While biologic disease-modifying antirheumatic drugs (bDMARDs) have transformed outcomes of people with rheumatoid arthritis (RA), a proportion of patients are refractory to multiple bDMARDs. ...Definitions of refractory RA thus far have been arbitrary, and outcome data and impact of such cohorts remain limited. Extrapolation from randomised controlled trial and some real-life data suggest approximately 20% progress onto a third bDMARD with a more modest proportion failing additional bDMARDs. This viewpoint discusses an opinion of refractory RA disease and proposes key principles to accurately identify refractory cohorts. These include demonstrating presence of persistent inflammation despite multiple therapies and acknowledging development of antidrug antibody. Potential basis of refractory disease is summarised, and suggestions for an initial approach in the future evaluation of refractory disease are offered. Specific investigation of refractory RA disease is necessary to inform the clinical need and provide a basis for robust investigation of underlying mechanisms.
Despite nearly three decades of advances in the management of rheumatoid arthritis (RA), a substantial minority of patients are exposed to multiple DMARDs without necessarily benefitting from them; a ...group of patients variously designated as having 'difficult to treat', 'treatment-resistant' or 'refractory' RA. This Review of refractory RA focuses on two types of patients: those for whom multiple targeted therapies lack efficacy and who have persistent inflammatory pathology, which we designate as persistent inflammatory refractory RA (PIRRA); and those with supposed refractory RA who have continued disease activity that is predominantly independent of objective evidence of inflammation, which we designate as non-inflammatory refractory RA (NIRRA). These two types of disease are not mutually exclusive, but identifying those individuals with predominant PIRRA or NIRRA is important, as it informs distinct treatment and management approaches. This Review outlines the clinical differences between PIRRA and NIRRA, the genetic and epigenetic mechanisms and immune pathways that might contribute to the immunopathogenesis of recalcitrant synovitis in PIRRA, and a possible basis for non-inflammatory symptomatology in NIRRA. Future approaches towards the definition of refractory RA and the application of single-cell and integrated omics technologies to the identification of refractory RA endotypes are also discussed.
Biologic disease-modifying antirheumatic drugs (bDMARDs) have revolutionised treatment and outcomes for rheumatoid arthritis (RA). The expanding repertoire allows the option of switching bDMARD if ...current treatment is not effective. For some patients, even after switching, disease control remains elusive. This analysis aims to quantify the frequency of, and identify factors associated with, bDMARD refractory disease.
Patients with RA starting first-line tumour necrosis factor inhibitor in the British Society for Rheumatology Biologics Register for RA from 2001 to 2014 were included. We defined patients as bDMARD refractory on the date they started their third class of bDMARD. Follow-up was censored at last follow-up date, 30 November 2016, or death, whichever came first. Switching patterns and stop reasons of bDMARDs were investigated. Cox regression identified baseline clinical factors associated with refractory disease. Multiple imputation of missing baseline data was used.
867 of 13 502 (6%) patients were bDMARD refractory; median time to third bDMARD class of 8 years. In the multivariable analysis, baseline factors associated with bDMARD refractory disease included patients registered more recently, women, younger age, shorter disease duration, higher patient global assessment, higher Health Assessment Questionnaire score, current smokers, obesity and greater social deprivation.
This first national study has identified the frequency of bDMARD refractory disease to be at least 6% of patients who have ever received bDMARDs. As the choice of bDMARDs increases, patients are cycling through bDMARDs quicker. The aetiopathogenesis of bDMARD refractory disease requires further investigation. Focusing resources, such as nursing support, on these patients may help them achieve more stable, controlled disease.
To update the evidence for the efficacy of biological disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism(EULAR) ...Task Force treatment recommendations.
Medline, Embase and Cochrane databases were searched for articles published between January 2009 and February 2013 on infliximab, etanercept, adalimumab, certolizumab-pegol, golimumab, anakinra, abatacept, rituximab, tocilizumab and biosimilar DMARDs (bsDMARDs) in phase 3 development. Abstracts from 2011 to 2012 American College of Rheumatology (ACR) and 2011-2013 EULAR conferences were obtained.
Fifty-one full papers, and 57 abstracts were identified. The randomised controlled trials (RCT) confirmed the efficacy of bDMARD+conventional synthetic DMARDs (csDMARDs) versus csDMARDs alone (level 1B evidence). There was some additional evidence for the use of bDMARD monotherapy, however bDMARD and MTX combination therapy for all bDMARD classes was more efficacious (1B). Clinical and radiographic responses were high with treat-to-target strategies. Earlier improvement in signs and symptoms were seen with more intensive initial treatment strategies, but outcomes were similar upon addition of bDMARDs in patients with insufficient response to MTX. In general, radiographic progression was lower with bDMARD use, mainly due to initial treatment effects. Although patients may achieve bDMARD- and drug-free remission, maintenance of clinical responses was higher with bDMARD continuation (1B), but bDMARD dose reduction could be applied (1B). There was still no RCT data for bDMARD switching.
The systematic literature review confirms efficacy of biological DMARDs in RA. It addresses different treatment strategies with the potential for reduction in therapy, particularly with early disease control, and highlights emerging therapies.
The European Alliance of Associations for Rheumatology recently defined difficult to treat (D2T) rheumatoid arthritis (RA) and provided points to consider in its management. This review summarises ...the key concepts of D2T-RA that underpinned this recent guidance. D2T-RA is primarily characterised by failure of at least two different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drug (DMARDs) with evidence of active/progressive disease. The basis for progressive disease, however, is not limited to clear inflammatory joint pathology, capturing wider contributors to treatment cycling such as comorbidity, obesity and fibromyalgia. This means D2T-RA comprises a heterogeneous population, with a proportion within this exhibiting bona fide treatment-refractory disease. The management points to consider, however, emphasise the importance of checking for the presence of inflammatory pathology before further treatment change. This review suggests additional considerations in the definition of D2T-RA, the potential value in identifying D2T traits and intervening before the development of D2T-RA state and the need for real world evidence of targeted synthetic DMARD in this population to compare to recent trial data. Finally, the review asks whether the presence of D2T-RA implies a failure to treat effectively from the outset, and the need for pharmacological and non-pharmacological management approaches to address the wider D2T-RA population effectively.
The beginning of the 21st century saw a biopharmaceutical revolution in the treatment of inflammatory rheumatic diseases, particularly rheumatoid arthritis. The fast-evolving use of biologic ...therapies highlighted the need to develop registers at national and international levels with the aim of collecting long-term data on patient outcomes. Over the past 15 years, many biologics registers have contributed a wealth of data and provided robust and reliable evidence on the use, effectiveness and safety of these therapies. The unavoidable challenges posed by the continuous introduction of new therapies, particularly with regard to understanding their long-term safety, highlights the importance of learning from experience with established biologic therapies. In this Perspectives article, the role of biologics registers in bridging the evidence gap between efficacy in clinical trials and real-world effectiveness is discussed, with a focus on methodological aspects of registers, their unique features and challenges and their role going forward.
Evaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of ...atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance.
Patients with RA aged ≥50 years with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. Hazard rations (HRs) were evaluated for the overall population and by history of ASCVD (exploratory analysis).
Risk of MACE, myocardial infarction and sudden cardiac death were increased with tofacitinib versus TNFi in ORAL Surveillance. In patients with history of ASCVD (14.7%; 640/4362), MACE incidence was higher with tofacitinib 5 mg two times per day (8.3%; 17/204) and 10 mg two times per day (7.7%; 17/222) versus TNFi (4.2%; 9/214). HR (combined tofacitinib doses vs TNFi) was 1.98 (95% confidence interval (CI) 0.95 to 4.14; interaction p values: 0.196 (for HR)/0.059 (for incidence rate difference)). In patients without history of ASCVD, MACE HRs for tofacitinib 5 mg two times per day (2.4%; 30/1251) and 10 mg two times per day (2.8%; 34/1234) versus TNFi (2.3%; 28/1237) were, respectively, 1.03 (0.62 to 1.73) and 1.25 (0.76 to 2.07).
This post hoc analysis observed higher MACE risk with tofacitinib versus TNFi in patients with RA and history of ASCVD. Among patients without history of ASCVD, all with prevalent CV risk factors, MACE risk did not appear different with tofacitinib 5 mg two times per day versus TNFi. Due to the exploratory nature of this analysis and low statistical power, we cannot exclude differential MACE risk for tofacitinib 5 mg two times per day versus TNFi among patients without history of ASCVD, but any absolute risk excess is likely low.
NCT02092467.
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