Safety of combination therapies in early rheumatoid arthritis: a systematic comparison between antirheumatic drugs and TNF inhibitors with methotrexate

Rheumatoid arthritis (RA) is a chronic inflammatory disease requiring long-term suppressive treatment. Early combination therapies using diseasemodifying antirheumatic drugs (DMARDs) or TNF inhibitors with methotrexate (TNFi/MTX) have been shown to be more efficacious than DMARD monotherapy in terms of clinical outcomes, disability and radiological progression [1–3]. New guidelines all recommend the early use of these intensive therapies in the ‘window of opportunity’ [4,5,101]. As therapies become increasingly intensive and aggressive, drug toxicity is now a crucial issue. Conventional synthetic DMARDs include MTX, sulfasalazine, hydroxychloroquine, leflunomide, cyclosporine and azathioprine. The majority of DMARD agents can cause bone marrow suppression, serious infections, liver damage and gastrointestinal disturbance. In addition, cyclosporine can also cause renal dysfunction, hirsutism and gingival hypertrophy. Toxicity of TNFi include serious infections, bone marrow suppression, reactivation of TB and serious infections. There are also concerns related to malignancy, worsening of heart failure and demyelination. Close monitoring of patients is recommended whilst on any synthetic DMARD or biological therapies. Evidence for risk of malignancy in TNF blockade is conflicting. A systematic review of infliximab and adalimumab found an increased risk of malignancy when compared with placebo therapy [6]. In addition, in the British Society for Rheumatology Biologics Register (BSRBR), patients with a history of malignancy were also at greater risk of developing new malignancies [7]. However, other registries (RABBIT and BIOBADASER) found no increase in malignancies in their cohorts compared with the general RA population [8,9]. In view of the adverse events related to individual DMARDs, there are concerns over the potential increase in toxicity when these agents are combined. This systematic review aims to compare the effects of combination DMARDs and anti-TNF with MTX (TNFi/MTX) to MTX monotherapy.