T.K. Kvien

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.

Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative

Objectives: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. Methods: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. Conclusions: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

ASDAS, a highly discriminatory ASAS-endorsed disease activity score in patients with ankylosing spondylitis

Objectives: To evaluate various validity aspects of four disease activity scores (ASDAS) for ankylosing spondylitis (AS) in comparison with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), its individual components and physician and patient global assessment of disease activity. Methods: The analyses were performed in two cohorts of patients with AS: (1) the NOR-DMARD database which includes patients starting on a disease-modifying antirheumatic drug or tumour necrosis factor (TNF) blocker and (2) patients participating in double-blind placebo controlled randomised clinical trials with TNF blockers in four centres. Discrimination between patients with low versus high disease activity according to various definitions and between various levels of change were analysed as the standardised mean difference (difference in the group means divided by the pooled SD of the group means) and t score. Results: The four ASDAS versions were highly discriminatory in differentiating patients with different levels of disease activity and patients with different levels of change. The ASDAS scores outperformed the BASDAI and its single components in all settings: patient- or physician-based, reflecting status or change, with normal or raised C-reactive protein (CRP), in the presence or absence of peripheral arthritis. There were no major differences between the four ASDAS scores. Based on feasibility, the ASAS membership selected the ASDAS version which included back pain, duration of morning stiffness, patient global assessment, peripheral joint complaints and CRP as the preferred version. Conclusions: The ASDAS is a validated, highly discriminatory instrument for assessing disease activity in AS, including patient-reported outcomes and CRP levels.

Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores

Background The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a new composite index to assess disease activity in ankylosing spondylitis (AS). It fulfils important aspects of truth, feasibility and discrimination. Criteria for disease activity states and improvement scores are important for use in clinical practice, observational studies and clinical trials and so far have not been developed for the ASDAS. Objective To determine clinically relevant cut-off values for disease activity states and improvement scores using the ASDAS. Methods For the selection of cut-offs data from the Norwegian disease modifying antirheumatic drug (NOR-DMARD) registry, a cohort of patients with AS starting conventional or biological DMARDs, were used. Receiver operating characteristic analysis against several external criteria was performed and several approaches to determine the optimal cut-offs used. The final choice was made on clinical and statistical grounds, after debate and voting by Assessment of SpondyloArthritis international Society members. Crossvalidation was performed in NOR-DMARD and in Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy, a database of patients with AS participating in a randomised placebo-controlled trial with a tumour necrosis factor blocker. Results Four disease activity states were chosen by consensus: inactive disease, moderate, high and very high disease activity. The three cut-offs selected to separate these states were: 1.3, 2.1 and 3.5 units. Selected cut-offs for improvement were: change ≥1.1 units for clinically important improvement and change ≥2.0 units for major improvement. Results of the crossvalidation strongly supported the cut-offs. Conclusions Cut-off values for disease activity states and improvement using the ASDAS have been developed. They proved to have external validity and a good performance compared to existing criteria.

Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis

Background Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA. Methods Preparation of this new document involved many international experts experienced in the treatment of RA. Following a meeting to agree upon the core agenda, a systematic literature review was undertaken to identify all relevant data. Data were then interrogated by a drafting committee, with subsequent review and discussion by a wider expert committee leading to the formulation of an updated consensus statement. These committees also included patients with RA. Results The new statement covers wide-ranging issues including the use of rituximab in earlier RA and impact on structural progression, and aspects particularly pertinent to rituximab such as co-medication, optimal dosage regimens, repeat treatment cycles and how to manage non-response. Biological therapy following rituximab usage is also addressed, and safety concerns including appropriate screening for hepatitis, immunoglobulin levels and infection risk. This consensus statement will support clinicians and inform patients when using B-cell depletion in the management of RA, providing up-to-date information and highlighting areas for further research. Conclusion New therapeutic strategies and treatment options for RA, a chronic destructive and disabling disease, have expanded over recent years. These have been summarised in general strategic suggestions and specific management recommendations, emphasising the importance of expedient disease-modifying antirheumatic drug implementation and tight disease control. This consensus statement is in line with these fundamental principles of management.

Current evidence for the management of rheumatoid arthritis with synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis

Objectives To assess the efficacy and safety of synthetic disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis (RA)—a first step in a European League Against Rheumatism (EULAR) initiative to produce recommendations for the management of RA. Methods A systematic review of the literature using PubMed, Embase and the Cochrane library was performed up to January 2009. All randomised controlled trials (RCTs) reporting the efficacy of synthetic DMARDs (vs placebo or other synthetic DMARDs) on signs and symptoms, disability and/or radiographic structural damage in patients with RA were selected. Studies of biological agents or glucocorticoids were excluded. A pooled effect size (ES) was calculated by meta-analysis. Safety and the occurrence of infections and neoplasia was also assessed. Results 97 RCTs (14 159 patients) were analysed for efficacy. The pooled analysis indicated that methotrexate (MTX) was more efficacious in reducing signs and symptoms, disability and radiographic structural damage than other synthetic DMARDs pooled: ES for swollen joint count (SJC) versus pooled DMARDs=1.42 (95% CI 0.65 to 2.18). Leflunomide appeared to be as effective as MTX. Sulfasalazine and injectable gold were efficacious in reducing signs and symptoms and structural damage. Ciclosporin, minocycline, tacrolimus and hydroxychloroquine showed some efficacy in reducing SJC. Auranofin and D-penicillamine showed no significant superiority over placebo. The risks of cancer and of infection were increased with cyclophosphamide and azathioprine. Conclusions MTX was well-tolerated and effective in reducing signs and symptoms, disability and structural damage. A comparison with other synthetic DMARDs was in favour of MTX, though at the tested doses MTX and leflunomide were equally effective.

Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative

Objective A patient-derived composite measure of the impact of rheumatoid arthritis (RA), the rheumatoid arthritis impact of disease (RAID) score, takes into account pain, functional capacity, fatigue, physical and emotional wellbeing, quality of sleep and coping. The objectives were to finalise the RAID and examine its psychometric properties. Methods An international multicentre cross-sectional and longitudinal study of consecutive RA patients from 12 European countries was conducted to examine the psychometric properties of the different combinations of instruments that might be included within the RAID combinations scale (numeric rating scales (NRS) or various questionnaires). Construct validity was assessed cross-sectionally by Spearman correlation, reliability by intraclass correlation coefficient (ICC) in 50 stable patients, and sensitivity to change by standardised response means (SRM) in 88 patients whose treatment was intensified. Results 570 patients (79% women, mean±SD age 56±13 years, disease duration 12.5±10.3 years, disease activity score (DAS28) 4.1±1.6) participated in the validation study. NRS questions performed as well as longer combinations of questionnaires: the final RAID score is composed of seven NRS questions. The final RAID correlated strongly with patient global (R=0.76) and significantly also with other outcomes (DAS28 R=0.69, short form 36 physical −0.59 and mental −0.55, p<0.0001 for all). Reliability was high (ICC 0.90; 95% CI 0.84 to 0.94) and sensitivity to change was good (SRM 0.98 (0.96 to 1.00) compared with DAS28 SRM 1.06 (1.01 to 1.11)). Conclusion The RAID score is a patient-derived composite score assessing the seven most important domains of impact of RA. This score is now validated; sensitivity to change should be further examined in larger studies.

Cortical hand bone loss after 1 year in early rheumatoid arthritis predicts radiographic hand joint damage at 5-year and 10-year follow-up

Objective: To examine 1-year hand bone loss in early rheumatoid arthritis (RA) as a predictor of radiographic damage at 5-year and 10-year follow-up Methods: A total of 136 patients with RA (disease duration 0–4 years) were followed for 10 years with clinical data and hand radiographs. Joint damage was scored according to the van der Heijde modification of the Sharp method (vdH Sharp score) and hand bone mineral density (BMD) was measured by digital x ray radiogrammetry (DXR). Group comparisons, correlation analyses and multivariate analyses were performed to evaluate the relationship between hand bone loss and radiographic joint damage. Results: Patients with hand BMD loss at 1 year had a higher median increase in vdH Sharp score compared to patients without loss at 5 years (12 vs 2, p = 0.001) and 10 years (22 vs 4, p = 0.002). In a linear regression model adjusting for age, gender, baseline C-reactive protein (CRP), anti-cyclic citrullinated peptide (CCP), IgM rheumatoid factor (RF) and radiographic damage, absolute hand DXR-BMD loss at 1 year was an independent predictor of radiographic outcome at 5 years (p<0.01) and 10 years (p = 0.02). In a logistic regression model the odds ratio (95% CI) for radiographic progression among patients with hand BMD loss was 3.5 (1.4 to 8.8) and 3.5 (1.4 to 8.4) at 5 and 10 years, respectively. Conclusion: Early hand bone loss measured by DXR-BMD is an independent predictor of subsequent radiographic damage. Our findings support that quantitative hand bone loss in RA precedes radiographic joint damage and may be used as a tool for assessment of bone involvement in RA.

Effectiveness of switching between TNF inhibitors in ankylosing spondylitis: data from the NOR-DMARD register

Objective To assess the effectiveness of switching to a second tumour necrosis factor inhibitor (TNFi) in patients with ankylosing spondylitis (AS). Methods Data were extracted from an ongoing longitudinal observational multicentre study in Norway. This study included anti-TNF naïve patients with AS starting treatment with a TNFi as well as treatment with a second TNFi in these same patients. Effectiveness data and 2-year drug survival were compared between switchers and non-switchers and within switchers (first and second TNFi). Results 514 anti-TNF naïve patients with AS were included; 77 patients switched to a second TNFi while 437 patients did not switch. The percentages of non-switchers using etanercept, infliximab or adalimumab were 53%, 32% and 15%, and the percentages of first and second TNFi in the switchers were 42%, 53% and 5% and 40%, 23% and 36%, respectively. The reason for switching was insufficient response (IR) in 30, adverse events (AEs) in 44 and not reported in 3 patients. Baseline disease activity was similar between the groups. Three-month BASDAI 50 and ASAS 40 responses were achieved by 49% and 38% of non-switchers, by 25% and 30% of switchers after the first TNFi and by 28% and 31% after the second TNFi. The 3-month disease activity level was higher for switchers on the second TNFi than for non-switchers. Drug withdrawal rate was higher during the second TNFi among switchers than for non-switchers (p=0.001). No difference was found in the effectiveness of the second TNFi between switchers due to IR and AE. Conclusion This study confirms that switching to a second TNFi can be effective in AS and can be as useful as in rheumatoid arthritis, although overall effectiveness seems to be somewhat lower than in non-switchers.

Adalimumab therapy reduces hand bone loss in early rheumatoid arthritis: Explorative analyses from the PREMIER study

Objective: The effect of adalimumab on hand osteoporosis was examined and related to radiographic joint damage in the three treatment arms of the PREMIER study: adalimumab plus methotrexate, adalimumab and methotrexate monotherapy. Predictors of hand bone loss were also searched for. Methods: 768 patients (537 fulfilled 2 years) with rheumatoid arthritis (RA) for less than 3 years, never treated with methotrexate, were included. Hand bone loss was assessed by digital x ray radiogrammetry (DXR) on the same hand radiographs scored with modified Sharp score at baseline, 26, 52 and 104 weeks. For DXR, metacarpal cortical index (MCI) was the primary bone measure. Results: At all time points the rate of percentage DXR–MCI loss was lowest in the combination group (−1.15; −2.16; −3.03) and greatest in the methotrexate monotherapy group (−1.42; −2.87; −4.62), with figures in between for the adalimumab monotherapy group (−1.33; −2.45; −4.03). Significant differences between the combination group and the methotrexate group were seen at 52 (p = 0.009) and 104 weeks (p<0.001). The order of hand bone loss across the three treatment arms was similar to the order of radiographic progression. Older age, elevated C-reactive protein and non-use of adalimumab were predictors of hand bone loss. Conclusion: This study supports a similar pathogenic mechanism for hand bone loss and erosions in RA. The combination of adalimumab and methotrexate seems to arrest hand bone loss less effectively than radiographic joint damage. Quantitative measures of osteoporosis may thus be a more sensitive tool for assessment of inflammatory bone involvement in RA.