Rheumatoid arthritis (RA) is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
It’s not common for RA patients to have pulmonary complications such as interstitial lung disease (ILD). However, when present, ILD leads to increased mortality rates. Some research suggests that treatment with tumor necrosis factor inhibitors (TNFi) may be linked to ILD development or worsening of ILD in RA patients. In 2005, the British Society for Rheumatology advised against using TNFi in patients with RA and ILD, but there was no data on whether rituximab (RTX) would have the same effect or may improve mortality in these patients. So researchers in the United Kingdom studied five-year mortality in RA-ILD patients who had started therapy with either RTX or TNFi.
“Treatment of the underlying arthritis among patients with RA-ILD can be complicated, as methotrexate is often contraindicated,” said Kimme Hyrich, MD, PhD, FRCPC, Professor of Epidemiology and Honorary Consultant in Rheumatology at the Arthritis Research UK Centre for Epidemiology at the University of Manchester. “It’s been unclear what the best choice of biologic therapy is for patients with RA-ILD and active arthritis given the relative contraindication for TNFi.”
The study’s aim was to analyze and compare mortality rates among patients with RA-ILD who had started either rituximab or TNFi as their first biologic, including causes of death. The researchers examined mortality data on participants in the British Society for Rheumatology Biologics Register for RA. They included patients with clinician-reported RA-ILD at baseline who started either TNFi or RTX as their first biologic therapy. They located the date and cause of death for each patient on study follow-up forms, as well as linkage with the UK National Death Register.
They calculated death rates per 1,000 person-years, and censoring occurred at death, at December 6, 2015, or five years after the patient’s first registration, whichever came first. They also examined the frequency of ILD mentions on death certificates. Their next step was to generate Kaplan-Meier survival curves with risk comparisons made between RTX and TNFi cohorts using Cox regression and an ever-exposed model, adjusted for potential confounders. They determined the eligibility of confounders by clinically relevant justification or statistical significance (p<0.05), after adjusting for treatment effects.
The study included 353 eligible patients with RA-ILD. Of these, 310 were treated with TNFi and 43 were treated with RTX. All the patients in both groups were recruited before 2008. During the first five years of follow-up examination, there were 76 deaths in 804.9 person-years in the TNFi cohort of patients, and eight deaths in 156.7 person-years in the RTX cohort. Total death rates were 94.4 (74.4-118.1) and 51.0 (22.0-100.5) per 1,000 person-years respectively. ILD was recorded on 36.5 percent of the 74 available death certificates from the TNFi cohort and on all of the three certificates available in RTX cohort.
The researchers concluded that the unadjusted mortality risk in patients treated with RTX was numerically half of the risk found in patients treated with TNFi, although this was not statistically significant. Adjustment for baseline age, sex, disability, disease activity and disease duration had little affect on these estimates. While patients with RA-ILD who received rituximab as their first-line therapy appeared to have a lower mortality risk than those who took TNFi first, the differences were not statistically significant, the researchers found. The registry data did not provide enough information on disease severity or ILD subtypes among these patients, so it was difficult to draw conclusions on the relative safety of these two therapies. In the future, larger and more detailed studies may help clarify safety issues for these therapies in this high-risk patient population.
“The main message is that the death rates among patients with RA-ILD who started RTX as their first biologic were lower compared to patients who started a TNFi. We did adjust our analysis for age, gender, disease duration and HAQ, which did differ between the two cohorts and are important risk factors themselves for mortality,” said Dr. Hyrich. “However, because we did not have data on the severity of the lung disease itself, which is also an important risk factor for mortality, it is unfortunately difficult to say with certainty that RTX is a better option for patients with RA-ILD in the absence of clinical trial data.”
“Key to understanding this issue further will be a greater collection of data from patients with this history either separate to or within national registries. This is a rare condition, and without robust studies, guidance on the best choice of therapy to treat the underlying arthritis will remain limited to anecdotal evidence.”
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About the American College of RheumatologyHeadquartered in Atlanta, Ga., the American College of Rheumatology is an international medical society representing over 9,400 rheumatologists and rheumatology health professionals with a mission to Advance Rheumatology! In doing so, the ACR offers education, research, advocacy and practice management support to help its members continue their innovative work and provide quality patient care. Rheumatologists are experts in the diagnosis, management and treatment of more than 100 different types of arthritis and rheumatic diseases. For more information, visit www.rheumatology.org.
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