Jackie Nam

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.

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.

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis

Objectives To update the evidence for the safety of synthetic disease-modifying antirheumatic drugs (sDMARDs), glucocorticoids (GC) and biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism (EULAR) recommendations for the management of RA. Methods Systematic literature review (SLR) of observational studies (including registries). Interventions were any bDMARD (anakinra, infliximab, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab or certolizumab pegol) or sDMARD (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, gold/auranofin, azathioprine, chlorambucil, chloroquine, cyclosporin, cyclophosphamide, mycophenolate, minocycline, penicillamine, tacrolimus or tofacitinib) and a comparator was required. Information on GCs was collected from the included studies. All safety outcomes were included. Results Forty-nine observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria. Substantial heterogeneity precluded meta-analysis of any of the outcomes. Patients on tumour necrosis factor inhibitors (TNFi) compared to patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1–1.8), a higher risk of tuberculosis, and an increased risk of infection by herpes zoster cannot be excluded. Patients on TNFi did not have an increased risk for malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). From the studies identified on conventional sDMARDs, no new safety signals were found. Conclusions The findings from this SLR confirm the known safety pattern of sDMARDs and bDMARDs for the treatment of RA.

Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis

Objectives To update the evidence for the efficacy of biological disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism(EULAR) Task Force treatment recommendations. Methods Medline, Embase and Cochrane databases were searched for articles published between January 2009 and February 2013 on infliximab, etanercept, adalimumab, certolizumab-pegol, golimumab, anakinra, abatacept, rituximab, tocilizumab and biosimilar DMARDs (bsDMARDs) in phase 3 development. Abstracts from 2011 to 2012 American College of Rheumatology (ACR) and 2011–2013 EULAR conferences were obtained. Results Fifty-one full papers, and 57 abstracts were identified. The randomised controlled trials (RCT) confirmed the efficacy of bDMARD+conventional synthetic DMARDs (csDMARDs) versus csDMARDs alone (level 1B evidence). There was some additional evidence for the use of bDMARD monotherapy, however bDMARD and MTX combination therapy for all bDMARD classes was more efficacious (1B). Clinical and radiographic responses were high with treat-to-target strategies. Earlier improvement in signs and symptoms were seen with more intensive initial treatment strategies, but outcomes were similar upon addition of bDMARDs in patients with insufficient response to MTX. In general, radiographic progression was lower with bDMARD use, mainly due to initial treatment effects. Although patients may achieve bDMARD- and drug-free remission, maintenance of clinical responses was higher with bDMARD continuation (1B), but bDMARD dose reduction could be applied (1B). There was still no RCT data for bDMARD switching. Conclusions The systematic literature review confirms efficacy of biological DMARDs in RA. It addresses different treatment strategies with the potential for reduction in therapy, particularly with early disease control, and highlights emerging therapies.

Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis

Objectives To update a previous systematic review assessing the efficacy of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in rheumatoid arthritis (RA). Methods Two systematic reviews of the literature using PubMed, Embase and the Cochrane library were performed from 2009 until January 2013 to assess the efficacy of csDMARDs (as monotherapy or combination therapy) in adults with RA, and the efficacy of glucocorticoids in early RA. A third systematic review was performed until March 2013 to assess the efficacy of tofacitinib by meta-analysis. Results For glucocorticoids, of 222 hits, five publications relating to four new trials were analysed for efficacy, confirming that initial treatment of RA with low-dose prednisone plus methotrexate (MTX) results in better clinical and structural outcomes at 1 and 2 years than treatment with MTX alone. For csDMARDs, of 498 studies, only two new studies were randomised controlled trials comparing MTX monotherapy with MTX in combination with another csDMARD without differences in glucocorticoid usage. Using tight control principles, clinical outcomes were no better with immediate triple therapy than with ‘step-up’ therapy. For tofacitinib, the pooled analysis of 10 trials showed that tofacitinib was more efficacious on signs and symptoms, disability and appeared to be more efficacious on structural damage than control treatment with placebo (OR (95% CI)—American College of Rheumatology 20% (ACR20) response: 2.44 (1.97 to 3.02)) or treatment with MTX (ACR20 response: 2.38 (1.66 to 3.43)). Conclusions Addition of low-dose glucocorticoids to csDMARD therapy produces benefits in early RA. Under tight control conditions, combination therapy with csDMARDs is no better than MTX monotherapy. Tofacitinib is a new DMARD with proven efficacy.

Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study)

Objectives In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis (RA), to compare the efficacy of methotrexate (MTX) and infliximab (IFX) with MTX and intravenous corticosteroid for remission induction. Methods In a 78-week multicentre randomised controlled trial, double-blinded to week 26, 112 treatment-naive RA patients (1987 American College of Rheumatology classification criteria) with disease activity score 44 (DAS44)>2.4 were randomised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg. A treat-to-target approach was used with treatment escalation if DAS44>2.4. In the IFX group, IFX was discontinued for sustained remission (DAS44<1.6 for 6 months). The primary outcome was change in modified total Sharp-van der Heijde score (mTSS) at week 50. Results The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units, respectively (adjusted difference (95% CI) −1.45 (−3.35 to 0.45); p=0.132). Radiographic non-progression (mTSS<2.0) occurred in 81% vs 71% (OR 1.77 (0.56 to 5.61); p=0.328). DAS44 remission was achieved at week 50 in 49% and 36% (OR 2.13 (0.91 to 5.00); p=0.082), and at week 78 in 48% and 50% (OR 1.12 (0.47 to 2.68); p=0.792). Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group. Of the IFX group, 25% (14/55) achieved sustained remission and stopped IFX. No substantive differences in adverse events were seen. Conclusions In DMARD-naive early RA patients, initial therapy with MTX+high-dose intravenous steroid resulted in good disease control with little structural damage. MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach.

Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study

Objectives To monitor progression to inflammatory arthritis (IA) in individuals with non-specific musculoskeletal (MSK) symptoms and positive anticyclic citrullinated peptide (anti-CCP) antibodies. To develop a pragmatic model to predict development of IA in this patient group. Methods In this prospective observational cohort, patients with new non-specific MSK symptoms and positive anti-CCP were recruited from regional primary care and secondary care referrals. Clinical, imaging and serological parameters were assessed at baseline. Cox regression analysis was performed to identify predictors of progression to IA and develop a risk score to stratify patients at presentation. Findings 100 consecutive patients (73 women, mean age 51 years) were followed up for median 19.8 months (range 0.1–69.0); 50 developed IA after a median 7.9 months (range 0.1–52.4), 34 within 12 months. The majority (43/50) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis. A model for progression to IA was devised using four variables: tenderness of hand or foot joints, early morning stiffness ≥30 min, high-positive autoantibodies, and positive ultrasonographic power Doppler signal. None of the five individuals at low risk (score 0) progressed to IA, compared with 31% of 29 at moderate risk (1–2) and 62% of 66 at high risk (≥3). Adding shared epitope increased the number at low risk (score 0–1; 0/11 progressed). Conclusions In patients presenting with non-specific MSK symptoms and anti-CCP, the risk of progression to IA could be quantified using data available in clinical practice. The proposed risk score may be used to stratify patients for early therapeutic intervention. Trial registration number NCT02012764 at ClinicalTrials.gov.

A systematic literature review of strategies promoting early referral and reducing delays in the diagnosis and management of inflammatory arthritis

Background Despite the importance of timely management of patients with inflammatory arthritis (IA), delays exist in its diagnosis and treatment. Objective To perform a systematic literature review to identify strategies addressing these delays to inform an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) taskforce. Methods The authors searched literature published between January 1985 and November 2010, and ACR and EULAR abstracts between 2007–2010. Additional information was obtained through a grey literature search, a survey conducted through ACR and EULAR, and a hand search of the literature. Results (1) From symptom onset to primary care, community case-finding strategies, including the use of a questionnaire and autoantibody testing, have been designed to identify patients with early IA. Several websites provided information on IA but were of varying quality and insufficient to aid early referral. (2) At a primary care level, education programmes and patient self-administered questionnaires identified patients with potential IA for referral to rheumatology. Many guidelines emphasised the need for early referral with one providing specific referral criteria. (3) Once referred, early arthritis clinics provided a point of early access for rheumatology assessment. Triage systems, including triage clinics, helped prioritise clinic appointments for patients with IA. Use of referral forms standardised information required, further optimising the triage process. Wait times for patients with acute IA were also reduced with development of rapid access systems. Conclusions This review identified three main areas of delay to care for patients with IA and potential solutions for each. A co-ordinated effort will be required by the rheumatology and primary care community to address these effectively.

Is There Subclinical Synovitis in Early Psoriatic Arthritis? A Clinical Comparison With Gray‐Scale and Power Doppler Ultrasound

Arthritis activity assessments in psoriatic arthritis (PsA) have traditionally relied on tender and swollen joint counts, but in rheumatoid arthritis, multiple studies have demonstrated subclinical inflammation using modern imaging. The aim of this study was to compare clinical examination and ultrasound (US) findings in an early PsA cohort.

FcγRIIIa Expression on Monocytes in Rheumatoid Arthritis: Role in Immune-Complex Stimulated TNF Production and Non-Response to Methotrexate Therapy

Objective The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. Methods FcγRIIIa/CD16 expression on CD14low and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. Results Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. Conclusion Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy.