), hydroxychloroquine (35 mg/kg per week or 200 mg per day), and intra-articular glucocorticoids in the swollen joint (maximally four joints and 80 mg per visit);
• the tumor necrosis factor (TNF) inhibitor certolizumab pegol with methotrexate;
• the T-cell co-stimulation modulator abatacept with methotrexate; or
• tocilizumab with methotrexate.

All of the patients were newly diagnosed, with symptoms for less than 24 months, and they had never taken a DMARD. Researchers used the Clinical Disease Activity Index (CDAI) as the primary tool for assessing remission. Patients started oral methotrexate initially at 10-15 mg per week and escalated within 4 weeks to a target dose of 25 mg per week.

In all groups, men achieved remission after 24 weeks at higher rates than women: 55% compared with 50% in the conventional arm; 57% vs. 52% with certolizumab pegol; 65% vs. 51% with abatacept; and 61% vs. 40% with tocilizumab. But in most cases, the 95% confidence intervals overlapped for men and women, meaning the differences didn’t reach statistical significance.

However, in the tocilizumab group, the difference was significant.

Ms. Lend said it was interesting to see this difference with tocilizumab. The drug is known to reduce acute-phase reactants, such as C-reactive protein (CRP). But the CDAI doesn’t take CRP or other acute phase reactants into account. Both men and women taking tocilizumab had significant reductions in CRP, and yet men ultimately did much better on the drug according to the CDAI, as well as other scales, such as the Disease Activity Score in 28 joints and Simplified Disease Activity Index.

Women in the conventional treatment arm actually achieved remission more often, at least in absolute numbers, than did women taking tocilizumab.

“It was surprising to see that men on tocilizumab treatment achieved higher remission rates than men in conventional treatment while women in tocilizumab treatment achieved lower remission rates than women in conventional treatment,” she said.

Several factors could account for the differences in remission, she said. Subjective components when assessing remission – such as tender joint counts and a patient’s own assessment of their disease activity – tend to be higher for women. Underlying biological mechanisms can play a role as well, with evidence suggesting that gonadal hormone concentrations modulate the immune system and affect pain signaling, influencing how the disease is experienced, she said.

Findings such as these could lead to a redrafting of treatment recommendations, Ms. Lend suggested.

“Conventional treatment is currently recommended over tocilizumab and other biologics for DMARD-naive men and women with early RA,” she said. “We do feel that the overall results of the NORD-STAR trial could lead to a reassessment of these recommendations, and that more personalized treatment decisions will become the standard.”

In an accompanying editorial, Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egaz Moniz in Lisbon, and Elena Nikiphorou, MD, consultant rheumatologist at King’s College London, said the analysis was generally well-designed, although perhaps too small.

“The NORD-STAR trial, compared to other studies, comes the closest to answering the question at hand,” they wrote. “A fair conclusion is that (with the exception of tocilizumab) men and women respond similarly to biological DMARDs compared with conventional therapy. If true, this is reassuring news both to patients and clinicians.”

They cautioned that the study was “probably underpowered” to answer the question authoritatively.

“Despite this, the study provides useful insights into sex-driven responses to treatment,” they said. “Differences in methodological and analytical approaches will need to be considered in studies with similar intentions when interpreting the findings.”

Ruth Fritsch-Stork, MD, PhD, professor of rheumatology at Sigmund Freud University in Vienna, who has studied sex and RA treatment in the Austrian BIOREG registry, said the findings are an important contribution to the literature.

“I think it is a very interesting paper, as little literature has been published about sex differences in RA patients regarding therapy,” she said. “And the little that is known is ambiguous. So this paper is a badly needed piece in the puzzle of treatment response in RA.”

She said she wondered how much these findings will be applicable to typical clinical scenarios, in which tocilizumab is usually at least a second-line therapy, after use of conventional synthetic DMARDs – and often after anti-TNF therapy as well. But this study population was DMARD naive.

“Also, the literature usually describes a better outcome in men for anti-TNF, which was not seen here,” she added.

“As the effect of tocilizumab seems to be greater in men not only in remission rates, but also in infection rates, I do believe an effect on the IL-6 signaling and immunological sequelae to be the underlying factor,” Dr. Fritsch-Stork said. “However, I agree with the authors that unknown, noninflammatory, sex-dependent effects on pain sensation might play a role.”

Even though the applicability of the study isn’t clear, she said, “it is important information for future investigations.”

Ms. Lend and Dr. Fritsch-Stork reported no relevant financial disclosures. Dr. Sepriano reported financial relationships with UCB, Novartis, and Lilly. Dr. Nikiphorou reported financial relationships with Pfizer, Gilead, Galapagos, Lilly, and Fresenius.

Men with early rheumatoid arthritis who had previously never been treated with disease-modifying antirheumatic drugs (DMARDs) achieved remission significantly more often than women when given the interleukin (IL)-6 inhibitor tocilizumab (Actemra), according to new findings published in The Lancet Rheumatology.

Researchers also found that men had higher rates of remission than women when treated with certolizumab pegol (Cimzia), abatacept (Orencia), or conventional synthetic DMARDs, but the differences were not statistically significant.

The findings are based on a post-hoc analysis of data from the randomized, controlled, phase 4 NORD-STAR trial performed across Scandinavia, Iceland, and the Netherlands that is believed to be the first study on treatment-naive patients to specifically analyze the interaction between sex and treatment using interaction terms. In the study, outcomes for men versus women were compared within each treatment group and also to the conventional treatment arm used as the reference group.

“Our findings could provide guidance about the optimal treatment choice for DMARD-naive men and women with early RA,” said first author Kristina Lend, MSc, research assistant at the Karolinska Institute, Stockholm, and PhD student at Amsterdam University Medical Center.

Researchers enrolled 812 patients between 2012 and 2018 and randomly assigned them to receive:

• Conventional treatment involving methotrexate plus prednisolone tapered from 20 mg per day to 5 mg per day within 9 weeks or methotrexate plus sulfasalazine (2 g per day), hydroxychloroquine (35 mg/kg per week or 200 mg per day), and intra-articular glucocorticoids in the swollen joint (maximally four joints and 80 mg per visit);
• the tumor necrosis factor (TNF) inhibitor certolizumab pegol with methotrexate;
• the T-cell co-stimulation modulator abatacept with methotrexate; or
• tocilizumab with methotrexate.

All of the patients were newly diagnosed, with symptoms for less than 24 months, and they had never taken a DMARD. Researchers used the Clinical Disease Activity Index (CDAI) as the primary tool for assessing remission. Patients started oral methotrexate initially at 10-15 mg per week and escalated within 4 weeks to a target dose of 25 mg per week.

In all groups, men achieved remission after 24 weeks at higher rates than women: 55% compared with 50% in the conventional arm; 57% vs. 52% with certolizumab pegol; 65% vs. 51% with abatacept; and 61% vs. 40% with tocilizumab. But in most cases, the 95% confidence intervals overlapped for men and women, meaning the differences didn’t reach statistical significance.

However, in the tocilizumab group, the difference was significant.

Ms. Lend said it was interesting to see this difference with tocilizumab. The drug is known to reduce acute-phase reactants, such as C-reactive protein (CRP). But the CDAI doesn’t take CRP or other acute phase reactants into account. Both men and women taking tocilizumab had significant reductions in CRP, and yet men ultimately did much better on the drug according to the CDAI, as well as other scales, such as the Disease Activity Score in 28 joints and Simplified Disease Activity Index.

Women in the conventional treatment arm actually achieved remission more often, at least in absolute numbers, than did women taking tocilizumab.

“It was surprising to see that men on tocilizumab treatment achieved higher remission rates than men in conventional treatment while women in tocilizumab treatment achieved lower remission rates than women in conventional treatment,” she said.

Several factors could account for the differences in remission, she said. Subjective components when assessing remission – such as tender joint counts and a patient’s own assessment of their disease activity – tend to be higher for women. Underlying biological mechanisms can play a role as well, with evidence suggesting that gonadal hormone concentrations modulate the immune system and affect pain signaling, influencing how the disease is experienced, she said.

Findings such as these could lead to a redrafting of treatment recommendations, Ms. Lend suggested.

“Conventional treatment is currently recommended over tocilizumab and other biologics for DMARD-naive men and women with early RA,” she said. “We do feel that the overall results of the NORD-STAR trial could lead to a reassessment of these recommendations, and that more personalized treatment decisions will become the standard.”

In an accompanying editorial, Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egaz Moniz in Lisbon, and Elena Nikiphorou, MD, consultant rheumatologist at King’s College London, said the analysis was generally well-designed, although perhaps too small.

“The NORD-STAR trial, compared to other studies, comes the closest to answering the question at hand,” they wrote. “A fair conclusion is that (with the exception of tocilizumab) men and women respond similarly to biological DMARDs compared with conventional therapy. If true, this is reassuring news both to patients and clinicians.”

They cautioned that the study was “probably underpowered” to answer the question authoritatively.

“Despite this, the study provides useful insights into sex-driven responses to treatment,” they said. “Differences in methodological and analytical approaches will need to be considered in studies with similar intentions when interpreting the findings.”

Ruth Fritsch-Stork, MD, PhD, professor of rheumatology at Sigmund Freud University in Vienna, who has studied sex and RA treatment in the Austrian BIOREG registry, said the findings are an important contribution to the literature.

“I think it is a very interesting paper, as little literature has been published about sex differences in RA patients regarding therapy,” she said. “And the little that is known is ambiguous. So this paper is a badly needed piece in the puzzle of treatment response in RA.”

She said she wondered how much these findings will be applicable to typical clinical scenarios, in which tocilizumab is usually at least a second-line therapy, after use of conventional synthetic DMARDs – and often after anti-TNF therapy as well. But this study population was DMARD naive.

“Also, the literature usually describes a better outcome in men for anti-TNF, which was not seen here,” she added.

“As the effect of tocilizumab seems to be greater in men not only in remission rates, but also in infection rates, I do believe an effect on the IL-6 signaling and immunological sequelae to be the underlying factor,” Dr. Fritsch-Stork said. “However, I agree with the authors that unknown, noninflammatory, sex-dependent effects on pain sensation might play a role.”

Even though the applicability of the study isn’t clear, she said, “it is important information for future investigations.”

Ms. Lend and Dr. Fritsch-Stork reported no relevant financial disclosures. Dr. Sepriano reported financial relationships with UCB, Novartis, and Lilly. Dr. Nikiphorou reported financial relationships with Pfizer, Gilead, Galapagos, Lilly, and Fresenius.

Men with early rheumatoid arthritis who had previously never been treated with disease-modifying antirheumatic drugs (DMARDs) achieved remission significantly more often than women when given the interleukin (IL)-6 inhibitor tocilizumab (Actemra), according to new findings published in The Lancet Rheumatology.

Researchers also found that men had higher rates of remission than women when treated with certolizumab pegol (Cimzia), abatacept (Orencia), or conventional synthetic DMARDs, but the differences were not statistically significant.

The findings are based on a post-hoc analysis of data from the randomized, controlled, phase 4 NORD-STAR trial performed across Scandinavia, Iceland, and the Netherlands that is believed to be the first study on treatment-naive patients to specifically analyze the interaction between sex and treatment using interaction terms. In the study, outcomes for men versus women were compared within each treatment group and also to the conventional treatment arm used as the reference group.

“Our findings could provide guidance about the optimal treatment choice for DMARD-naive men and women with early RA,” said first author Kristina Lend, MSc, research assistant at the Karolinska Institute, Stockholm, and PhD student at Amsterdam University Medical Center.

Researchers enrolled 812 patients between 2012 and 2018 and randomly assigned them to receive:

• Conventional treatment involving methotrexate plus prednisolone tapered from 20 mg per day to 5 mg per day within 9 weeks or methotrexate plus sulfasalazine (2 g per day), hydroxychloroquine (35 mg/kg per week or 200 mg per day), and intra-articular glucocorticoids in the swollen joint (maximally four joints and 80 mg per visit);
• the tumor necrosis factor (TNF) inhibitor certolizumab pegol with methotrexate;
• the T-cell co-stimulation modulator abatacept with methotrexate; or
• tocilizumab with methotrexate.

All of the patients were newly diagnosed, with symptoms for less than 24 months, and they had never taken a DMARD. Researchers used the Clinical Disease Activity Index (CDAI) as the primary tool for assessing remission. Patients started oral methotrexate initially at 10-15 mg per week and escalated within 4 weeks to a target dose of 25 mg per week.

In all groups, men achieved remission after 24 weeks at higher rates than women: 55% compared with 50% in the conventional arm; 57% vs. 52% with certolizumab pegol; 65% vs. 51% with abatacept; and 61% vs. 40% with tocilizumab. But in most cases, the 95% confidence intervals overlapped for men and women, meaning the differences didn’t reach statistical significance.

However, in the tocilizumab group, the difference was significant.

Ms. Lend said it was interesting to see this difference with tocilizumab. The drug is known to reduce acute-phase reactants, such as C-reactive protein (CRP). But the CDAI doesn’t take CRP or other acute phase reactants into account. Both men and women taking tocilizumab had significant reductions in CRP, and yet men ultimately did much better on the drug according to the CDAI, as well as other scales, such as the Disease Activity Score in 28 joints and Simplified Disease Activity Index.

Women in the conventional treatment arm actually achieved remission more often, at least in absolute numbers, than did women taking tocilizumab.

“It was surprising to see that men on tocilizumab treatment achieved higher remission rates than men in conventional treatment while women in tocilizumab treatment achieved lower remission rates than women in conventional treatment,” she said.

Several factors could account for the differences in remission, she said. Subjective components when assessing remission – such as tender joint counts and a patient’s own assessment of their disease activity – tend to be higher for women. Underlying biological mechanisms can play a role as well, with evidence suggesting that gonadal hormone concentrations modulate the immune system and affect pain signaling, influencing how the disease is experienced, she said.

Findings such as these could lead to a redrafting of treatment recommendations, Ms. Lend suggested.

“Conventional treatment is currently recommended over tocilizumab and other biologics for DMARD-naive men and women with early RA,” she said. “We do feel that the overall results of the NORD-STAR trial could lead to a reassessment of these recommendations, and that more personalized treatment decisions will become the standard.”

In an accompanying editorial, Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egaz Moniz in Lisbon, and Elena Nikiphorou, MD, consultant rheumatologist at King’s College London, said the analysis was generally well-designed, although perhaps too small.

“The NORD-STAR trial, compared to other studies, comes the closest to answering the question at hand,” they wrote. “A fair conclusion is that (with the exception of tocilizumab) men and women respond similarly to biological DMARDs compared with conventional therapy. If true, this is reassuring news both to patients and clinicians.”

They cautioned that the study was “probably underpowered” to answer the question authoritatively.

“Despite this, the study provides useful insights into sex-driven responses to treatment,” they said. “Differences in methodological and analytical approaches will need to be considered in studies with similar intentions when interpreting the findings.”

Ruth Fritsch-Stork, MD, PhD, professor of rheumatology at Sigmund Freud University in Vienna, who has studied sex and RA treatment in the Austrian BIOREG registry, said the findings are an important contribution to the literature.

“I think it is a very interesting paper, as little literature has been published about sex differences in RA patients regarding therapy,” she said. “And the little that is known is ambiguous. So this paper is a badly needed piece in the puzzle of treatment response in RA.”

She said she wondered how much these findings will be applicable to typical clinical scenarios, in which tocilizumab is usually at least a second-line therapy, after use of conventional synthetic DMARDs – and often after anti-TNF therapy as well. But this study population was DMARD naive.

“Also, the literature usually describes a better outcome in men for anti-TNF, which was not seen here,” she added.

“As the effect of tocilizumab seems to be greater in men not only in remission rates, but also in infection rates, I do believe an effect on the IL-6 signaling and immunological sequelae to be the underlying factor,” Dr. Fritsch-Stork said. “However, I agree with the authors that unknown, noninflammatory, sex-dependent effects on pain sensation might play a role.”

Even though the applicability of the study isn’t clear, she said, “it is important information for future investigations.”

Ms. Lend and Dr. Fritsch-Stork reported no relevant financial disclosures. Dr. Sepriano reported financial relationships with UCB, Novartis, and Lilly. Dr. Nikiphorou reported financial relationships with Pfizer, Gilead, Galapagos, Lilly, and Fresenius.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

Clinical research in rheumatology was suffering from an identity crisis of sorts 40 years ago. A lack of consensus across continents resulted in differing views about clinical outcome measures and judgments about treatments.

Patients were not allowed to be the generating source of a clinical outcome, according to Peter Tugwell, MSc, MD. “The only outcomes that were acceptable were clinician assessments, blood tests, and imaging,” said Dr. Tugwell, professor of medicine, epidemiology, and public health at the University of Ottawa (Ont.) and a practicing rheumatologist at Ottawa Hospital.

Clinicians were coming to different conclusions about patient responses to treatment when managing rheumatoid arthritis in clinical practice.

OMERACT sought to address this lack of uniformity. This international group, formed in 1992, leverages stakeholder groups to improve outcome measurement in rheumatology endpoints through a consensus-building, data-driven format.

It was originally known as “Outcome Measures in Rheumatoid Arthritis Clinical Trials,” but its leaders have since broadened its scope to “Outcome Measures in Rheumatology.” Over the years, it has evolved into an international network that assesses measurement across a wide variety of intervention studies. Now 30 years old, the network spans 40 active working groups and has influenced work in patient outcomes across 500 peer-reviewed publications.

The network meets every 2 years to address what is always a challenging agenda, said Dr. Tugwell, one of its founding members and chair. “There’s lots of strong opinions.” Participating in the discussions are individuals from all stages of seniority in rheumatology and clinical epidemiology, patient research partners, industry, approval agencies, and many countries who are committed to the spirit of OMERACT.

“The secret to our success has been getting world leaders to come together and have those discussions, work them through, and identify common ground in such a way that the approval agencies accept these outcome measures in clinical trials,” he added.

“My impression was the founders perceived a problem in the early 1990s and devised a consensus method in an attempt to quantify clinical parameters to define disease activity in rheumatoid arthritis – an important first step to do clinical trials and allow comparisons between them,” said Patricia Woo, CBE, FMedSci, FRCP, emeritus professor of pediatric rheumatology and previous head of the Centre for Paediatric and Adolescent Rheumatology at UCL, London. At that time, even disease definitions varied between the United States and Europe and other parts of the world, said Dr. Woo, who is not a part of OMERACT. “This was especially true for pediatric rheumatology.”
 

Fusing the continental divide

OMERACT arose from a need to streamline clinical outcome measures in rheumatology. Research papers during the 1980s demonstrated a lack of coherence in managing patients with rheumatoid arthritis in routine practice. In addition, the measures used to define clinical endpoints in clinical trials operated in silos – they were either too specific to a certain trial, overlapped with other concepts, or didn’t reflect changes in treatment.

Approval agencies in Europe and North America were approving only outcomes measures developed by their respective researchers. This was also true of patients they tested on. “This seemed crazy,” Dr. Tugwell said.

Dr. Tugwell was involved in the Cochrane collaboration, which conducts systematic reviews of best evidence across the world that assesses the magnitude of benefits versus harms.

To achieve this goal, “you need to pull studies from around the world,” he said. Maarten Boers, MD, PhD, a rheumatologist (and later professor of clinical epidemiology at Amsterdam University Medical Center) from the Netherlands, spent a year in Ontario, Canada, to train as a clinical epidemiologist. Together, Dr. Tugwell and Dr. Boers began discussing options to develop more streamlined outcome measures.

Courtesy OMERACT

They initiated the first OMERACT conference in Maastricht, the Netherlands, in 1992. The Food and Drug Administration and European Medicines Agency participated, along with leaders of outcomes measurement in Europe and in North America.

Discussions centered on methods to develop outcomes in a meaningful fashion. During the first meeting, North American and European approval agencies agreed to accept each other’s studies and endpoints and patient reported outcomes.

Agreement was achieved on a preliminary set of outcome domains and measures that later became known as the WHO-ILAR (World Health Organization–International League of Associations for Rheumatology) core set. The set included seven outcome domains: tender joints, swollen joints, pain, physician global assessment, patient global assessment, physical disability, and acute phase reactants, and one additional outcome domain for studies lasting 1 year or more: radiographs of the joints.

“A proactive program was planned to test not only the validity of these endpoints, but also the methods for their measurement. This was the start of a continuing process,” OMERACT members said in a joint statement for this article. Meetings have since taken place every 2 years.

Courtesy OMERACT

OMERACT accomplishments

OMERACT now requires buy-in from four continents: Asia, Australia, Europe, and North America.

Its leaders have developed an explicit process for gaining endorsement of core outcome domains and instrument measurement sets. To fully capture the possibilities of “what to measure,” i.e., “measurable aspects of health conditions,” OMERACT has developed a framework of concepts, core areas, and outcome domains. The key concepts are pathophysiology (with a core area termed “manifestations/abnormalities”) and impact (with core areas of “death/lifespan,” and “life impact,” and the optional area of “societal/resource use”). An outcome domain defines an element of a core area to measure the effects of a treatment, such as blood markers, pain intensity, physical function, or emotional well-being.

A core outcome domain set is developed by agreeing to at least one outcome domain within one of the three core areas. Subsequently, a core outcome measurement set is developed by agreeing to at least one applicable measurement instrument for each core outcome domain. This requires documentation of validity, summarized under three metrics: truth, discrimination, and feasibility.

OMERACT’s handbook provides tutelage on establishing and implementing core outcomes, and several workbooks offer guidance on developing core outcome domain sets, selecting instruments for core outcome measurement sets, and OMERACT methodology.

All this work has led to widespread adoption.

Approval agencies have accepted OMERACT’s filter and methods advances, which have been adopted by many research groups in rheumatology and among nonrheumatology research groups. Organizations such as the U.S. National Institutes of Health’s National Institute of Neurological Disorders and Stroke have sought its advice.

Its core outcomes have been adopted and used for approval in the great majority of studies on rheumatoid arthritis, Dr. Tugwell said.

Several BMJ articles underscore the influence and uptake of OMERACT’s core outcome set. One 2017 paper, which analyzed 273 randomized trials of rheumatoid arthritis drug treatments on ClinicalTrials.gov, found that the WHO-ILAR arthritis core outcome set was reported in 81% of the studies. “The adoption of a core outcome set has the potential to increase consistency in outcomes measured across trials and ensure that trials are more likely to measure appropriate outcomes,” the authors concluded.

Since the initial 1992 meeting, OMERACT has broadened its focus from rheumatoid arthritis to 25 other musculoskeletal conditions.

For example, other OMERACT conferences have led to consensus on core sets of measures for osteoarthritis and osteoporosis, psoriasis/psoriatic arthritis, psychosocial measures, and a core set of data for cost-effectiveness evaluations.
 

‘Speed is a limitation’

OMERACT is a bottom-up volunteer organization. It doesn’t represent any official organization of any clinical society. “We’ve not asked to be adopted by the American College of Rheumatology, EULAR [European Alliance of Associations for Rheumatology], or other international organizations,” Dr. Tugwell said. It offers a chance for patients, users, and doers of research to work together to agree on rigorous criteria accepted by the approval agencies and take the necessary time to work things through.

This is not a fast process, usually taking 4-6 years to initiate and establish an outcome domain set, he emphasized. “It would be beneficial to do it faster if we had the resources to meet every year. The fact is we’re a volunteer organization that meets every 2 years.”

Speed is a limitation, he acknowledged, but it’s an acceptable trade-off for doing things correctly.

The group has faced other challenges during the COVID-19 pandemic, pivoting to a virtual format that had benefits and limitations.

In one respect, moving to a virtual meeting increased uptake in participation and voting, Dr. Tugwell said. Patient participants with severe rheumatoid arthritis no longer faced the challenges of travel. “On the other hand, we didn’t have the same opportunity to achieve common ground virtually,” he said. “Where there are strong disagreements, I’m a great believer that people need to know one another. There needs to be relationship building.”

OMERACT’s emerging leader program has been a cornerstone of its in-person meetings, engaging young rheumatologists to interact with some of the leaders of outcome measurement. The virtual format dampened this process somewhat, eliminating those important “café chats” between the stakeholders.

The hope is to bring people face-to-face once more at the next meeting in May 2023. The agenda will focus on relationship building, identifying controversial areas, and bringing younger people to develop relationships, Dr. Tugwell said. OMERACT will retain a virtual option for the worldwide voting, “which will allow for more buy-in from so many more people,” he added.
 

A consensus on pain

The onus of developing outcome measures that move with the times is sometimes too great for one group to manage. In 2018, OMERACT became a part of the Red Hat Group (RHG), an organization conceived at the COMET (Core Outcome Measures in Effectiveness Trials) VII meeting in Amsterdam.

RHG aims to improve the choice of outcomes in health research. It includes eight groups: COMET; OMERACT; the Cochrane Skin Core Outcome Set Initiative; Grading of Recommendations, Assessment, Development and Evaluations; Center for Medical Technology Policy; COnsensus-based Standards for the selection of health Measurement Instruments; Clinical Data Interchange Standards Consortium; and Standardized Outcomes in Nephrology.

The collaboration between groups offers a “very interesting interface between consensus building as well as hard evidence,” Dr. Tugwell said. The focus goes beyond rheumatology to other clinical areas of common interest, exploring how one classifies outcome domains in terms of symptoms, life impact, or death.

Pain is an important common denominator that the RHG has evaluated.

“We believe it’s too general. We’re trying to define pain across all Red Hat Groups because it’s clear that the research community has all these different scales for defining pain severity,” Dr. Tugwell said. “We have to find a way to make ruthless decisions and rules for doing it. And of course, it has to be transparent.”
 

Looking ahead

As part of its ongoing work, OMERACT is evaluating the robustness of instruments that rheumatologists use as outcome measures in clinical trials, which can be a laborious process. The OMERACT Filter 2.0, part of the latest iteration of the handbook, offers strong guidance for researchers but needs a long-term strategy and key methodological support. “To that end, we set up a technical advisory group to help people in the instrument selection work and that remains an ongoing process,” OMERACT leaders said in their joint statement.

OMERACT is looking at opportunities to create benchmark processes for developing core sets outside of rheumatology and a methodology around outcome measures such as contextual factors, composites, and surrogates.

It will also be taking a step back to solicit opinions from the approval agencies represented by the OMERACT membership on the OMERACT handbook.

The goal is to make sure the handbook aligns with everyone else’s approval and labeling requirements.
 

OMERACT’s patient participants bring important perspectives

OMERACT over the years has sought to become a more patient-centered group. Patients have been involved in OMERACT activities since its sixth meeting, forming an independent, yet integrated, group within the network. They have their own steering committee and produced and helped to update a glossary for OMERACT patients and professionals. 

Catherine (McGowan) Hofstetter, who was diagnosed with rheumatoid arthritis 30 years ago, chairs OMERACT’s Patient Research Partners Support Team. In a Q&A, she discussed the importance of patient voices and OMERACT’s plans to further educate and include patients in the dialogue on outcomes.

Question: Have patients always been a part of OMERACT meetings? 

Answer: Patients have been involved with OMERACT since 2002. The patient voice adds relevance to all the work that OMERACT does. You can’t begin to talk about outcomes unless there is a patient at the table with lived experience.

Q: Can you cite a few examples of how the patient voice enriches the conversation on outcomes research? 

A: Outcomes and priorities that are important to patients are often completely different than those of the clinician. For instance, a work outcome is important to someone who doesn’t have any medical insurance or disability insurance, so that you can ensure that there is food on the table and a roof over your head. Or it may be important to someone because the employment provides medical and disability insurance to provide security for them and their family. These are two different perspectives on work and therefore work priorities and outcomes.

Q: What have been some of the challenges of getting patients to participate?

A: Training patients is one challenge. OMERACT’s work has a very steep learning curve, and while the basics are the same between the groups in terms of looking at what we measure and how we measure it, the nuances of different working groups require a lot of time and energy to be comfortable enough with the work, and then be confident enough to bring your perspective and lived experience to the table. It’s also a very accomplished group, which can be quite intimidating. Self-disclosure is a very personal and intimate undertaking that requires patience, compassion, and respect.

Q: Are there any plans to enhance patient engagement?

A: When we had OMERACT 2020 it was a virtual conference that took place over about 6 months. We had far more patient research partners [PRPs] participate than we have ever had at any OMERACT face-to-face meeting. There is a desire and passion on the part of patients to lend their voices to the work. The working groups meet virtually throughout the year to advance their agendas, and PRPs are a part of each of the working groups. 

Hopefully, we can start working toward including more voices at the conferences by enabling a hybrid model. The PRP Support Team will begin engaging patients this fall with education, mentoring, and team-building exercises so by the time we meet in person in May 2023, they will have enough background knowledge and information to give them the confidence that will enhance their experience at the face-to-face meeting.

We also need to ensure that those patients who want to stay engaged can. This means that the education and training should continue long after the face-to-face meeting is over. We need to build capacity in the PRP group and look to succession planning and be a resource to working groups struggling to find PRPs to work with them on a longer-term basis.

Clinical research in rheumatology was suffering from an identity crisis of sorts 40 years ago. A lack of consensus across continents resulted in differing views about clinical outcome measures and judgments about treatments.

Patients were not allowed to be the generating source of a clinical outcome, according to Peter Tugwell, MSc, MD. “The only outcomes that were acceptable were clinician assessments, blood tests, and imaging,” said Dr. Tugwell, professor of medicine, epidemiology, and public health at the University of Ottawa (Ont.) and a practicing rheumatologist at Ottawa Hospital.

Clinicians were coming to different conclusions about patient responses to treatment when managing rheumatoid arthritis in clinical practice.

OMERACT sought to address this lack of uniformity. This international group, formed in 1992, leverages stakeholder groups to improve outcome measurement in rheumatology endpoints through a consensus-building, data-driven format.

It was originally known as “Outcome Measures in Rheumatoid Arthritis Clinical Trials,” but its leaders have since broadened its scope to “Outcome Measures in Rheumatology.” Over the years, it has evolved into an international network that assesses measurement across a wide variety of intervention studies. Now 30 years old, the network spans 40 active working groups and has influenced work in patient outcomes across 500 peer-reviewed publications.

The network meets every 2 years to address what is always a challenging agenda, said Dr. Tugwell, one of its founding members and chair. “There’s lots of strong opinions.” Participating in the discussions are individuals from all stages of seniority in rheumatology and clinical epidemiology, patient research partners, industry, approval agencies, and many countries who are committed to the spirit of OMERACT.

“The secret to our success has been getting world leaders to come together and have those discussions, work them through, and identify common ground in such a way that the approval agencies accept these outcome measures in clinical trials,” he added.

“My impression was the founders perceived a problem in the early 1990s and devised a consensus method in an attempt to quantify clinical parameters to define disease activity in rheumatoid arthritis – an important first step to do clinical trials and allow comparisons between them,” said Patricia Woo, CBE, FMedSci, FRCP, emeritus professor of pediatric rheumatology and previous head of the Centre for Paediatric and Adolescent Rheumatology at UCL, London. At that time, even disease definitions varied between the United States and Europe and other parts of the world, said Dr. Woo, who is not a part of OMERACT. “This was especially true for pediatric rheumatology.”
 

Fusing the continental divide

OMERACT arose from a need to streamline clinical outcome measures in rheumatology. Research papers during the 1980s demonstrated a lack of coherence in managing patients with rheumatoid arthritis in routine practice. In addition, the measures used to define clinical endpoints in clinical trials operated in silos – they were either too specific to a certain trial, overlapped with other concepts, or didn’t reflect changes in treatment.

Approval agencies in Europe and North America were approving only outcomes measures developed by their respective researchers. This was also true of patients they tested on. “This seemed crazy,” Dr. Tugwell said.

Dr. Tugwell was involved in the Cochrane collaboration, which conducts systematic reviews of best evidence across the world that assesses the magnitude of benefits versus harms.

To achieve this goal, “you need to pull studies from around the world,” he said. Maarten Boers, MD, PhD, a rheumatologist (and later professor of clinical epidemiology at Amsterdam University Medical Center) from the Netherlands, spent a year in Ontario, Canada, to train as a clinical epidemiologist. Together, Dr. Tugwell and Dr. Boers began discussing options to develop more streamlined outcome measures.

Courtesy OMERACT

They initiated the first OMERACT conference in Maastricht, the Netherlands, in 1992. The Food and Drug Administration and European Medicines Agency participated, along with leaders of outcomes measurement in Europe and in North America.

Discussions centered on methods to develop outcomes in a meaningful fashion. During the first meeting, North American and European approval agencies agreed to accept each other’s studies and endpoints and patient reported outcomes.

Agreement was achieved on a preliminary set of outcome domains and measures that later became known as the WHO-ILAR (World Health Organization–International League of Associations for Rheumatology) core set. The set included seven outcome domains: tender joints, swollen joints, pain, physician global assessment, patient global assessment, physical disability, and acute phase reactants, and one additional outcome domain for studies lasting 1 year or more: radiographs of the joints.

“A proactive program was planned to test not only the validity of these endpoints, but also the methods for their measurement. This was the start of a continuing process,” OMERACT members said in a joint statement for this article. Meetings have since taken place every 2 years.

Courtesy OMERACT

OMERACT accomplishments

OMERACT now requires buy-in from four continents: Asia, Australia, Europe, and North America.

Its leaders have developed an explicit process for gaining endorsement of core outcome domains and instrument measurement sets. To fully capture the possibilities of “what to measure,” i.e., “measurable aspects of health conditions,” OMERACT has developed a framework of concepts, core areas, and outcome domains. The key concepts are pathophysiology (with a core area termed “manifestations/abnormalities”) and impact (with core areas of “death/lifespan,” and “life impact,” and the optional area of “societal/resource use”). An outcome domain defines an element of a core area to measure the effects of a treatment, such as blood markers, pain intensity, physical function, or emotional well-being.

A core outcome domain set is developed by agreeing to at least one outcome domain within one of the three core areas. Subsequently, a core outcome measurement set is developed by agreeing to at least one applicable measurement instrument for each core outcome domain. This requires documentation of validity, summarized under three metrics: truth, discrimination, and feasibility.

OMERACT’s handbook provides tutelage on establishing and implementing core outcomes, and several workbooks offer guidance on developing core outcome domain sets, selecting instruments for core outcome measurement sets, and OMERACT methodology.

All this work has led to widespread adoption.

Approval agencies have accepted OMERACT’s filter and methods advances, which have been adopted by many research groups in rheumatology and among nonrheumatology research groups. Organizations such as the U.S. National Institutes of Health’s National Institute of Neurological Disorders and Stroke have sought its advice.

Its core outcomes have been adopted and used for approval in the great majority of studies on rheumatoid arthritis, Dr. Tugwell said.

Several BMJ articles underscore the influence and uptake of OMERACT’s core outcome set. One 2017 paper, which analyzed 273 randomized trials of rheumatoid arthritis drug treatments on ClinicalTrials.gov, found that the WHO-ILAR arthritis core outcome set was reported in 81% of the studies. “The adoption of a core outcome set has the potential to increase consistency in outcomes measured across trials and ensure that trials are more likely to measure appropriate outcomes,” the authors concluded.

Since the initial 1992 meeting, OMERACT has broadened its focus from rheumatoid arthritis to 25 other musculoskeletal conditions.

For example, other OMERACT conferences have led to consensus on core sets of measures for osteoarthritis and osteoporosis, psoriasis/psoriatic arthritis, psychosocial measures, and a core set of data for cost-effectiveness evaluations.
 

‘Speed is a limitation’

OMERACT is a bottom-up volunteer organization. It doesn’t represent any official organization of any clinical society. “We’ve not asked to be adopted by the American College of Rheumatology, EULAR [European Alliance of Associations for Rheumatology], or other international organizations,” Dr. Tugwell said. It offers a chance for patients, users, and doers of research to work together to agree on rigorous criteria accepted by the approval agencies and take the necessary time to work things through.

This is not a fast process, usually taking 4-6 years to initiate and establish an outcome domain set, he emphasized. “It would be beneficial to do it faster if we had the resources to meet every year. The fact is we’re a volunteer organization that meets every 2 years.”

Speed is a limitation, he acknowledged, but it’s an acceptable trade-off for doing things correctly.

The group has faced other challenges during the COVID-19 pandemic, pivoting to a virtual format that had benefits and limitations.

In one respect, moving to a virtual meeting increased uptake in participation and voting, Dr. Tugwell said. Patient participants with severe rheumatoid arthritis no longer faced the challenges of travel. “On the other hand, we didn’t have the same opportunity to achieve common ground virtually,” he said. “Where there are strong disagreements, I’m a great believer that people need to know one another. There needs to be relationship building.”

OMERACT’s emerging leader program has been a cornerstone of its in-person meetings, engaging young rheumatologists to interact with some of the leaders of outcome measurement. The virtual format dampened this process somewhat, eliminating those important “café chats” between the stakeholders.

The hope is to bring people face-to-face once more at the next meeting in May 2023. The agenda will focus on relationship building, identifying controversial areas, and bringing younger people to develop relationships, Dr. Tugwell said. OMERACT will retain a virtual option for the worldwide voting, “which will allow for more buy-in from so many more people,” he added.
 

A consensus on pain

The onus of developing outcome measures that move with the times is sometimes too great for one group to manage. In 2018, OMERACT became a part of the Red Hat Group (RHG), an organization conceived at the COMET (Core Outcome Measures in Effectiveness Trials) VII meeting in Amsterdam.

RHG aims to improve the choice of outcomes in health research. It includes eight groups: COMET; OMERACT; the Cochrane Skin Core Outcome Set Initiative; Grading of Recommendations, Assessment, Development and Evaluations; Center for Medical Technology Policy; COnsensus-based Standards for the selection of health Measurement Instruments; Clinical Data Interchange Standards Consortium; and Standardized Outcomes in Nephrology.

The collaboration between groups offers a “very interesting interface between consensus building as well as hard evidence,” Dr. Tugwell said. The focus goes beyond rheumatology to other clinical areas of common interest, exploring how one classifies outcome domains in terms of symptoms, life impact, or death.

Pain is an important common denominator that the RHG has evaluated.

“We believe it’s too general. We’re trying to define pain across all Red Hat Groups because it’s clear that the research community has all these different scales for defining pain severity,” Dr. Tugwell said. “We have to find a way to make ruthless decisions and rules for doing it. And of course, it has to be transparent.”
 

Looking ahead

As part of its ongoing work, OMERACT is evaluating the robustness of instruments that rheumatologists use as outcome measures in clinical trials, which can be a laborious process. The OMERACT Filter 2.0, part of the latest iteration of the handbook, offers strong guidance for researchers but needs a long-term strategy and key methodological support. “To that end, we set up a technical advisory group to help people in the instrument selection work and that remains an ongoing process,” OMERACT leaders said in their joint statement.

OMERACT is looking at opportunities to create benchmark processes for developing core sets outside of rheumatology and a methodology around outcome measures such as contextual factors, composites, and surrogates.

It will also be taking a step back to solicit opinions from the approval agencies represented by the OMERACT membership on the OMERACT handbook.

The goal is to make sure the handbook aligns with everyone else’s approval and labeling requirements.
 

OMERACT’s patient participants bring important perspectives

OMERACT over the years has sought to become a more patient-centered group. Patients have been involved in OMERACT activities since its sixth meeting, forming an independent, yet integrated, group within the network. They have their own steering committee and produced and helped to update a glossary for OMERACT patients and professionals. 

Catherine (McGowan) Hofstetter, who was diagnosed with rheumatoid arthritis 30 years ago, chairs OMERACT’s Patient Research Partners Support Team. In a Q&A, she discussed the importance of patient voices and OMERACT’s plans to further educate and include patients in the dialogue on outcomes.

Question: Have patients always been a part of OMERACT meetings? 

Answer: Patients have been involved with OMERACT since 2002. The patient voice adds relevance to all the work that OMERACT does. You can’t begin to talk about outcomes unless there is a patient at the table with lived experience.

Q: Can you cite a few examples of how the patient voice enriches the conversation on outcomes research? 

A: Outcomes and priorities that are important to patients are often completely different than those of the clinician. For instance, a work outcome is important to someone who doesn’t have any medical insurance or disability insurance, so that you can ensure that there is food on the table and a roof over your head. Or it may be important to someone because the employment provides medical and disability insurance to provide security for them and their family. These are two different perspectives on work and therefore work priorities and outcomes.

Q: What have been some of the challenges of getting patients to participate?

A: Training patients is one challenge. OMERACT’s work has a very steep learning curve, and while the basics are the same between the groups in terms of looking at what we measure and how we measure it, the nuances of different working groups require a lot of time and energy to be comfortable enough with the work, and then be confident enough to bring your perspective and lived experience to the table. It’s also a very accomplished group, which can be quite intimidating. Self-disclosure is a very personal and intimate undertaking that requires patience, compassion, and respect.

Q: Are there any plans to enhance patient engagement?

A: When we had OMERACT 2020 it was a virtual conference that took place over about 6 months. We had far more patient research partners [PRPs] participate than we have ever had at any OMERACT face-to-face meeting. There is a desire and passion on the part of patients to lend their voices to the work. The working groups meet virtually throughout the year to advance their agendas, and PRPs are a part of each of the working groups. 

Hopefully, we can start working toward including more voices at the conferences by enabling a hybrid model. The PRP Support Team will begin engaging patients this fall with education, mentoring, and team-building exercises so by the time we meet in person in May 2023, they will have enough background knowledge and information to give them the confidence that will enhance their experience at the face-to-face meeting.

We also need to ensure that those patients who want to stay engaged can. This means that the education and training should continue long after the face-to-face meeting is over. We need to build capacity in the PRP group and look to succession planning and be a resource to working groups struggling to find PRPs to work with them on a longer-term basis.

Clinical research in rheumatology was suffering from an identity crisis of sorts 40 years ago. A lack of consensus across continents resulted in differing views about clinical outcome measures and judgments about treatments.

Patients were not allowed to be the generating source of a clinical outcome, according to Peter Tugwell, MSc, MD. “The only outcomes that were acceptable were clinician assessments, blood tests, and imaging,” said Dr. Tugwell, professor of medicine, epidemiology, and public health at the University of Ottawa (Ont.) and a practicing rheumatologist at Ottawa Hospital.

Clinicians were coming to different conclusions about patient responses to treatment when managing rheumatoid arthritis in clinical practice.

OMERACT sought to address this lack of uniformity. This international group, formed in 1992, leverages stakeholder groups to improve outcome measurement in rheumatology endpoints through a consensus-building, data-driven format.

It was originally known as “Outcome Measures in Rheumatoid Arthritis Clinical Trials,” but its leaders have since broadened its scope to “Outcome Measures in Rheumatology.” Over the years, it has evolved into an international network that assesses measurement across a wide variety of intervention studies. Now 30 years old, the network spans 40 active working groups and has influenced work in patient outcomes across 500 peer-reviewed publications.

The network meets every 2 years to address what is always a challenging agenda, said Dr. Tugwell, one of its founding members and chair. “There’s lots of strong opinions.” Participating in the discussions are individuals from all stages of seniority in rheumatology and clinical epidemiology, patient research partners, industry, approval agencies, and many countries who are committed to the spirit of OMERACT.

“The secret to our success has been getting world leaders to come together and have those discussions, work them through, and identify common ground in such a way that the approval agencies accept these outcome measures in clinical trials,” he added.

“My impression was the founders perceived a problem in the early 1990s and devised a consensus method in an attempt to quantify clinical parameters to define disease activity in rheumatoid arthritis – an important first step to do clinical trials and allow comparisons between them,” said Patricia Woo, CBE, FMedSci, FRCP, emeritus professor of pediatric rheumatology and previous head of the Centre for Paediatric and Adolescent Rheumatology at UCL, London. At that time, even disease definitions varied between the United States and Europe and other parts of the world, said Dr. Woo, who is not a part of OMERACT. “This was especially true for pediatric rheumatology.”
 

Fusing the continental divide

OMERACT arose from a need to streamline clinical outcome measures in rheumatology. Research papers during the 1980s demonstrated a lack of coherence in managing patients with rheumatoid arthritis in routine practice. In addition, the measures used to define clinical endpoints in clinical trials operated in silos – they were either too specific to a certain trial, overlapped with other concepts, or didn’t reflect changes in treatment.

Approval agencies in Europe and North America were approving only outcomes measures developed by their respective researchers. This was also true of patients they tested on. “This seemed crazy,” Dr. Tugwell said.

Dr. Tugwell was involved in the Cochrane collaboration, which conducts systematic reviews of best evidence across the world that assesses the magnitude of benefits versus harms.

To achieve this goal, “you need to pull studies from around the world,” he said. Maarten Boers, MD, PhD, a rheumatologist (and later professor of clinical epidemiology at Amsterdam University Medical Center) from the Netherlands, spent a year in Ontario, Canada, to train as a clinical epidemiologist. Together, Dr. Tugwell and Dr. Boers began discussing options to develop more streamlined outcome measures.

Courtesy OMERACT

They initiated the first OMERACT conference in Maastricht, the Netherlands, in 1992. The Food and Drug Administration and European Medicines Agency participated, along with leaders of outcomes measurement in Europe and in North America.

Discussions centered on methods to develop outcomes in a meaningful fashion. During the first meeting, North American and European approval agencies agreed to accept each other’s studies and endpoints and patient reported outcomes.

Agreement was achieved on a preliminary set of outcome domains and measures that later became known as the WHO-ILAR (World Health Organization–International League of Associations for Rheumatology) core set. The set included seven outcome domains: tender joints, swollen joints, pain, physician global assessment, patient global assessment, physical disability, and acute phase reactants, and one additional outcome domain for studies lasting 1 year or more: radiographs of the joints.

“A proactive program was planned to test not only the validity of these endpoints, but also the methods for their measurement. This was the start of a continuing process,” OMERACT members said in a joint statement for this article. Meetings have since taken place every 2 years.

Courtesy OMERACT

OMERACT accomplishments

OMERACT now requires buy-in from four continents: Asia, Australia, Europe, and North America.

Its leaders have developed an explicit process for gaining endorsement of core outcome domains and instrument measurement sets. To fully capture the possibilities of “what to measure,” i.e., “measurable aspects of health conditions,” OMERACT has developed a framework of concepts, core areas, and outcome domains. The key concepts are pathophysiology (with a core area termed “manifestations/abnormalities”) and impact (with core areas of “death/lifespan,” and “life impact,” and the optional area of “societal/resource use”). An outcome domain defines an element of a core area to measure the effects of a treatment, such as blood markers, pain intensity, physical function, or emotional well-being.

A core outcome domain set is developed by agreeing to at least one outcome domain within one of the three core areas. Subsequently, a core outcome measurement set is developed by agreeing to at least one applicable measurement instrument for each core outcome domain. This requires documentation of validity, summarized under three metrics: truth, discrimination, and feasibility.

OMERACT’s handbook provides tutelage on establishing and implementing core outcomes, and several workbooks offer guidance on developing core outcome domain sets, selecting instruments for core outcome measurement sets, and OMERACT methodology.

All this work has led to widespread adoption.

Approval agencies have accepted OMERACT’s filter and methods advances, which have been adopted by many research groups in rheumatology and among nonrheumatology research groups. Organizations such as the U.S. National Institutes of Health’s National Institute of Neurological Disorders and Stroke have sought its advice.

Its core outcomes have been adopted and used for approval in the great majority of studies on rheumatoid arthritis, Dr. Tugwell said.

Several BMJ articles underscore the influence and uptake of OMERACT’s core outcome set. One 2017 paper, which analyzed 273 randomized trials of rheumatoid arthritis drug treatments on ClinicalTrials.gov, found that the WHO-ILAR arthritis core outcome set was reported in 81% of the studies. “The adoption of a core outcome set has the potential to increase consistency in outcomes measured across trials and ensure that trials are more likely to measure appropriate outcomes,” the authors concluded.

Since the initial 1992 meeting, OMERACT has broadened its focus from rheumatoid arthritis to 25 other musculoskeletal conditions.

For example, other OMERACT conferences have led to consensus on core sets of measures for osteoarthritis and osteoporosis, psoriasis/psoriatic arthritis, psychosocial measures, and a core set of data for cost-effectiveness evaluations.
 

‘Speed is a limitation’

OMERACT is a bottom-up volunteer organization. It doesn’t represent any official organization of any clinical society. “We’ve not asked to be adopted by the American College of Rheumatology, EULAR [European Alliance of Associations for Rheumatology], or other international organizations,” Dr. Tugwell said. It offers a chance for patients, users, and doers of research to work together to agree on rigorous criteria accepted by the approval agencies and take the necessary time to work things through.

This is not a fast process, usually taking 4-6 years to initiate and establish an outcome domain set, he emphasized. “It would be beneficial to do it faster if we had the resources to meet every year. The fact is we’re a volunteer organization that meets every 2 years.”

Speed is a limitation, he acknowledged, but it’s an acceptable trade-off for doing things correctly.

The group has faced other challenges during the COVID-19 pandemic, pivoting to a virtual format that had benefits and limitations.

In one respect, moving to a virtual meeting increased uptake in participation and voting, Dr. Tugwell said. Patient participants with severe rheumatoid arthritis no longer faced the challenges of travel. “On the other hand, we didn’t have the same opportunity to achieve common ground virtually,” he said. “Where there are strong disagreements, I’m a great believer that people need to know one another. There needs to be relationship building.”

OMERACT’s emerging leader program has been a cornerstone of its in-person meetings, engaging young rheumatologists to interact with some of the leaders of outcome measurement. The virtual format dampened this process somewhat, eliminating those important “café chats” between the stakeholders.

The hope is to bring people face-to-face once more at the next meeting in May 2023. The agenda will focus on relationship building, identifying controversial areas, and bringing younger people to develop relationships, Dr. Tugwell said. OMERACT will retain a virtual option for the worldwide voting, “which will allow for more buy-in from so many more people,” he added.
 

A consensus on pain

The onus of developing outcome measures that move with the times is sometimes too great for one group to manage. In 2018, OMERACT became a part of the Red Hat Group (RHG), an organization conceived at the COMET (Core Outcome Measures in Effectiveness Trials) VII meeting in Amsterdam.

RHG aims to improve the choice of outcomes in health research. It includes eight groups: COMET; OMERACT; the Cochrane Skin Core Outcome Set Initiative; Grading of Recommendations, Assessment, Development and Evaluations; Center for Medical Technology Policy; COnsensus-based Standards for the selection of health Measurement Instruments; Clinical Data Interchange Standards Consortium; and Standardized Outcomes in Nephrology.

The collaboration between groups offers a “very interesting interface between consensus building as well as hard evidence,” Dr. Tugwell said. The focus goes beyond rheumatology to other clinical areas of common interest, exploring how one classifies outcome domains in terms of symptoms, life impact, or death.

Pain is an important common denominator that the RHG has evaluated.

“We believe it’s too general. We’re trying to define pain across all Red Hat Groups because it’s clear that the research community has all these different scales for defining pain severity,” Dr. Tugwell said. “We have to find a way to make ruthless decisions and rules for doing it. And of course, it has to be transparent.”
 

Looking ahead

As part of its ongoing work, OMERACT is evaluating the robustness of instruments that rheumatologists use as outcome measures in clinical trials, which can be a laborious process. The OMERACT Filter 2.0, part of the latest iteration of the handbook, offers strong guidance for researchers but needs a long-term strategy and key methodological support. “To that end, we set up a technical advisory group to help people in the instrument selection work and that remains an ongoing process,” OMERACT leaders said in their joint statement.

OMERACT is looking at opportunities to create benchmark processes for developing core sets outside of rheumatology and a methodology around outcome measures such as contextual factors, composites, and surrogates.

It will also be taking a step back to solicit opinions from the approval agencies represented by the OMERACT membership on the OMERACT handbook.

The goal is to make sure the handbook aligns with everyone else’s approval and labeling requirements.
 

OMERACT’s patient participants bring important perspectives

OMERACT over the years has sought to become a more patient-centered group. Patients have been involved in OMERACT activities since its sixth meeting, forming an independent, yet integrated, group within the network. They have their own steering committee and produced and helped to update a glossary for OMERACT patients and professionals. 

Catherine (McGowan) Hofstetter, who was diagnosed with rheumatoid arthritis 30 years ago, chairs OMERACT’s Patient Research Partners Support Team. In a Q&A, she discussed the importance of patient voices and OMERACT’s plans to further educate and include patients in the dialogue on outcomes.

Question: Have patients always been a part of OMERACT meetings? 

Answer: Patients have been involved with OMERACT since 2002. The patient voice adds relevance to all the work that OMERACT does. You can’t begin to talk about outcomes unless there is a patient at the table with lived experience.

Q: Can you cite a few examples of how the patient voice enriches the conversation on outcomes research? 

A: Outcomes and priorities that are important to patients are often completely different than those of the clinician. For instance, a work outcome is important to someone who doesn’t have any medical insurance or disability insurance, so that you can ensure that there is food on the table and a roof over your head. Or it may be important to someone because the employment provides medical and disability insurance to provide security for them and their family. These are two different perspectives on work and therefore work priorities and outcomes.

Q: What have been some of the challenges of getting patients to participate?

A: Training patients is one challenge. OMERACT’s work has a very steep learning curve, and while the basics are the same between the groups in terms of looking at what we measure and how we measure it, the nuances of different working groups require a lot of time and energy to be comfortable enough with the work, and then be confident enough to bring your perspective and lived experience to the table. It’s also a very accomplished group, which can be quite intimidating. Self-disclosure is a very personal and intimate undertaking that requires patience, compassion, and respect.

Q: Are there any plans to enhance patient engagement?

A: When we had OMERACT 2020 it was a virtual conference that took place over about 6 months. We had far more patient research partners [PRPs] participate than we have ever had at any OMERACT face-to-face meeting. There is a desire and passion on the part of patients to lend their voices to the work. The working groups meet virtually throughout the year to advance their agendas, and PRPs are a part of each of the working groups. 

Hopefully, we can start working toward including more voices at the conferences by enabling a hybrid model. The PRP Support Team will begin engaging patients this fall with education, mentoring, and team-building exercises so by the time we meet in person in May 2023, they will have enough background knowledge and information to give them the confidence that will enhance their experience at the face-to-face meeting.

We also need to ensure that those patients who want to stay engaged can. This means that the education and training should continue long after the face-to-face meeting is over. We need to build capacity in the PRP group and look to succession planning and be a resource to working groups struggling to find PRPs to work with them on a longer-term basis.