Maxime Dougados

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs

Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.

Treating rheumatoid arthritis to target: recommendations of an international task force

Background Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA). Objective To develop recommendations for achieving optimal therapeutic outcomes in RA. Methods A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure. Levels of evidence, strength of recommendations and levels of agreement were derived. Results The treat-to-target activity resulted in 10 recommendations. The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended. Follow-up examinations ought to employ composite measures of disease activity which include joint counts. Additional items provide further details for particular aspects of the disease. Levels of agreement were very high for many of these recommendations (≥9/10). Conclusion The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.

The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection

Objective: To validate and refine two sets of candidate criteria for the classification/diagnosis of axial spondyloarthritis (SpA). Methods: All Assessment of SpondyloArthritis international Society (ASAS) members were invited to include consecutively new patients with chronic (⩾3 months) back pain of unknown origin that began before 45 years of age. The candidate criteria were first tested in the entire cohort of 649 patients from 25 centres, and then refined in a random selection of 40% of cases and thereafter validated in the remaining 60%. Results: Upon diagnostic work-up, axial SpA was diagnosed in 60.2% of the cohort. Of these, 70% did not fulfil modified New York criteria and, therefore, were classified as having “non-radiographic” axial SpA. Refinement of the candidate criteria resulted in new ASAS classification criteria that are defined as: the presence of sacroiliitis by radiography or by magnetic resonance imaging (MRI) plus at least one SpA feature (“imaging arm”) or the presence of HLA-B27 plus at least two SpA features (“clinical arm”). The sensitivity and specificity of the entire set of the new criteria were 82.9% and 84.4%, and for the imaging arm alone 66.2% and 97.3%, respectively. The specificity of the new criteria was much better than that of the European Spondylarthropathy Study Group criteria modified for MRI (sensitivity 85.1%, specificity 65.1%) and slightly better than that of the modified Amor criteria (sensitivity 82.9, specificity 77.5%). Conclusion: The new ASAS classification criteria for axial SpA can reliably classify patients for clinical studies and may help rheumatologists in clinical practice in diagnosing axial SpA in those with chronic back pain. Trial registration number: NCT00328068.

2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease‐modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis

The American College of Rheumatology (ACR) most recently published recommendations for use of disease modifying anti-rheumatic drugs (DMARDs) and biologics in the treatment of rheumatoid arthritis (RA) in 2008 (1). These recommendations covered indications for use, monitoring of side-effects, assessment of the clinical response to DMARDs and biologics, screening for tuberculosis (TB), and assessment of the roles of cost and patient preference in decision-making for biologic agents (1). Recognizing the rapidly evolving knowledge in RA management and the accumulation of new evidence regarding the safety and efficacy of existing and newer therapies, the ACR commissioned an update of the 2008 recommendations in select topic areas. The 2012 revision updates the 2008 ACR recommendations in the following areas: (1) indications for DMARDs and biologics; (2) switching between DMARD and biologic therapies; (3) use of biologics in high-risk patients (those with hepatitis, congestive heart failure, and malignancy); (4) screening for TB in patients starting or currently receiving biologics; and (5) vaccination in patients starting or currently receiving DMARDs or biologics (Table 1). Table 1 Overview Comparison of Topics and Medications Included in the 2008 and 2012 ACR RA Recommendations METHODS We utilized the same methodology as described in detail in the 2008 guidelines (1) to maintain consistency and to allow cumulative evidence to inform this 2012 recommendation update. These recommendations were developed by two expert panels: (1) a non-voting working group and Core Expert Panel (CEP) of clinicians and methodologists responsible for the selection of the relevant topic areas to be considered, the systematic literature review, and the evidence synthesis and creation of “clinical scenarios”; and (2) a Task Force Panel (TFP) of 11 internationally-recognized expert clinicians, patient representatives and methodologists with expertise in RA treatment, evidence-based medicine and patient preferences who were tasked with rating the scenarios created using an ordinal scale specified in the Research and Development/University of California at Los Angeles (RAND/UCLA) Appropriateness method (2–4). This method solicited formal input from a multi-disciplinary TFP panel to make recommendations informed by the evidence. The methods used to develop the updated ACR recommendations are described briefly below. Systematic Literature Review – Sources, Databases and Domains Literature searches for both DMARDs and biologics relied predominantly on PubMed searches) with medical subject headings (MeSH) and relevant keywords similar to those used for the 2008 ACR RA recommendations (see Appendices 1 and 2). We included randomized clinical trials (RCTs), controlled clinical trials (CCTs), quasi-experimental designs, cohort studies (prospective or retrospective), and case-control studies, with no restrictions on sample size. More details about inclusion criteria are listed below and in Appendix 3. The 2008 recommendations were based on a literature search that ended on February 14, 2007. The literature search end date for the 2012 Update was February 26, 2010 for the efficacy and safety studies and September 22, 2010 for additional qualitative reviews related to TB screening, immunization and hepatitis (similar to the 2008 methodology). Studies published subsequent to that date were not included. For biologics, we also reviewed the Cochrane systematic reviews and overviews (published and in press) in the Cochrane Database of Systematic Reviews to identify additional studies (5–8) and further supplemented by hand-checking the bibliographies of all included articles. Finally, the CEP and TFP confirmed that relevant literature was included for evidence synthesis. Unless they were identified by the literature search and met the article inclusion criteria (see Appendix 3), we did not review any unpublished data from product manufacturers, investigators, or the Food and Drug Administration (FDA) Adverse Event Reporting System. We searched the literature for the eight DMARDs and nine biologics most commonly used for the treatment of RA. Literature was searched for eight DMARDS including azathioprine, cyclosporine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds and sulfasalazine. As in 2008, azathioprine, cyclosporine and gold were not included in the recommendations based on infrequent use and lack of new data (Table 1). Literature was searched for nine biologics including abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab; anakinra was not included in the recommendations due to infrequent use and lack of new data. Details of the bibliographic search strategy are listed in Appendix 1.

American College of Rheumatology/European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials

OBJECTIVE Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. METHODS A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. RESULTS Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patients RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤ 1, or (b) when the score on the Simplified Disease Activity Index is ≤ 3.3. CONCLUSION We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

ASAS/EULAR recommendations for the management of ankylosing spondylitis

Objective: To develop evidence based recommendations for the management of ankylosing spondylitis (AS) as a combined effort of the ‘ASsessment in AS’ international working group and the European League Against Rheumatism. Methods: Each of the 22 participants was asked to contribute up to 15 propositions describing key clinical aspects of AS management. A Delphi process was used to select 10 final propositions. A systematic literature search was then performed to obtain scientific evidence for each proposition. Outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, relative risk, number needed to treat, and incremental cost effectiveness ratio were calculated. On the basis of the search results, 10 major recommendations for the management of AS were constructed. The strength of recommendation was assessed based on the strength of the literature evidence, risk-benefit trade-off, and clinical expertise. Results: The final recommendations considered the use of non-steroidal anti-inflammatory drugs (NSAIDs) (conventional NSAIDs, coxibs, and co-prescription of gastroprotective agents), disease modifying antirheumatic drugs, treatments with biological agents, simple analgesics, local and systemic steroids, non-pharmacological treatment (including education, exercise, and physiotherapy), and surgical interventions. Three general recommendations were also included. Research evidence (categories I–IV) supported 11 interventions in the treatment of AS. Strength of recommendation varied, depending on the category of evidence and expert opinion. Conclusion: Ten key recommendations for the treatment of AS were developed and assessed using a combination of research based evidence and expert consensus. Regular updating will be carried out to keep abreast of new developments in the management of AS.

Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis.

OBJECTIVE To develop criteria for symptomatic improvement in patients with ankylosing spondylitis (AS), using outcome domain data from placebo-controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs). METHODS Patient data from 5 short-term, randomized, controlled trials were used to assess equivalence, reliability, and responsiveness of multiple items in the 5 outcome domains for AS treatment: physical function, pain, spinal mobility, patient global assessment, and inflammation. At least one measure per domain was responsive (standardized response mean of > 0.5), except for the spinal mobility domain, which was omitted from the criteria. We developed and tested candidate improvement criteria in a random two-thirds subset from the 3 largest trials and used the remaining one-third for validation. These 3 largest trials included 923 patients (631 receiving NSAIDs, 292 in placebo groups). We selected the multiple domain definition that best distinguished NSAID treatment from placebo by chi-square test and that had a placebo response rate of < or = 25%. RESULTS Candidate definitions were changes in single domains and in multiple measure indices, as well as combinations of improvements in multiple domains. Worsening in a domain was defined as a change for the worse of > or = 20% and a net change for the worse of > or = 10 units on a scale of 0-100. Partial remission (for comparison purposes) was defined as an end-of-trial value of < 20/100 in each of the 4 domains. Among 20 candidate criteria, change of > or = 20% and > or = 10 units in each of 3 domains and absence of worsening in the fourth discriminated best in the development subset (51% of patients improved with NSAIDs, 25% with placebo; chi2 = 36.4, P < 0.001). Results were confirmed in the validation subset. Almost all patients satisfying the definition of partial disease remission at the end of the trial had also improved by this criterion. Among all 923 patients, improvement rates using this criterion were 49% for NSAID-treated patients and 24% for placebo-treated patients. CONCLUSION Although further validation using data from new trials is still needed, we conclude that we have developed a clinically valid, easy-to-use measure of short-term improvement in AS.

EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT)

BACKGROUND Osteoarthritis (OA) is the most common joint disease encountered throughout Europe. A task force for the EULAR Standing Committee for Clinical Trials met in 1998 to determine the methodological and logistical approach required for the development of evidence based guidelines for treatment of knee OA. The guidelines were restricted to cover all currently available treatments for knee OA diagnosed either clinically and/or radiographically affecting any compartment of the knee. METHODS The first stage was the selection of treatment modalities to be considered. The second stage comprised a search of the electronic databases Medline and Embase using a combination of subject headings and keywords. All European language publications in the form of systematic reviews, meta-analyses, randomised controlled trials, controlled trials, and observational studies were included. During stage three all the relevant studies were quality scored. The summary statistics for validated outcome measures, when available, were recorded and, where practical, the numbers needed to treat and the effect size for each treatment were calculated. In the fourth stage key clinical propositions were determined by expert consensus employing a Delphi approach. The final stage ranked these propositions according to the available evidence. A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach. RESULTS Over 2400 English language publications and 400 non-English language publications were identified. Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA. Quantitative analysis of treatment effect was possible in only 61 studies. Recommendations for the management of knee OA based on currently available data and expert opinion are presented. Proposals for a future research agenda are highlighted. CONCLUSIONS These are the first clinical guidelines on knee OA to combine an evidence based approach and a consensus approach across a wide range of treatment modalities. It is apparent that certain clinical propositions are supported by substantial research based evidence, while others are not. There is thus an urgent need for future well designed trials to consider key clinical questions.

The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal

Objective: Non-radiographic axial spondyloarthritis (SpA) is characterised by a lack of definitive radiographic sacroiliitis and is considered an early stage of ankylosing spondylitis. The objective of this study was to develop candidate classification criteria for axial SpA that include patients with but also without radiographic sacroiliitis. Methods: Seventy-one patients with possible axial SpA, most of whom were lacking definite radiographic sacroiliitis, were reviewed as “paper patients” by 20 experts from the Assessment of SpondyloArthritis international Society (ASAS). Unequivocally classifiable patients were identified based on the aggregate expert opinion in conjunction with the expert-reported level of certainty of their judgement. Draft criteria for axial SpA were formulated and tested using classifiable patients. Results: Active sacroiliitis on magnetic resonance imaging (MRI) (odds ratio 45, 95% CI 5.3 to 383; p<0.001) was strongly associated with the classification of axial SpA. The knowledge of MRI findings led to a change in the classification of 21.1% of patients. According to the first set of candidate criteria (sensitivity 97.1%; specificity 94.7%) a patient with chronic back pain is classified as axial SpA in the presence of sacroiliitis by MRI or x rays in conjunction with one SpA feature or, if sacroilitiis is absent, in the presence of at least three SpA features. In a second set of candidate criteria, inflammatory back pain is obligatory in the clinical arm (sensitivity 86.1%; specificity 94.7%). Conclusion: The ASAS group has developed candidate criteria for the classification of axial SpA that include patients without radiographic sacroiliitis. The candidate criteria need to be validated in an independent international study.

European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies

Background Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). Methods The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. Results Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined. Conclusion These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.