Robert Landewé

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

OBJECTIVEnRemission 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.nnnMETHODSnA 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.nnnRESULTSnSurvey 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.nnnCONCLUSIONnWe 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.

Assessment of global disease activity in RA patients monitored in the METEOR database: the patient's versus the rheumatologist's opinion

The objectives of this study were to compare the patients (PtGDA) and physicians (PhGDA) assessment of global disease activity and to identify factors that might influence these differences as well as factors that may influence the patients and the physicians scores separately. Anonymous data were used from 2,117 Dutch patients included in the Measurement of efficacy of Treatment in the Era of Rheumatology database. PtGDA and PhGDA were scored independently on a 100-mm visual analog scale (VAS) with 0 and 100 as extremes. The agreement, intraclass correlation coefficients (ICC), was calculated and a Bland–Altman plot was created to visualize the differences between PtGDA and PhGDA. Linear mixed model analysis was used to model PtGDA and PhGDA. Logistic repeated measurements were used to model the difference in PtGDA and PhGDA (PtGDAu2009>u2009PhGDA versus PtGDAu2009≤u2009PhGDA). Gender patient, gender physician, age, swollen joint count (SJC), tender joint count, VAS pain, disease duration, and erythrocyte sedimentation rate (ESR) were considered as possible determinants in both models. Mean (standard deviation) age was 57 (15)u2009years and 67xa0% of the patients were female. Agreement between PtGDA and PhGDA was moderate (ICC, 0.57). Patients scored on average 11 units higher (worse) than rheumatologists (95xa0% limits of agreement, −25.2 to 47.6). Patients perception of pain (VAS) was positively associated with a PtGDA being higher than PhGDA. Similarly, ESR and swollen joint counts were positively associated with a PtGDA being lower or equal to the PhGDA. Patients rate global disease activity consistently higher than their rheumatologists. Patients base their judgment primarily on the level of pain, physicians on the level of SJC and ESR.

Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years

IntroductionAnkylosing spondylitis (AS) is a chronic rheumatic disease associated with spinal inflammation that subsequently leads to progression of structural damage and loss of function. The fully human anti-tumor necrosis factor (anti-TNF) antibody adalimumab reduces the signs and symptoms and improves overall quality of life in patients with active AS; these benefits have been maintained through 2 years of treatment. Our objective was to compare the progression of structural damage in the spine in patients with AS treated with adalimumab for up to 2 years versus patients who had not received TNF antagonist therapy.MethodsRadiographs from patients with AS who received adalimumab 40 mg every other week subcutaneously were pooled from the Adalimumab Trial Evaluating Long-Term Efficacy and Safety for Ankylosing Spondylitis (ATLAS) study and a Canadian AS study (M03-606). Radiographic progression from baseline to 2 years in the spine of adalimumab-treated patients from these two studies (adalimumab cohort, n = 307) was compared with an historic anti-TNF-naïve cohort (Outcome in AS International Study [OASIS], n = 169) using the modified Stoke AS Spine Score (mSASSS) method.ResultsmSASSS results were not significantly different between the adalimumab cohort and the OASIS cohort, based on baseline and 2-year radiographs. Mean changes in mSASSS from baseline to 2 years were 0.9 for the OASIS cohort and 0.8 for the adalimumab cohort (P = 0.771), indicating similar radiographic progression in both groups. When results for patients in the OASIS cohort who met the baseline disease activity criteria for the ATLAS and Canadian studies (OASIS-Eligible cohort) were analyzed, there was no significant difference in mean change in mSASSS from baseline to 2 years between OASIS-Eligible patients and adalimumab-treated patients; the mean changes in mSASSS were 0.9 for the OASIS-Eligible cohort and 0.8 for the adalimumab cohort (P = 0.744).ConclusionsTwo years of treatment with adalimumab did not slow radiographic progression in patients with AS, as assessed by the mSASSS scoring system, when compared with radiographic data from patients naïve to TNF antagonist therapy.Trial registrationCanadian study (M03-606) ClinicalTrials.gov identifier: NCT00195819; ATLAS study (M03-607) ClinicalTrials.gov identifier: NCT00085644.

Economic aspects of treatment options in rheumatoid arthritis: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis

Objective To review the cost effectiveness of rheumatoid arthritis (RA) treatments and inform the clinical recommendations by the European League Against Rheumatism. Methods A systematic literature search and review of the health economic evidence on RA treatment options was performed. Results Despite diverse methodological approaches, health economic analyses are concordant: at onset of disease, traditional disease-modifying antirheumatic drugs (DMARDs) are cost effective—that is, treatment merits outweigh treatment costs. If DMARDs fail, therapeutic escalation with tumour necrosis factor α inhibitors (TNFi) is cost effective when standard dosing schemes are employed. If TNFi fail, rituximab or abatacept is cost effective. Economic evidence for switching TNFi remains sparse. Conclusions The costly sequelae of insufficiently controlled RA justify intensive escalations of treatment in this disease. By maintaining function, patients are kept in the work process, reducing indirect costs. Quality of life is improved at an expense commonly accepted for chronic diseases. Effective control of disease activity seems to be a prudent use of societal resources.

EULAR recommendations for the role of the nurse in the management of chronic inflammatory arthritis

Objectives The authors aim to develop European League Against Rheumatism recommendations for the role of the nurse in the management of patients with chronic inflammatory arthritis, to identify a research agenda and to determine an educational agenda. Methods A task force made up of a multidisciplinary expert panel including nurses, rheumatologists, occupational therapist, physiotherapist, psychologist, epidemiologist and patient representatives, representing 14 European countries, carried out the development of the recommendations, following the European League Against Rheumatism standardised operating procedures. The task force met twice. In the first meeting, the aims of the task force were defined, and eight research questions were developed. This was followed by a comprehensive, systematic literature search. In the second meeting, the results from the literature review were presented to the task force that subsequently formulated the recommendations, research agenda and educational agenda. Results In total, 10 recommendations were formulated. Seven recommendations covered the contribution of nurses to care and management: education, satisfaction with care, access to care, disease management, psychosocial support, self-management and efficiency of care. Three recommendations focused on professional support for nurses: availability of guidelines or protocols, access to education and encouragement to undertake extended roles. The strength of the recommendations varied from A to C, dependent on the category of evidence (1A–3), and a high level of agreement was achieved. Additionally, the task force agreed upon 10 topics for future research and an educational agenda. Conclusion 10 recommendations for the role of the nurse in the management of chronic inflammatory arthritis were developed using a combination of evidence-based and expert consensus approach.

The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis

Background Glucocorticoids (GCs) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis (RA) and the need to start disease-modifying antirheumatic drugs (DMARDs). Objective To test the effect of GCs on patients with very early arthritis (symptom duration of <16 weeks) in a randomised controlled trial. Methods Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo (PL) and were followed up for 52 weeks. Primary end point was drug-free clinical remission, both at weeks 12 and 52. Among secondary outcomes were fulfilment of remission criteria at weeks 2, 12 or 52, time course of ‘core set variables’ and proportion of patients starting DMARDs. Results 17.0% of all analysed subjects (65/383) achieved persistent remission: 17.8% (33/185) of the PL group, 16.2% (32/198) of the patients receiving methylprednisolone (OR=1.13, 95% CI 0.66 to 1.92, p=0.6847). Analyses of secondary end points showed significant clinical benefits of the GC only at week 2. These differences subsequently disappeared. DMARDs were started in 162 patients: 50.3% methylprednisolone and 56.7% PL patients had to start DMARD treatment (OR=0.78, 95% CI 0.49 to 1.22, p=0.30). Significantly more patients with polyarthritis than with oligoarthritis received DMARDs (OR=2.84, 95% CI 1.75 to 4.60, p<0.0001). Conclusions Neither remission nor development of RA is delayed by GC treatment. Remission is rare in the first year of very early arthritis, occurring in <20% of the patients. Also, the need to start DMARDs was not influenced by GC treatment.

Baseline RANKL:OPG ratio and markers of bone and cartilage degradation predict annual radiological progression over 11 years in rheumatoid arthritis

Objective To determine to what extent baseline measurements of the ratio receptor activator of nuclear factor-κB ligand (RANKL):osteoprotegerin (OPG) and C-terminal cross linking of type-I and type-II (CTX-I and CTX-II), in addition to traditional markers of disease severity, could predict annual radiological progression. Methods A cohort of 155 patients with early, active, untreated rheumatoid arthritis (RA) who participated in the Combination Therapy in Early Rheumatoid Arthritis trial (COBRA trial) was followed up for 11 years. Urine was sampled at baseline and after 3 months from the start of treatment and analysed for CTX-I and CTX-II. Baseline serum samples were analysed for RANKL and OPG. Available traditional markers of disease severity included baseline measurements of erythrocyte sedimentation rate, rheumatoid factor and baseline radiological damage. A digital database of frequent radiographs was available, scored according to the Sharp/van der Heijde method. Individual annual progression rates were calculated and used as outcome variable. Multiple linear regression analyses identified the strongest predictors of annual radiological progression. Results In multivariable analyses the RANKL:OPG ratio and CTX-I or CTX-II proved to be independent predictors of annual radiological damage over 11 years. The prediction of annual radiological progression was strongest when the RANKL:OPG ratio and CTX-I or CTX-II were evaluated in the same model (36–39% explained variance). Adding the effect of treatment at 3 months to the baseline models improved the predictive ability of the models up to 44–46%. Conclusion Unfavourable baseline levels of the RANKL:OPG ratio as well as CTX-I and CTX-II in patients with early, active, untreated RA are strong independent predictors of rapid and persistent damage progression over the 11-year follow-up. Early improvement in bone markers by treatment predicts a better outcome.

Impact of ankylosing spondylitis on sick leave, presenteeism and unpaid productivity, and estimation of the societal cost.

Aim To describe the influence of ankylosing apondylitis (AS) on sick leave, presenteeism and unpaid work restrictions and to estimate related productivity costs. Methods 142 consecutive and unselected patients with AS under the care of rheumatologists participated in a longitudinal observational study and completed the Health and Labour Questionnaire (HLQ) assessing disease-related sick leave, presenteeism and restrictions in unpaid work over the previous 2 weeks. Logistic regressions explored which explanatory variables were associated with work outcome. Productivity loss was valued in monetary terms. Results Among 72 patients in paid employment, 12% had sick leave over a period of 2 weeks and 53% experienced an adverse influence of AS on work productivity while at work. Over this period they reported on average of 5.8 h sick leave and 2.4 inefficient working hours, for which they estimated an extra 1.9 h were needed to complete unfinished work. Among all patients (n=137), 71% had experienced restrictions in unpaid work during the previous 2 weeks with 42% needing help for these tasks for an average of 8 h. The annual production costs for the total group were €1451 (95% CI 425 to 2742) per patient for sick leave, €967 (95% CI 503 to 1496) to compensate for hours worked inefficiently while at work and €1930 (95% CI 1404 to 2471) to substitute loss of unpaid work production. Conclusion Patients with AS not only have substantial sick leave but also experience restrictions while being at work and when performing unpaid tasks. Limitations in physical functioning are strongly associated with work restrictions. Societal costs of formal and informal care are comparable with the costs of sick leave and presenteeism combined.

EULAR points to consider when establishing, analysing and reporting safety data of biologics registers in rheumatology

Objectives The introduction of biological therapies for the treatment of rheumatic diseases has drawn attention to the limitations of traditional means of assessing drug safety. Consequently, a series of European academic biologics registers dedicated to this task have been established. Increasing reliance upon safety data generated from observational drug registers makes it important to convert the lessons learned from such registers into recommendations for rheumatologists embarking upon the establishment of future registers, or analysing and reporting from new and existing registers. Methods The Task Force encompassed 11 scientists from European Rheumatology drug registers. Through an informal inventory of critical elements in the establishment of existing rheumatoid arthritis drug registers, of analytical strategies used and of limitations of their results, several ‘points to consider’—beyond established generic guidelines for observational registers/studies but with particular relevance to biologics registers on safety in rheumatology—were assembled. For each ‘point to consider’, contextual and methodological background and examples were compiled. Results A set of seven points to consider was assembled for the establishment of new drug registers with a focus on purpose, population to be targeted, data collection, handling and storage as well as ethical and legal considerations. For analysis and reporting, nine points to consider were assembled (setting, participant, variable, statistical method, descriptive data, outcome data, main results, other analyses and limitations). Conclusions Thoughtful design and planning before the establishment of biologics registers will increase their sustainability, versatility and raw data quality. Harmonisation of analyses and reporting from such registers will improve interpretation of drug safety studies.

ASAS modification of the Berlin algorithm for diagnosing axial spondyloarthritis: results from the SPondyloArthritis Caught Early (SPACE)-cohort and from the Assessment of SpondyloArthritis international Society (ASAS)-cohort

Objective To compare the original Berlin algorithm for diagnosing axial Spondyloarthritis (axSpA) with two modifications in the SPondyloArthritis Caught Early (SPACE)-cohort and the Assessment of SpondyloArthritis international Society (ASAS) axSpA criteria validation (ASAS)-cohort. Methods Patients in the SPACE-cohort (back pain ≥3u2005months, ≤2u2005years, onset <45u2005years) and the ASAS-cohort (undiagnosed chronic back pain) were diagnosed according to three algorithms: original (inflammatory back pain (IBP) mandatory), modification 1 (IBP defined by ≥3/5 IBP-features instead of ≥4/5) and modification 2 (IBP deleted as obligatory entry criterion, added as SpA-feature). Diagnosis by rheumatologist, ASAS axSpA criteria and likelihood ratio product were used as external standards to test the performance of the algorithms. Results SPACE-cohort: Compared to the diagnosis by rheumatologist (either axSpA or no-axSpA), the original algorithm agreed in 120 patients (76.4%). Agreement decreased using modification 1 (119 patients; 75.8%), increased using modification 2 (125 patients; 79.6%). Sensitivity increased from 66.2% (original) to 72.3% (modification 1) and 78.5% (modification 2). Specificity decreased more using modification 1 (83.7% to 78.3%) than when using modification 2 (83.7% to 79.6%). ASAS-cohort: Compared to the diagnosis by rheumatologist (either axSpA or no-axSpA), the original algorithm agreed in 484 patients (70.7%). Agreement increased using modification 1 (520 patients; 75.9%) and modification 2 (548 patients; 80.0%). Sensitivity increased from 65.3% (original) to 77.9% (modification 1) and 79.6% (modification 2). Specificity decreased more using modification 1 (79.2% to 72.2%) than when using modification 2 (79.2% to 75.6%). Conclusions ASAS accepted a modified algorithm for diagnosing axSpA in which IBP is excluded as obligatory entry criterion and added as SpA-feature.