In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at

/pdf/eular-recommendations-for-the-management-of-rheumatoid-4fujp4paik.pdf

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

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.

Treating rheumatoid arthritis to target: recommendations of an international task force (vol 69, pg 631, 2010)

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-a-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.

https://ard.bmj.com/content/annrheumdis/69/6/964.full.pdf

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

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 specifi c 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.

https://ard.bmj.com/content/annrheumdis/early/2011/03/06/ard.2010.144998.full.pdf

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

Objectives Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA). Methods Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme. Results As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had >5 years’ follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/ 100 patient-years (3.26/100 patient-years in patients observed for >5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ≥4 months after ≥1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed. Conclusions This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation.

https://ard.bmj.com/content/annrheumdis/72/9/1496.full.pdf

Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients

Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naive to prior biological treatment. Methods Patients with active disease on stable MTX (10–25 mg/week) were randomised to rituximab 2×500 mg (n=168), rituximab 2×1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) ≥2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2×500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. Results At week 24, both doses of rituximab showed statistically superior efficacy (p Conclusions Rituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses.

https://ard.bmj.com/content/annrheumdis/69/9/1629.full.pdf

Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE))

Objective

To assess the effect of rituximab plus methotrexate (MTX) compared with MTX alone on patient-reported outcomes (PROs) and health-related quality of life (HRQOL) in patients with active early rheumatoid arthritis (RA) previously untreated with MTX.



Methods

Patients with active early RA were randomized to groups receiving placebo, rituximab 500 mg, or rituximab 1,000 mg. Rituximab was given by intravenous infusion on days 1 and 15. From week 24, patients with a Disease Activity Score in 28 joints–erythrocyte sedimentation rate of ≥2.6 were eligible for retreatment. Physical function was assessed by Health Assessment Questionnaire (HAQ) disability index (DI) and Short Form 36 (SF-36) scores. Patients achieving a minimal clinically important difference (MCID) for PROs were determined. Additional PROs, including fatigue and pain, were assessed.



Results

A total of 748 patients were randomized and received the study drug. Patient characteristics were well balanced. At week 52, treatment with rituximab in both dose groups showed significant improvements in the HAQ DI compared to the MTX alone group (−0.905 and −0.916 in the rituximab 500 mg plus MTX and 1,000 mg plus MTX groups, respectively, versus −0.628 in the MTX alone group; P < 0.0001). Higher proportions of patients achieved MCID in the HAQ DI in the rituximab plus MTX groups compared to MTX alone. Treatment with rituximab plus MTX led to a significant reduction in the SF-36 physical component summary for both rituximab dose groups, but did not show statistically significant differences in the SF-36 mental component summary. Compared to the MTX alone group, both doses of rituximab plus MTX were associated with significant reductions in the patient global assessment of disease activity and pain, and a significantly higher improvement in Functional Assessment of Chronic Illness Therapy–Fatigue scores from baseline to 52 weeks.



Conclusions

Rituximab plus MTX was associated with significant improvement in physical function and HRQOL outcomes compared with MTX alone in patients previously untreated with MTX.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/acr.20419

Gillian Armstrong

Papers

Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE))

Effect of rituximab on physical function and quality of life in patients with rheumatoid arthritis previously untreated with methotrexate.