Resistance to Biologics in RA Underestimated

Janis C. Kelly

July 26, 2018

British Society for Rheumatology researchers report in the Annals of the Rheumatic Diseases that at least 6% of all patients with rheumatoid arthritis (RA) who had ever received a biologic disease-modifying antirheumatic drug (bDMARD) had bDMARD-refractory disease. The actual incidence might be considerably higher, as the British Society for Rheumatology analysis used an unusually constrained definition of "refractory" that defined it as an inadequate response to three different classes of bDMARD, not just to drugs with different mechanisms of action.

Daniel E. Furst, MD, who was not involved in the study, told Medscape Medical News that this analysis likely underestimates the number of patients with RA who have some form of bDMARD resistance. Furst is professor of rheumatology, University of California in Los Angeles; University of Washington, Seattle; and University of Florence, Italy.

Furst said, "The whole article is shaped by an unusual definition of refractory, which differs from that used in most other publications. These researchers defined refractory RA as resistant to three classes of biologic DMARDs. Refractory is more commonly defined as resistant to two or three different biologics, not necessarily from different bDMARD classes. Clinically, this matters."

"A patient could be resistant to two or more [tumor necrosis factor inhibitors (TNFis)] and not meet the criteria for resistant RA used in this study. That is in part why the reported resistance rate of 6% is much lower than the 30% to 50% resistance commonly seen. In fact, this study also reported that 59% of patients had failed more than one TNFi," he explained.

Furst added that another unusual aspect of the British Society for Rheumatology study was that patients had, on average, 10 years of active disease. "In most studies of refractory disease, the average time is 3 to 5 years," he said.

Lianne Kearsley-Fleet, a research assistant at the Arthritis Research UK Centre for Epidemiology, Manchester Academic Health Science Centre, the University of Manchester, United Kingdom, and colleagues used data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis to study 13,502 patients with RA who began taking first-line TNFi treatment during the years 2001 to 2008 and 2011 to 2014. They reviewed bDMARD courses and clustered them according to class: TNFi (adalimumab, certolizumab, etanercept, golimumab infliximab), B-cell depleting agents (rituximab, ocrelizumab), interleukin 1 receptor antagonist (anakinra), interleukin 6 pathway inhibitor (tocilizumab), and T-cell costimuation blocker (abatacept). Median disease duration of recruited patients was 10 years, median Disease Activity Score 28 at the start of first TNFi was 6.5, 22% of patients were current smokers, and 26% were obese.

Six percent of patients (867/13,502) were bDMARD refractory, using the researchers' definition, and the median time from first TNFi exposure to third bDMARD class for those patients was 8 years. Patients treated during 2001 to 2008 had higher rates of bDMARD refractory disease, a longer time from first TNFi to bDMARD refractory, a longer time receiving the first TNFi, and a longer time receiving the second class of bDMARD than those treated during 2011 to 2014. The earlier cohort was also more likely to have taken more than one TNFi before switching to a second bDMARD class (59% vs 19%).

Kearsley-Fleet told Medscape Medical News that the differences in cohorts are probably artifacts of changes in clinical practice. "In the older cohort, there were fewer biologics available at the time, so they had to cycle through different TNFi for a while until the others became available, hence longer time on first TNFi, high frequency of TNFi cycling and overall longer time to bDMARD refractory disease. More recently, some clinicians may have adopted a 'treat-to-target' approach, and with many different classes of biologics available, it is possible for patients to switch biologic class multiple times," she explained.

Kearsley-Fleet also noted that patients more likely to become bDMARD refractory included smokers and those with a higher body mass index (>30 kg/m2). "This supports recent recommendations for difficult-to-treat patients with RA, where evaluation of these modifiable lifestyle factors is important," she said.

Meeting the Clinical Challenge of bDMARD Resistance

The increasing availability of bDMARDs has heightened the challenge for clinicians, Furst said. "My experience is that if the patient's clinical disease activity index has not improved 3 to 5 units by 4 to 6 weeks, that patient has about a 90% probability of not responding adequately to that drug," he explained.

Furst advised clinicians to focus on each drug's mechanisms of action rather than just on bDMARD classes when designing RA treatment. "A reasonable definition of resistance would involve resistance to at least two different mechanisms of action, which can occur within the same drug class. For example, if the patient on the [TNFi] etanercept is changed to the TNFi adalimumab, that is two mechanisms of action. Defining resistance as resistant to one or two mechanisms of action will give a very different look at how to treat patients," he said.

Kearsley-Fleet said the researchers were surprised at how many patients had switched biologic multiple times: more than one fifth of the cohort had received at least three biologics (regardless of class), and 8.5% had received at least four biologics.

She commented, "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. This information will also help with future treatment guideline development, such as the management of difficult-to-treat RA, currently the focus of a new [European League Against Rheumatism] task force."

The study was funded by the British Society for Rheumatology. Several authors report multiple types of financial relationships with numerous companies. For the full disclosure, please see the journal website. Furst has disclosed no relevant financial relationships.

Ann Rheum Dis. Published online July 6, 2018. Full text

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