A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.
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Dr. John J. Cush
The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.
Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
Swedes show biologics may reduce excess lymphoma risk in RA
Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.
The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.
Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.
“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”
Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.
“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”
Bruce Jancin/MDedge News
Dr. Arthur Kavanaugh
Beware underappreciated hazards of very-low-dose glucocorticoids
The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.
Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.
Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.
A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.
“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”
Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”
Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?
”Because when we find something that works, we stick to it,” Dr. Cush replied.