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

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]