1. Introduction 13
1.1. The current role of methotrexate in the treatment of rheumatoid arthritis 13
1.2. History of methotrexate treatment 13
1.2.1. The beginnings 13
1.2.2. Early studies for rheumatoid arthritis 14
1.2.3. Placebo-controlled short-term studies 14
1.2.4. Comparative studies with rarely used standard therapeutic agents 15
1.2.4.1. Meta-analysis of early DMARD comparative studies 18
1.2.5. Assessment of potential methotrexate toxicity 18
1.3. Recommendations and guidelines for the treatment of rheumatoid arthritis 19
1.4. References 20
2. Pharmacology of methotrexate 23
2.1. Structure 23
2.2. Absorption and route of administration 23
2.3. Pharmacokinetics and metabolization 24
2.4. Mechanism of action 25
2.5. Folic acid supplementation 27
2.6. Methotrexate effect as a combination partner with biologics 28
2.7. Genetic markers as predictors of methotrexate effect 28
2.8. Interactions 28
2.9. Dosage in elderly patients and in renal insufficiency 29
2.10. References 31
3. Methotrexate monotherapy in rheumatoid arthritis 34
3.1. Effectivity in long-term studies 34
3.1.1. Long-term observational studies 34
3.1.2. Influence on life expectancy and the Ratingen long-term study 34
3.2. Effectivity in old age, steroid-sparing effect 35
3.3. Influence on functional capacity 36
3.4. Duration of treatment as an indicator of effectivity 36
3.5. Comparison with leflunomide 37
3.6. Methotrexate monotherapy vs triple therapy 37
3.7. Comparison with biologics 38
3.7.1. Etanercept 38
3.7.2. Adalimumab 39
3.7.3. Abatacept 40
3.7.4. Tocilizumab 40
3.8. New substances, small molecules 41
3.8.1. Tofacitinib 41
3.8.2. Baricitinib 41
3.8.3. Upadacitinib 41
3.8.4. Filgotinib 42
3.8.5. Side effects of JAK inhibitors 42
3.9. References 42
4. Methotrexate as a component of combination therapy for rheumatoid
arthritis 45
4.1. Studies with MTX/csDMARD combinations that are no longer or rarely used today 45
4.1.1. Azathioprine and D-penicillamine / bucillamine 45
4.1.2. Gold 46
4.1.3. Ciclosporin A 46
4.2. Studies with commonly used MTX-csDMARD combinations 47
4.2.1. Leflunomide 47
4.2.2. Triple combination MTX + SSZ + HCQ (O'Dell regimen) 48
4.2.3. Combinations MTX + SSZ and MTX + HCQ / MTX + CQ 50
4.2.4. Studies using the COBRA regimen 50
4.3. Studies on the combination of methotrexate + TNF inhibitors 51
4.3.1. Infliximab 51
4.3.2. Etanercept 52
4.3.3. Adalimumab 54
4.3.4. Certolizumab pegol and golimumab 54
4.4. Studies on the combination of methotrexate with non-TNF biologics 56
4.5. Studies on the combination of methotrexate with JAK inhibitors 60
4.6. References 61
5. Influence of methotrexate on radiographic progression 67
5.1. Radiographic progression in open long-term studies 67
5.2. Comparison of progression before and during methotrexate treatment 68
5.3. Comparison of progression using methotrexate vs other basic therapeutic agents 69
5.3.1. Comparison with azathioprine 69
5.3.2. Comparison with auranofin 69
5.3.3. Comparison with aurothiomalate 69
5.3.4. Comparison with sulfasalazine 70
5.3.5. Comparison with leflunomide 70
5.3.6. Comparison with various other DMARDs 70
5.4. Comparison of methotrexate / placebo with respect to inhibition of progression 70
5.5. Comparison of methotrexate / biologics or small molecules (JAK inhibitors) with respect to
inhibition of progression 71
5.6. References 75
6. Methotrexate for spondyloarthritis, vasculitis and connective tissue
diseases 78
6.1. Spondyloarthritis 78
6.1.1. Psoriatic arthritis 78
6.2. Arteritis and vasculitis 79
6.2.1. Giant cell arteritis 79
6.2.2. Vasculitis of small and medium-sized vessels 79
6.3. Connective tissue diseases 80
6.3.1. Systemic lupus erythematosus 80
6.3.2. Systemic sclerosis 80
6.3.3. Poly- and dermatomyositis 81
6.3.4. Mixed connective tissue disease 82
6.4. Summary 82
6.5. References 82
7. Methotrexate in childhood and adolescence 84
7.1. Efficacy in juvenile idiopathic arthritis 84
7.2. Juvenile idiopathic arthritis-associated uveitis 86
7.3. Predictors of treatment response in juvenile idiopathic arthritis 86
7.4. Dosage and form of administration of methotrexate in pediatric rheumatology 88
7.5. Tolerability of methotrexate 88
7.6. Adherence to therapy 89
7.7. References 91
8. Methotrexate for dermatological indications 93
8.1. Mechanisms of action of methotrexate in the skin 93
8.2. Methotrexate in the treatment of psoriasis vulgaris 93
8.2.1. Methotrexate as monotherapy for chronic plaque psoriasis 93
8.2.2. Methotrexate for other forms of psoriasis 94
8.2.2.1. Pustular psoriasis and nail psoriasis 94
8.2.3. Methotrexate in combination with other therapeutic agents 94
8.2.3.1. Combination with external therapeutic agents 94
8.2.3.2. Combinations with systemic therapeutics 95
8.2.4. Psoriasis-specific safety aspects of the use of methotrexate 96
8.3. Methotrexate in the treatment of localized scleroderma 98
8.4. Methotrexate in the treatment of bullous dermatoses 99
8.4.1. Bullous pemphigoid and related diseases 99
8.4.2. Pemphigus vulgaris 99
8.5. Methotrexate in the treatment of atopic dermatitis 99
8.6. Methotrexate for the treatment of rare skin diseases 100
8.7. References 100
9. Methotrexate in gastroenterology 102
9.1. Methotrexate for Crohn's disease 102
9.2. Methotrexate for ulcerative colitis 104
9.3. Mechanism of action of methotrexate in chronic inflammatory bowel disease 104
9.4. Side effects of methotrexate therapy for gastrointestinal diseases 105
9.5. Risk management when using methotrexate for chronic inflammatory bowel disease 105
9.6. Methotrexate for other gastroenterological diseases 106
9.7. Summary 106
9.8. References 106
10. Side effects of methotrexate 108
10.1. Toxicity of methotrexate compared to other standard therapeutic agents 108
10.2. Predictors of methotrexate toxicity 108
10.3. Gastrointestinal side effects 109
10.3.1. Hepatotoxicity 109
10.4. Pulmonary toxicity 109
10.5. Hematological toxicity 110
10.6. Side effects affecting the skin, mucous membranes and subcutaneous tissue 110
10.7. Infections 111
10.8. Drug interactions 111
10.9. Carcinogenicity 112
10.10. Teratogenicity and pregnancy 112
10.11. Rate of side effects depending on the route of administration and concomitant
medication 112
10.12. Summary 113
10.13. References 113
11. Methotrexate and family planning 117
11.1. Planning a pregnancy 117
11.2. Conception 117
11.3. Consequences of (accidental) use during pregnancy 118
11.4. Breastfeeding 118
11.5. References 118
12. Abbreviations 119
Index 121
