Welcome to the Rheumatology Resource Centre.
The Rheumatology Resource Centre is hosted by the journal Best Practice and Research Clinical Rheumatology. It aims to provide healthcare professionals with educational resources and the latest peer-reviewed research on rheumatoid arthritis. Funded by an educational grant, the Rheumatology Resource Centre is freely available. Content is selected by the editorial board; Dr. Thasia Woodworth, Dr. Sarah Mackie and Prof. Tony Woolf.
Healthcare professionals, will have access to articles and videos covering key topics in rheumatoid arthritis, focusing on targeted therapies, including the role of the IL-6 pathway in inflammation, as well as best practices in early diagnosis, treatment and patient care.
To keep up-to-date with the latest additions to the Resource Centre, you can sign up for our E-Alerts.
TREAT TO TARGET (T2T)
Where are we with implementation of treat to target (T2T) recommendations/guidelines in clinical practice?
In the last several months, we have interviewed some of the experts who have contributed to the Guidelines/Recommendations published by EULAR [Smolen et al., Smolen et al., Woodworth et al.] and ACR [Singh et al.] in 2015/16, to gain additional insight into application of these guidelines in clinical practice.
Both EULAR Recommendations and ACR Guidelines are aimed at providing evidence-based algorithms for treating RA patients “to target” – that is, to optimal symptom control and maximal function and quality of life (QoL) as quickly as possible. Each is based on systematic literature reviews (SLRs) [Gaujoux-Viala et al.], and consensus among experts, including patients [de Wit et al.], regarding the evidence for treatment choices. They emphasize initiation of a disease modifying antirheumatic drug (DMARD), methotrexate being the anchor drug unless contraindicated, and shared decision making between the rheumatologist and the patient; each includes input from patients. There is strong consensus among experts that periodic monitoring of disease activity status, with treatment adjustments as necessary, to achieve and maintain remission, or at least low disease activity (LDA), is critical to improve outcomes regardless of the duration of disease. Measurement with an established instrument such as the DAS, CDAI, SDAI, or RAPID3 should be done at every visit and discussed with the patient, to determine when “the target” is reached and maintained [Gaujoux-Viala et al.],[Hendrikx et al.].
We interviewed Josef Smolen, Professor of Internal Medicine and Chairman, Department of Rheumatology, Vienna General Hospital, University of Vienna; and Chairman, 2nd Dept. of Medicine – Center for Rheumatic Diseases Hietzing Hospital Vienna, at APLAR 2016. He is the first author of the EULAR T2T Recommendations, and creates a compelling case for their development and application, to prevent joint damage and loss of function. Importantly, he makes the point that consistent measurement of disease activity is critical to achieving “the target” – remission. Nowadays the DAS28 is probably not sufficient, as it’s recognized that inflammation may still be present; he discusses an example – the U-ACT-EARLY study [Biljsma et al.], and also makes a case for strong patient involvement in the process of achieving remission. The CDAI (clinical disease activity index) or the SDAI (simplified disease activity index) – the algebraic sum detect absence of inflammation/remission more comprehensively [Gaujoux-Viala et al.]. If a patient has not improved by 50% within 3 months of beginning MTX, regardless of the measure, additional therapy is likely to be needed.
Jasvinder Singh, Professor of Medicine and Epidemiology at University of Alabama in Birmingham, spoke with us at ACR 2016. He is the first author of the ACR Guidelines, and describes the process of reaching expert consensus using the GRADE method and presentation of the evidence for T2T and treatment choices, aimed at enabling personalized treatment choices. He also specifically discusses the approach to tapering and dose optimization.
As noted, International Recommendations represent expert opinion describing the efficacy and safety of conventional synthetic DMARDS (csDMARDs) and biologic DMARDs (bDMARDs) based on SLRs of clinical trials and registries. From EULAR, there are a total of 10 recommendations are detailed from four "Overarching Principles": (1) treatment decisions are shared between patient and rheumatologist; (2) the primary goal is to maximize long-term quality of life by controlling the symptoms, preventing joint damage, and by normalizing the function and social and work participation; (3) abrogation (not just control) of inflammation is the most effective method to achieve this goal; (4) T2T by measuring disease activity regularly and adjusting therapy to achieve remission/LDA optimizes outcomes in RA. The SLRs provide solid evidence that methotrexate is the "anchor" of csDMARD and that step-up therapy by adding/substituting other csDMARDs, such as sulfasalazine (SSZ), hydroxychloroquine (HCQ), or/and leflunomide (LEF) is as effective as combination therapy to initiate treatment. Tofacitinib, a recently marketed csDMARD, may be more effective in comparison to MTX, and can be used alone or in combination. Rapid disease control can be achieved by "bridging" with various regimens of glucocorticoids (GCs), but tapering to doses ≤7.5 mg/day within several months, and then discontinuing as soon as possible, is critical to limit side effects.
The ACR Guidelines are overall comparable, with some key differences in methodology and presentation [Singh et al.]. Experts, including patients, conducted or/and reviewed SLRs to gain consensus regarding the strength of evidence – strong versus conditional - was achieved using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. Using this method, quality of evidence is determined by considering within-study risk of bias (methodological quality), directness of evidence, heterogeneity of studies, precision of effect estimates, and risk of publication bias. Guidance is provided for the use of traditional disease modifying antirheumatic drugs (DMARDs), targeted biologic agents, tofacitinib, and glucocorticoids in early RA (<6months) versus established RA (≥6 months) with a T2T approach, including tapering. Importantly, guidance is also provided for vaccination and screening for tuberculosis. Ultimately 74 recommendations are presented – 23% strong, meaning that recommendations are not expected to change with additional evidence. Thus, 77% of recommendations are conditional and changes may occur as more data related to the experience with the guidelines becomes available.
At EULAR, APLAR and ACR we interviewed several practicing clinician experts, who provide additional perspective on the implementation of T2T. Check out these videos.
Professor Joel Kremer, founder and Chief Medical Officer of CORRONA (Consortium Of Rheumatology Researchers of North America) also spoke with us at ACR. He describes results of a pragmatic T2T study conducted within the CORRONA cohort of more than 48,000 RA patients. In particular, reasons for patients not agreeing to escalate therapy were examined. Because the most prominent one is fear of side effects, Professor Kremer offers advice for shared decision making, to try to overcome this barrier.
Cem Gabay, Professor of Rheumatology at the University Hospital in Geneva, Switzerland, summarizes his EULAR presentation on novel T2T treatment strategies for MTX inadequate responders and those with an inadequate response to TNFi. He discusses the role of glucocorticoids, as well as the new JAK inhibitor, baricitinib.
Ian McInnes, Professor of Experimental Medicine/Director of Research Institute, University of Glasgow, Scotland spoke to us at APLAR 2016. As a principle investigator for the TICORA study, one of the first to demonstrate the importance of T2T, Professor McInnes provides his perspective on RA pathophysiology that requires aggressive treatment of the “whole patient”, to prevent the comorbidities that are associated with inflammation. He also emphasizes the need for new medicines for the 20-30% of patients who don’t achieve adequate persistent disease control.
Hani El Gabalawy, Professor of Medicine and Immunology, University of Manitoba, Winnepeg provides novel perspective on implementing T2T in the setting of indigenous peoples in Canada. Professor El Gabalawy focuses on the geographic and cultural challenges of T2T in the indigenous population in Canada, in which RA is 2-3x more common, and discusses approaches being taken to address these challenges. In particular, he describes prevention strategies by identifying individuals at risk among first- degree relatives, and also initiatives providing remote monitoring, noting similar projects in other parts of the world.
In practice settings, there are practical issues to be addressed. The use of bDMARDs is influenced by reimbursement among other factors, so the increasing availability of biosimilars is likely to improve access. Tumor necrosis factor inhibitors (TNFi) are highly used, but as more data emerge, there appear to be no major differences in risk-benefit to more recently available targeted bDMARD monoclonal antibodies such as abatacept (co-stimulation blockade), rituximab (B cell depleting), tocilizumab (TCZ) (interleukin (IL)-6 receptor blockade). Rituximab appears to be most effective for seropositive patients, and tocilizumab may be more effective as a monotherapy in patients intolerant to csDMARDs. Besides T2T, attention to managing treatment and optimizing outcomes should take into account potential adverse effects, such as risk of serious infection, as well as potential morbidity/mortality related to cardiovascular events, pulmonary disease, osteoporosis, diabetes, and fibromyalgia which often influence some patient reported outcomes (PROs), such as the Health Assessment Questionnaire (HAQ) used to assess benefit-risk.
We will be addressing comorbidities in our next segment.
Treat to target articles
Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force.
Smolen JS, Breedveld FC, Burmester GR, Bykerk V et al.Ann Rheum Dis. 2016 Jan;75(1):3-15.
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update
Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados MAnn Rheum Dis 2017 Mar 6. [Epub ahead of print]
Treating to target in established rheumatoid arthritis: Challenges and opportunities in an era of novel targeted therapies and biosimilars
Thasia G. Woodworth MD Visiting Clinical Research Scientist and Alfons A. den Broeder
Best Practice & Research Clinical Rheumatology, Volume 29, Issue 4-5, AugustÔÇôDecember 2015, Pages 543 - 549
Evaluating disease activity in rheumatoid arthritis: Which composite index is best? A systematic literature analysis of studies comparing the psychometric properties of the DAS, DAS28, SDAI and CDAI
Cécile Gaujoux-Viala, Gaël Mouterde, Athan Baillet, Pascal Claudepierre, Bruno Fautrel, Xavier Le Loët, Jean-Francis Maillefert
Joint Bone Spine, Volume 79, Issue 2, March 2012, Pages 149 - 155
de Wit MP, Smolen JS, Gossec L, van der Heijde DMAnn Rheum Dis. 2011 Jun;70(6):891-5.
Systematic review of patient-reported outcome measures (PROMs) for assessing disease activity in rheumatoid arthritis.
Hendrikx J, de Jonge MJ, Fransen J, Kievit W, van Riel PLRMD Open. 2016 Aug 18;2(2):e000202.
Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial.
Bijlsma JW, Welsing PM, Woodworth TG, Middelink LM, Pethö-Schramm A, Bernasconi C et al.Lancet. 2016 Jul 23;388(10042):343-55.
Measures of rheumatoid arthritis disease activity: Patient (PtGA) and Provider (PrGA) Global Assessment of Disease Activity, Disease Activity Score (DAS) and Disease Activity Score with 28-Joint Counts (DAS28), Simplified Disease Activity Index (SDAI)....
Anderson JK, Zimmerman L, Caplan L, Michaud K.Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S14-36.