Common Characteristics in RA Patients Who Don’t Respond to Biologics

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At least 6% of patients who used biologic disease-modifying anti-rheumatic drugs (bDMARDs) suffered refractory disease, according to a recent study based on data from the British Society for Rheumatology Biologics Registry for Rheumatoid Arthritis.¹ This observational study evaluated the extent of biologic refractory rheumatoid arthritis (RA).

The study defined biologic refractory disease as occurring in patients exposed to at least three different classes of biologics. Study authors identified patients with RA who were starting first-line tumor necrosis factor inhibitors (TNFi) and who were part of the British Society for Rheumatology Biologics Register for RA from 2001–2014. The register began as a prospective observational cohort study to collect data from adults with diagnosed RA who were starting a biologic. A variety of patient data were collected, including demographics, disease characteristics, disease activity (via the 28-joint Disease Activity Score [DAS28]), the Health Assessment Questionnaire (HAQ) for patient function, the Medical Outcomes Study 36-item short-form health survey and current or previous anti-rheumatic therapies. Follow-up data were collected every six months for three years; after that, disease activity and anti-rheumatic therapy data were collected annually.

For the current study, patients starting TNFi were recruited from 2001–2008, followed by a second recruitment that started in 2011. “For each patient, the total number of bDMARD treatment courses was identified, irrespective of bDMARD class or whether the bDMARD had been received previously,” the authors wrote.

The biologics used by patients were categorized by class: TNFi (adalimumab, certolizumab, etanercept, golimumab and infliximab), B cell-depleting agent (rituximab or ocrelizumab), interleukin (IL) 1 receptor antagonist (anakinra), IL-6 pathway inhibitor (tocilizumab), and T cell co-stimulation blocker (abatacept).

Patients were classified as biologic refractory the day they started their third biologic class.

The Patients

A total of 13,502 patients with a median age of 57 were registered at the start of first TNFi use; 86% of them were recruited in the first eight years vs. the second half of the 2001–2014 study period; 76% were women; 53% had at least one initial comorbidity; and 22% smoked. The median DAS28 score was 6.5 at the start of TNFi use.

The authors found that 6.4% (867 pa­tients) were biologic refractory. The median time period from first use of a TNFi to biologic refractory disease was 7.9 years. Refractory disease was more common in the earlier recruitment cohort (from 2001–2008); these patients also had a longer median time (8.4 years) to refractory status. That compares with 4.8% of patients in the second cohort who were biologic refractory over a median time of two years.

Patients with biologic refractory disease remained on their first TNFi for a median of 3.9 years. The reasons patients stopped using their first TNFi included loss of effectiveness (52%), the occurrence of adverse events (24%), other reasons (3%) and reasons not recorded (21%).

“Patients with bDMARD refractory disease then spent a median of 1.5 years on their second class and 1.5 years on their third class of bDMARD, although this was longer in patients recruited [from] 2001–2008 compared with 2011 onward; 1.5 vs. 0.8 years, and 1.6 vs. 1.0 years for second and third bDMARD class, respectively,” the authors wrote.

Regarding treatment pathways, most of the refractory patients switched to a B cell-depleting agent as the second class of treatment, but that proportion decreased after 2011.

Thirty-eight percent of biologic-refractory patients used four different biologics; 20% used five biologics; and 8% used six or more. The remaining biologic-refractory patients used three or fewer biologics.

Compared with non-refractory patients, the patients with refractory disease were more likely than to be women, 50 years old or younger, have a disease duration of less than 10 years, have a higher patient global assessment and have a higher HAQ. They were also more likely than the non-refractory patients to be smokers and obese at the start of the first TNFi use.

“Notably, the HR [hazard ratio] for developing bDMARD refractory disease was 15 times higher among patients recruited from 2011 onward compared with 2001–2008,” the authors wrote. They speculate this may be due to the increased class availability and higher expectations of biologics in the later cohort. They say this may be the “result of selection bias rather than a true biologic effect.”

The association between a younger age and refractory disease may relate to more aggressive treatment in this age category compared with older patients.

The prevalence of shorter disease duration is not 100% clear, but it may reflect the current practice of early DMARD introduction and the use of treat-to-target to improve outcomes, the authors wrote.

The analysis also found biologic refractory disease was more common in patients from lower socioeconomic areas, which may be linked to the higher prevalence of obesity and smoking in those communities. “All three variables were found to be independent predictors of bDMARD refractory disease in our analysis,” they wrote.

The Practical Implications

The findings can help rheumatologists with patient management decisions, according to the authors.

“Quantifying the frequency of multiple bDMARD class failure is crucial, particularly in an environment where bDMARD choice is largely based on custom and experience rather than by individual biomarkers,” the authors wrote.

Study researcher Kimme L. Hyrich, MD, PhD, from the Arthritis Research UK Centre for Epidemiology at the University of Manchester, England, had some additional thoughts. “This is an important finding [because] it allows the rheumatology community and funders the opportunity to better design services with the knowledge of the numbers of patients who will require regular clinical review,” Dr. Hyrich says. “As the choice of biologics and other related therapies increases, particularly with respect to new modes of action, it will be important for budget planning to ensure that funding for these drugs is not rejected based solely on the number of biologics a patient has previously received.”

The findings also can help with guideline development, including the management of difficult-to-treat RA, which is a focus of a new European League Against Rheumatism task force, Dr. Hyrich says.

Stanley Cohen, MD, a clinical professor in the department of internal medicine at the UT Southwestern Medical Center in Dallas, and in private practice in Dallas, expresses surprise that a higher percentage of patients wasn’t biologic refractory, although that may be due to the authors’ definition of refractory, he says. “It was interesting that rheumatologists are cycling therapies more frequently now than in the past, which I think reflects the treat-to-target approach targeting remission/low disease activity status as well as patient expectations,” Dr. Cohen says.

Dr. Cohen would like to see similar research performed in the U.S. and a consistent definition of refractory disease established so clinicians can accurately compare observational study results in different populations.

Vanessa Caceres is a medical writer in Bradenton, Fla.

References

1. Kearsley-Fleet L, Davies R, De Cock D, et al. Biologic refractory disease in rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. 2018 Oct;77(10):1405–1412.