Karel Pavelka

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.

Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.

BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis. METHODS In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat. FINDINGS Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups. INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.

Eular evidence based recommendations for the management of hand osteoarthritis - report of a task force of the Eular Standing Committee for International Clinical Studies Including Therapeutics(ESCISIT)

Objectives: To develop evidence based recommendations for the management of hand osteoarthritis (OA). Methods: The multidisciplinary guideline development group comprised 16 rheumatologists, one physiatrist, one orthopaedic surgeon, two allied health professionals, and one evidence based medicine expert, representing 15 different European countries. Each participant contributed up to 10 propositions describing key clinical points for management of hand OA. Final recommendations were agreed using a Delphi consensus approach. A systematic search of Medline, Embase, CINAHL, Science Citation Index, AMED, Cochrane Library, HTA, and NICE reports was used to identify the best available research evidence to support each proposition. Where possible, the effect size and number needed to treat were calculated for efficacy. Relative risk or odds ratio was estimated for safety, and incremental cost effectiveness ratio was used for cost effectiveness. The strength of recommendation was provided according to research evidence, clinical expertise, and perceived patient preference. Results: Eleven key propositions involving 17 treatment modalities were generated through three Delphi rounds. Treatment topics included general considerations (for example, clinical features, risk factors, comorbidities), non-pharmacological (for example, education plus exercise, local heat, and splint), pharmacological (for example, paracetamol, NSAIDs, NSAIDs plus gastroprotective agents, COX-2 inhibitors, systemic slow acting disease modifying drugs, intra-articular corticosteroids), and surgery. Of 17 treatment modalities, only six were supported by research evidence (education plus exercise, NSAIDs, COX-2 inhibitors, topical NSAIDs, topical capsaicin, and chondroitin sulphate). Others were supported either by evidence extrapolated from studies of OA affecting other joint sites or by expert opinion. Strength of recommendation varied according to level of evidence, benefits and harms/costs of the treatment, and clinical expertise. Conclusion: Eleven key recommendations for treatment of hand OA were developed using a combination of research based evidence and expert consensus. The evidence was evaluated and the strength of recommendation was provided.

Treatment of rheumatoid arthritis with recombinant human interleukin‐1 receptor antagonist

OBJECTIVE To evaluate the efficacy and safety of interleukin-1 receptor antagonist (IL-1Ra) in patients with rheumatoid arthritis (RA). METHODS Patients with active and severe RA (disease duration <8 years) were recruited into a 24-week, double-blind, randomized, placebo-controlled, multicenter study. Doses of nonsteroidal antiinflammatory drugs and/or oral corticosteroids (< or =10 mg prednisolone daily) remained constant throughout the study. Any disease-modifying antirheumatic drugs that were being administered were discontinued at least 6 weeks prior to enrollment. Patients were randomized to 1 of 4 treatment groups: placebo or a single, self-administered subcutaneous injection of IL-1Ra at a daily dose of 30 mg, 75 mg, or 150 mg. RESULTS A total of 472 patients were recruited. At enrollment, the mean age, sex ratio, disease duration, and percentage of patients with rheumatoid factor and erosions were similar in the 4 treatment groups. The clinical parameters of disease activity were similar in each treatment group and were consistent with active and severe RA. At 24 weeks, of the patients who received 150 mg/day IL-1Ra, 43% met the American College of Rheumatology criteria for response (the primary efficacy measure), 44% met the Paulus criteria, and statistically significant improvements were seen in the number of swollen joints, number of tender joints, investigators assessment of disease activity, patients assessment of disease activity, pain score on a visual analog scale, duration of morning stiffness, Health Assessment Questionnaire score, C-reactive protein level, and erythrocyte sedimentation rate. In addition, the rate of radiologic progression in the patients receiving IL-1Ra was significantly less than in the placebo group at 24 weeks, as evidenced by the Larsen score and the erosive joint count. IL-1Ra was well tolerated and no serious adverse events were observed. An injection-site reaction was the most frequently observed adverse event, and this resulted in a 5% rate of withdrawal from the study among those receiving IL-1Ra at 150 mg/day. CONCLUSION This study confirmed both the efficacy and the safety of IL-1Ra in a large cohort of patients with active and severe RA. IL-1Ra is the first biologic agent to demonstrate a beneficial effect on the rate of joint erosion.

2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis

This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made — if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good.

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.

FRI0298 The Impact of DMARD Co-Therapy on Abatacept Effectiveness in Rheumatoid Arthritis Patients. A Pan-European Analysis of RA Registries

Background Biological disease-modifying anti-rheumatic drugs (bioDMARDs) are generally used in combination with conventional synthetic DMARDs (csDMARDs) in the treatment of rheumatoid arthritis (RA). Anti-TNF agents are more effective in combination with csDMARDs (COMBO) than as monotherapy (MONO), while this is debated with some of the newer bioDMARDs.(1) In particular, no difference was found in patients (pts) with insufficient response to TNF-inhibitors taking abatacept (ABA) in MONO vs. COMBO.(2) Objectives To compare the effectiveness of ABA started as MONO or in COMBO in RA pts treated in routine care. Methods This is a pooled observational database analysis of 9 prospective cohorts of RA pts (Czech Republic, Denmark, France, Italy, Norway, Portugal, Spain, Sweden, Switzerland). We included all RA pts treated with ABA with information on concomitant csDMARDs use at initiation of ABA treatment. Primary endpoint was drug retention of ABA, defined as the time between drug initiation and last administration plus one dispensation interval, and analyzed using a Cox proportional hazards model. A secondary endpoint was EULAR good or moderate response rate at one year, estimated by longitudinal interpolation and corrected for drug retention (Lundex (3)). All analyses were adjusted for potential confounders, e.g. calendar year, demographics, country and disease characteristics. Results We identified 3461 pts initiating ABA with 5475 pt-years of follow-up. Of these, 2314 pts (67%) received ABA in COMBO (53% - methotrexate, 8% - leflunomide, 6% - other csDMARDs) and 1147 pts (33%) in MONO. Pts on MONO were older (mean 59 vs. 57 years, p<0.001) and had longer disease duration (mean 11 vs. 12 years, p=0.005). Other demographic and disease characteristics were balanced. The median retention time of ABA in MONO was 2.02 years (IQR: 1.76 – 2.27) compared to 2.05 years (IQR: 1.90 – 2.22) in COMBO (p=0.76). No significant difference in ABA retention rates was found with or without sDMARD cotherapy (Hazard Ratio (HR) MONO vs COMBO: 1.02 (95%CI: 0.92 – 1.13)). Furthermore, ABA drug retention did not differ between the various sDMARDs cotherapy combinations. Results remained similar when examining only ABA treatment discontinuations for ineffectiveness (HR MONO vs COMBO: 0.97 (95%CI: 0.84 – 1.13)). Furthermore, both the EULAR response rates and the Lundex based on EULAR response rates at one year were similar with or without sDMARD cotherapy (81% EULAR good or moderate responses on ABA MONO vs. 80% on COMBO, p=0.55. Lundex responders 55% on ABA MONO vs. 55% on COMBO, p=0.91). We found no effect modification by country. Conclusions The results of this large pooled RA population of mostly inadequate responders to anti-TNFs, suggest that ABA retention and response to ABA treatment are not influenced by csDMARDs cotherapy. References Emery P. et al. Ann Rheum Dis. 2013 Dec;72(12):1897-904. Schiff M et al. Ann Rheum Dis 2009;68:1708–14. Kristensen LE. et al. Arthritis Rheum. 2006 Feb;54(2):600-6. Disclosure of Interest A. Finckh Grant/research support: Unrestricted Research grant from BMS, D. Neto Grant/research support: Unrestricted Research grant from BMS, J. Gomez-Reino: None declared, F. Iannone: None declared, E. Lie: None declared, H. Canhão: None declared, K. Pavelka: None declared, C. Turesson: None declared, X. Mariette: None declared, J.-E. Gottenberg: None declared, M. Hetland: None declared DOI 10.1136/annrheumdis-2014-eular.3004

Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: Findings of a fifty-two–week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study†‡

OBJECTIVE To evaluate the efficacy and safety of 2 dosage regimens of lyophilized certolizumab pegol (a novel PEGylated anti-tumor necrosis factor agent) as adjunctive therapy to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with an inadequate response to MTX therapy alone. METHODS In this 52-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 982 patients were randomized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0, 2, and 4, with a subsequent dosage of 200 mg or 400 mg given every 2 weeks, plus MTX, or placebo plus MTX. Co-primary end points were the response rate at week 24 according to the American College of Rheumatology 20% criteria for improvement (ACR20) and the mean change from baseline in the modified total Sharp score at week 52. RESULTS At week 24, ACR20 response rates using nonresponder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8% and 60.8%, respectively, as compared with 13.6% for the placebo group. Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 (P < 0.001). At week 52, mean radiographic progression from baseline was reduced in patients treated with certolizumab pegol 200 mg (0.4 Sharp units) or 400 mg (0.2 Sharp units) as compared with that in placebo-treated patients (2.8 Sharp units) (P < 0.001 by rank analysis). Improvements in all ACR core set of disease activity measures, including physical function, were observed by week 1 with both certolizumab pegol dosage regimens. Most adverse events were mild or moderate. CONCLUSION Treatment with certolizumab pegol 200 or 400 mg plus MTX resulted in a rapid and sustained reduction in RA signs and symptoms, inhibited the progression of structural joint damage, and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX.

EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis

The objective was to develop evidence -based recommendations and a research and educational agenda for the non-pharmacological management of hip and knee osteoarthritis (OA). The multidisciplinary task force comprised 21 experts: nurses, occupational therapists, physiotherapists, rheumatologists, orthopaedic surgeons, general practitioner, psychologist, dietician, clinical epidemiologist and patient representatives. After a preliminary literature review, a first task force meeting and five Delphi rounds, provisional recommendations were formulated in order to perform a systematic review. A literature search of Medline and eight other databases was performed up to February 2012. Evidence was graded in categories I–IV and agreement with the recommendations was determined through scores from 0 (total disagreement) to 10 (total agreement). Eleven evidence-based recommendations for the non-pharmacological core management of hip and knee OA were developed, concerning the following nine topics: assessment, general approach, patient information and education, lifestyle changes, exercise, weight loss, assistive technology and adaptations, footwear and work. The average level of agreement ranged between 8.0 and 9.1. The proposed research agenda included an overall need for more research into non-pharmacological interventions for hip OA, moderators to optimise individualised treatment, healthy lifestyle with economic evaluation and long-term follow-up, and the prevention and reduction of work disability. Proposed educational activities included the required skills to teach, initiate and establish lifestyle changes. The 11 recommendations provide guidance on the delivery of non-pharmacological interventions to people with hip or knee OA. More research and educational activities are needed, particularly in the area of lifestyle changes.

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

Objectives To review the evidence for the efficacy and safety of biological agents in patients with rheumatoid arthritis (RA) to provide data to develop treatment recommendations by the European League Against Rheumatism (EULAR) Task Force. Methods Medline, Embase and Cochrane databases were searched for relevant articles on infliximab (IFX), etanercept (ETN), adalimumab (ADA), certolizumab-pegol (CZP), golimumab (GLM), anakinra (ANA), abatacept (ABT), rituximab (RTX) and tocilizumab (TCZ) published between 1962 and February 2009; published abstracts from the 2007–2008 American College of Rheumatology (ACR) and EULAR conference were obtained. Results 87 articles and 40 abstracts were identified. In methotrexate (MTX) naïve patients, biological therapy with IFX, ETN, ADA, GLM or ABT has been shown to improve clinical outcomes (level of evidence 1B). In MTX/other synthetic disease-modifying antirheumatic drug (DMARD) failures all nine biological agents confer benefit (1B), with lower efficacy noted for ANA. RTX, ABT, TCZ and GLM demonstrate efficacy in tumour necrosis factor inhibitor (TNFi) failures (1B). Less evidence exists for switching between IFX, ETN and ADA (3B). Biological and MTX combination therapy is more efficacious than a biological agent alone (1B). A safety review shows no increased malignancy risk compared with conventional DMARDs (3B). TNFi are generally associated with an increased risk of serious bacterial infection, particularly within the first 6 months of treatment initiation; increased tuberculosis (TB) rates with TNFi are highest with the monoclonal antibodies (3B). Conclusions There is good evidence for the efficacy of biological agents in patients with RA. Safety data confirm an increased risk of bacterial infection and TB with TNFi compared with conventional DMARDs.