Objectives To summarise, by a systematic literature review (SLR), the evidence regarding pharmacological and non-pharmacological therapeutic strategies in difficult-to-treat rheumatoid arthritis (D2T RA), informing the EULAR recommendations for the management of D2T RA.
Methods PubMed, Embase and Cochrane databases were searched up to December 2019. Relevant papers were selected and appraised.
Results Two hundred seven (207) papers studied therapeutic strategies. Limited evidence was found on effective and safe disease-modifying antirheumatic drugs (DMARDs) in patients with comorbidities and other contraindications that limit DMARD options (patients with obesity, hepatitis B and C, risk of venous thromboembolisms, pregnancy and lactation). In patients who previously failed biological (b-)DMARDs, all currently used b/targeted synthetic (ts-)DMARDs were found to be more effective than placebo. In patients who previously failed a tumour necrosis factor inhibitor (TNFi), there was a tendency of non-TNFi bDMARDs to be more effective than TNFis. Generally, effectiveness decreased in patients who previously failed a higher number of bDMARDs. Additionally, exercise, psychological, educational and self-management interventions were found to improve non-inflammatory complaints (mainly functional disability, pain, fatigue), education to improve goal setting, and self-management programmes, educational and psychological interventions to improve self-management.
The identified evidence had several limitations: (1) no studies were found in patients with D2T RA specifically, (2) heterogeneous outcome criteria were used and (3) most studies had a moderate or high risk of bias.
Conclusions This SLR underscores the scarcity of high-quality evidence on the pharmacological and non-pharmacological treatment of patients with D2T RA. Effectiveness of b/tsDMARDs decreased in RA patients who had failed a higher number of bDMARDs and a subsequent b/tsDMARD of a previously not targeted mechanism of action was somewhat more effective. Additionally, a beneficial effect of non-pharmacological interventions was found for improvement of non-inflammatory complaints, goal setting and self-management.
- biological therapy
- occupational therapy
- patient reported outcome measures
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Presented at Parts of this manuscript have been presented at EULAR 2020 (Roodenrijs NMT, Hamar A, Kedves MH, et al. SAT0052 Therapeutic strategies in difficult-to-treat rheumatoid arthritis: preliminary results of a systematic literature review informing the 2020 EULAR recommendations for the management of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2020;79:953, and Roodenrijs NMT, Hamar A, Kedves MH, et al. FRI0047 Strategies regarding goal setting and self-management in difficult-to-treat rheumatoid arthritis: preliminary results of a systematic literature review informing the 2020 EULAR recommendations for the management of difficult-totreat rheumatoid arthritis. Ann Rheum Dis 2020;79:595).
Contributors NMTR drafted the clinical questions, performed the systematic literature review including risk of bias assessment, contributed to data analysis and interpretation of data, and drafted the manuscript. AH and MK contributed to the systematic literature review including risk of bias assessment. GN, JMvL and DvdH contributed to interpretation of data and manuscript preparation. PMJW drafted the clinical questions, supervised the systematic literature review including risk of bias assessment, contributed to interpretation of data and manuscript preparation. All authors reviewed and approved the final manuscript.
Funding This project was funded by the European League Against Rheumatism.
Competing interests NMTR, AH, MK and PMJW declare to have no competing interests. GN received fees from Amgen, AbbVie, BMS, Boehringer Ingelheim, Janssen, KRKA, Merck, MSD, Novartis, Pfizer, Roche and UCB; research grants from Pfizer and AbbVie. JMvL reports personal fees from Arxx Tx, Gesyntha, Magenta, Sanofi Genzyme, Leadiant, Boehringer-Ingelheim and Galapagos; grants and personal fees from Roche; grants from AstraZeneca, MSD, ThermoFisher. DvdH received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB. All competing interests are outside the submitted work.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available from the corresponding author upon reasonable request.
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