1.Introduction131.1.The current role of methotrexate in the treatment of rheumatoid arthritis131.2.History of methotrexate treatment131.2.1.The beginnings131.2.2.Early studies for rheumatoid arthritis141.2.3.Placebo-controlled short-term studies141.2.4.Comparative studies with rarely used standard therapeutic agents151.2.4.1.Meta-analysis of early DMARD comparative studies181.2.5.Assessment of potential methotrexate toxicity181.3.Recommendations and guidelines for the treatment of rheumatoid arthritis191.4.References202.Pharmacology of methotrexate232.1.Structure232.2.Absorption and route of administration232.3.Pharmacokinetics and metabolization242.4.Mechanism of action252.5.Folic acid supplementation272.6.Methotrexate effect as a combination partner with biologics282.7.Genetic markers as predictors of methotrexate effect282.8.Interactions282.9.Dosage in elderly patients and in renal insufficiency292.10.References313.Methotrexate monotherapy in rheumatoid arthritis343.1.Effectivity in long-term studies343.1.1.Long-term observational studies343.1.2.Influence on life expectancy and the Ratingen long-term study343.2.Effectivity in old age, steroid-sparing effect353.3.Influence on functional capacity363.4.Duration of treatment as an indicator of effectivity363.5.Comparison with leflunomide373.6.Methotrexate monotherapy vs triple therapy373.7.Comparison with biologics383.7.1.Etanercept383.7.2.Adalimumab393.7.3.Abatacept403.7.4.Tocilizumab403.8.New substances, small molecules413.8.1.Tofacitinib413.8.2.Baricitinib413.8.3.Upadacitinib413.8.4.Filgotinib423.8.5.Side effects of JAK inhibitors423.9.References424.Methotrexate as a component of combination therapy for rheumatoid arthritis454.1.Studies with MTX/csDMARD combinations that are no longer or rarely used today454.1.1.Azathioprine and D-penicillamine / bucillamine454.1.2.Gold464.1.3.Ciclosporin A464.2.Studies with commonly used MTX-csDMARD combinations474.2.1.Leflunomide474.2.2.Triple combination MTX + SSZ + HCQ (O'Dell regimen)484.2.3.Combinations MTX + SSZ and MTX + HCQ / MTX + CQ504.2.4.Studies using the COBRA regimen504.3.Studies on the combination of methotrexate + TNF inhibitors514.3.1.Infliximab514.3.2.Etanercept524.3.3.Adalimumab544.3.4.Certolizumab pegol and golimumab544.4.Studies on the combination of methotrexate with non-TNF biologics564.5.Studies on the combination of methotrexate with JAK inhibitors604.6.References615.Influence of methotrexate on radiographic progression675.1.Radiographic progression in open long-term studies675.2.Comparison of progression before and during methotrexate treatment685.3.Comparison of progression using methotrexate vs other basic therapeutic agents695.3.1.Comparison with azathioprine695.3.2.Comparison with auranofin695.3.3.Comparison with aurothiomalate695.3.4.Comparison with sulfasalazine705.3.5.Comparison with leflunomide705.3.6.Comparison with various other DMARDs705.4.Comparison of methotrexate / placebo with respect to inhibition of progression705.5.Comparison of methotrexate / biologics or small molecules (JAK inhibitors) with respect toinhibition of progression715.6.References756.Methotrexate for spondyloarthritis, vasculitis and connective tissue diseases786.1.Spondyloarthritis786.1.1.Psoriatic arthritis786.2.Arteritis and vasculitis796.2.1.Giant cell arteritis796.2.2.Vasculitis of small and medium-sized vessels796.3.Connective tissue diseases806.3.1.Systemic lupus erythematosus806.3.2.Systemic sclerosis806.3.3.Poly- and dermatomyositis816.3.4.Mixed connective tissue disease826.4.Summary826.5.References827.Methotrexate in childhood and adolescence847.1.Efficacy in juvenile idiopathic arthritis847.2.Juvenile idiopathic arthritis-associated uveitis867.3.Predi