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Table 4 The mechanism of action and side effects of commonly used medications for JIA treatment. DMARDs - disease-modifying anti-rheumatic drugs, GC – glucocorticoids, ERA - enthesitis-related arthritis, IL - interleukin, NK - natural killer, MAS – macrophage activation syndrome, MTX – Methotrexate, sJIA – systemic JIA, TNF - tumor necrosis factor

From: Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches

Drug Mechanism of Action Therapeutic Options Adverse Event Reference
Non-Biologic DMARDs
 MTX • MTX is a structural analogue of folic acid that inhibits dihydrofolate reductase and DNA synthesis• Acts in different pathway: cytokine production, arachidonic acid metabolism and cell apoptosis • Polyarticular JIA• Oligoarticular JIA• JIA-related uveitis refractory to topical treatment• sJIA with predominant joint inflammation and without active systemic symptoms• Psoriatic JIA • Nausea• Oral ulceration• Infections (herpes zoster)• Severe complications in less than 1% of cases include:- Cirrhosis- Pneumonitis- Leucopenia- Thrombocytopenia- Anaemia [49,50,51, 53, 54]
 Leflunomide • Inhibition of T-cell proliferation by blocking pyrimidine synthesis • Polyarticular JIA patients who cannot tolerate MTX• Used rarely in pediatric patients because of its teratogenicity and long half-life • Diarrhoea• Rashes• Cytopenia• Abnormal liver-function test• Teratogenicity [52]
 Sulfasalazine • Immune-suppressive effect not fully established • ERA with moderate activity, but not in other types of JIA • Gastrointestinal toxicity• Sulphonamide allergy• Neuropsychiatric complications (headache, anxiety)• Pancytopenia• Pneumonitis• Myelosuppression• Hypogammaglobulinaemia [18, 54]
Biologic DMARDs
 TNF inhibitors
  Adalimumab • Subcutaneous recombinant human IgG1κ monoclonal antibody• Neutralises TNFα by binding with soluble and membrane-bound TNF • JIA patients with resistance or intolerance to MTX• Polyarticular JIA• JIA with uveitis• ERA refractory to sulfasalazine• Psoriatic JIA • Risk of reactivation of latent infections such as tuberculosis, and new infections caused by viruses, fungi, or bacteria• Rare reports of:- Lymphoma- Demyelinating central nervous system disorders- Cardiac failure [58]
  Infliximab • Intravenous chimeric monoclonal antibody against TNFα• Binding with soluble and transmembrane TNFα, that mediates complement and antibody-dependent cytotoxicity of expressed TNFα cells (macrophages and monocytes) • Polyarticular JIA where there has been the use of MTX for at least 3 months with poor response• Uveitis• Psoriatic JIA • Opportunistic infections: herpes, tuberculosis, pseudomonas pneumonia, reactivation of hepatitis B, fungal infection [56, 57]
  Etanercept • Fusion protein consisting of the extracellular domain of the human p75 TNFα receptor• Linked to the Fc region of human IgG1, binds and inhibits soluble TNFα • Polyarticular JIA with resistance or intolerance to MTX• ERA• Psoriatic JIA • Central nervous system events (headache, neuritis)• Varicella infections• Rare:- Malignancy [54,55,56]
 IL1 inhibitors
  Anakinra • Recombinant IL1 receptor antagonist binds to IL1 receptors (IL1r1)• Inhibits the binding of IL1α and IL1β • Refractory sJIA with persistent systemic symptoms• MAS - Vomiting, nausea, diarrhea- Headache- Abdominal pain- Upper respiratory and urinary tract infections- Neutropenia [61, 63]
  Canakinumab • Human Monoclonal antibody• Selectively blocks IL1β • sJIA patients with continued disease activity after treatment with GC monotherapy and MTX or leflunomide, anakinra or tocilizumab • Thrombocytopenia• Neutropenia• Upper respiratory tract infection• Cough• Abdominal pain• Gastroenteritis, vomiting, diarrhea• Pyrexia• Very rare:- pneumococcal sepsis [64]
  Rilonacept • Fusion protein between the Fc portion of IgG and the IL1 receptor• Blocks the interaction of IL1 with cell surface receptors preventing IL1 signalling • Active sJIA • Infections• Developed elevations in liver transaminases• High cholesterol or triglycerides• Abdominal pain• Gastroenteritis, nausea, diarrhea [67]
 T-cell inhibitors
  Abatacept • Inhibitor of naïve T-cell activation• Soluble fusion protein of CTLA-4 with the Fc portion of IgG that binds to CD80/CD86 and blockades signal following MHC-peptide: TCR engagement necessary for T cell activation • Severe sJIA• Polyarticular JIA patients with inadequate response to MTX and TNF-blockers • Bacterial and opportunistic infections• Rare:- acute lymphoblastic leukemia [54, 59]
 IL6 inhibitors
  Tocilizumab • Humanised monoclonal antibody against the IL6 ubiquitous receptor (IL-6R)• Block IL6 signaling pathway by binding to cell-surface and soluble IL-6R • sJIA• Polyarticular JIA with resistance and continued disease activity after treatment with MTX and TNF-blockers • Headache• Upper respiratory tract infections (more than 10%)• Varicella, herpes zoster• Neutropenia• Elevation of aminotransferases [30, 31]
 Anti-B-cells therapy
  Rituximab • Chimeric monoclonal antibody against B-cells with mouse variable and human constant regions• Binds CD20 on the surface of B-cells forming a cap that allow NK cells to destroy B cells• Leads to B-cell death and removal from circulation • JIA refractory to anti-TNF agents and standard immunosuppressive therapy • Infusion reactions (headache, throat irritation, rash, itchiness, pyrexia) in one third of patients• Bacterial infections• Hepatitis B reactivation• Rare:- cardiac arrest- cytokine release syndrome- multifocal leukoencephalopathy- pulmonary toxicity [54, 70]
Janus Kinase (JAK) inhibitors
 Tofacitinib • Inhibit JAK1 and JAK3• Interrupt the JAK-STAT signalling pathway, which is responsible for the transmission of extracellular multiple proinflammatory cytokines, including IL-6, into the nucleus, leading to changes in DNA transcriptome • Refractory polyarticular JIA• sJIA refractory to other therapy • Diarrhea• Headache• High blood pressure• Upper respiratory tract infections• Varicella zoster virus reactivation• Cytomegalovirus infection• Pulmonary embolism• Rare:- Lymphoma or other malignancies [74]
Other medications
 Glucocorticoids (GC) • Binding to glucocorticoid receptors inhibits calcium and sodium cycle across plasma membranes, reducing activation and proliferation of immune cells• Post-transciptional destabilisation of messenger RNA resulting in reduced production of proinflammatory cytokines including IL1 and IL6 √ Systemic steroids for:• sJIA with serious organ involvement (including pericarditis, myocarditis)• Patients with features indicative of MAS• High disease activity in oligo- and polyarticular JIA• Intraarticular steroids for oligo- and polyarticular JIA • Infections• Myopathy• Neuropsychiatric symptoms• Osteoporosis• Obesity• Insulin resistance• Cushing syndrome• Gastric ulcer• Cataract• Glaucoma [48]
 Cyclosporine A • A fungal cyclic polypeptide• Binds to the cellular protein cytophilin, resulting in inhibition of the enzyme calcineurin• Specifically and reversibly inhibits CD4+ immunocompetent lymphocytes in the G0-G1 phase of the cell cycle• Then inhibits IL2 production and release by T-helpers • sJIA with indication of MAS • Nausea• Headache• Renal complications• Neuronal complications (paresthesia),• Hepatotoxiety [48]