Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

polyarticular JIA: 5 or more joints ever involved

1st line – conventional synthetic disease-modifying antirheumatic drug (DMARD)

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ONGOING
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polyarticular JIA: 5 or more joints ever involved
1st line – 

conventional synthetic disease-modifying antirheumatic drug (DMARD)

Patients with JIA should be managed by a specialist pediatric rheumatology multidisciplinary team.[60] 

Synthetic DMARDs are used as initial therapy for children with polyarticular JIA.[61] 

Methotrexate is first-line and can be given orally, subcutaneously, or intramuscularly. Randomized controlled trials have demonstrated improvement in joint symptoms and a reduction in disease activity with methotrexate.[71][72] Folic acid is usually given concomitantly to decrease the side effects of methotrexate, and antiemetics may be used to reduce nausea. Patients should be counseled to avoid alcohol and pregnancy while taking methotrexate. 

Before starting methotrexate, a complete blood count, serum creatinine, and liver enzymes should be checked. Measurements should be repeated every 3 to 4 months during treatment.[73] Patients at risk of hepatitis B or hepatitis C infection should have a screening antibody test before starting methotrexate.[62] Elevation of aspartate aminotransferase or alanine aminotransferase above 2 times the upper limit justifies temporary suspension of methotrexate, which can be re-started following normalization of serum liver enzyme levels.[62]

Some trials have demonstrated the safety and efficacy of leflunomide as a second-line conventional synthetic DMARD in pediatric patients who are intolerant or unresponsive to methotrexate. Most of the pediatric patients responsive to leflunomide maintained their response in a 2-year open-label extension study.[74] 

Sulfasalazine may also be used as a second-line option.[61]

Primary options

methotrexate: children ≥2 years of age and adolescents: 10-15 mg/square meter of body surface area orally/subcutaneously/intramuscularly once weekly on the same day of each week, adjust dose according to response, maximum 25 mg/week

More

Secondary options

leflunomide: children and adolescents: consult specialist for guidance on dose

OR

sulfasalazine: children ≥6 years of age and adolescents: 30-50 mg/kg/day orally given in 2 divided doses, maximum 2000 mg/day

Plus – supportive care

Back
ONGOING
|
polyarticular JIA: 5 or more joints ever involved
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[60] Ongoing input from physical therapists and occupational therapists is required.[60] 

Patients with JIA have an increased risk of psychiatric morbidity.[70] Support and strategies for managing any difficulties should be provided.[60]

Consider – biologic agent

Back
ONGOING
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polyarticular JIA: 5 or more joints ever involved
Consider – 

biologic agent

Treatment recommended for SOME patients in selected patient group

This therapy is typically given in addition to a conventional synthetic DMARD. It may be given as part of initial therapy in patients with risk factors for a poor prognosis, or started after an inadequate response to a conventional synthetic DMARD.[61] Risk factors for poor prognosis include: presence of anticyclic citrullinated peptide antibodies, presence of rheumatoid factor, joint damage at presentation, high-risk joint involvement (cervical spine, wrist, or hip), high disease activity, or patient judged by physician to be at high risk of disabling joint damage.[61]

A tumor necrosis factor (TNF)-alpha inhibitor is first-line. Treatment with etanercept or adalimumab is preferred to treatment with infliximab. Infliximab carries a risk of infusion-associated reactions and is not approved for the treatment of any form of JIA.

Tocilizumab (an interleukin-6 inhibitor) or abatacept (a fusion protein) are used if the patient does not respond to a TNF-alpha inhibitor.

Caution is advised in patients with recurrent infections, conditions predisposing to infections, preexisting demyelinating disorders, or hematologic diseases, due to the immunosuppressive nature of these medicines.[84] One study evaluating etanercept and adalimumab showed an increase in number of infections but no clear evidence that the overall malignancy risk was increased.[79] Chronic carriers of tuberculosis and hepatitis B are susceptible to disease reactivation. Tuberculosis skin tests, and viral hepatitis screening for patients with risk factors for infection, are recommended prior to treatment.[62][84] Live vaccines should be avoided during treatment.[85]

Serious hepatotoxicity (including acute liver failure, hepatitis, and jaundice) has been identified with tocilizumab. The American College of Rheumatology recommends monitoring alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at initiation of treatment, within 4 to 8 weeks of treatment and every 3 to 4 months thereafter.[73] Be cautious when considering starting tocilizumab treatment in patients with ALT or AST levels higher than 1.5 times the upper limit of normal. Tocilizumab is not recommended if ALT or AST levels are higher than 5 times the upper limit of normal. If liver enzyme abnormalities are identified, consider a dose modification (reduction, interruption, or discontinuation) according to the manufacturer’s recommendations.[87] 

Primary options

adalimumab: children ≥2 years of age and adolescents (10-14 kg body weight): 10 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (15-29 kg body weight): 20 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (≥30 kg body weight): 40 mg subcutaneously every 2 weeks

OR

etanercept: children ≥2 years of age and adolescents (<63 kg body weight): 0.8 mg/kg subcutaneously once weekly, maximum 50 mg/week; children ≥2 years of age and adolescents (≥63 kg body weight): 50 mg subcutaneously once weekly

Secondary options

tocilizumab: children ≥2 years of age and adolescents (<30 kg body weight): 10 mg/kg intravenously every 4 weeks, or 162 mg subcutaneously every 3 weeks; children ≥2 years of age and adolescents (≥30 kg body weight): 8 mg/kg intravenously every 4 weeks, or 162 mg subcutaneously every 2 weeks

OR

abatacept: children and adolescents: consult specialist for guidance on dose

OR

infliximab: children and adolescents: consult specialist for guidance on dose

Consider – nonsteroidal anti-inflammatory drug (NSAID)

Back
ONGOING
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polyarticular JIA: 5 or more joints ever involved
Consider – 

nonsteroidal anti-inflammatory drug (NSAID)

Treatment recommended for SOME patients in selected patient group

NSAIDs are used to control pain and stiffness in children with polyarticular JIA while systemic therapies take effect.

Specific NSAIDs are approved for children with JIA (e.g., ibuprofen, naproxen, meloxicam). Others are commonly used off-label. No specific NSAID is superior to another.[92] Sequential trials of different NSAIDs are used to identify the most effective medicine for individual patients. 

Possible adverse effects include renal impairment, gastrointestinal symptoms (nausea, constipation, diarrhea, abdominal pain), headache, and rash.[92]

Primary options

ibuprofen: children and adolescents: 30-50 mg/kg/day orally given in 3-4 divided doses, maximum 3200 mg/day

OR

naproxen: children ≥2 years of age and adolescents: 5 mg/kg orally twice daily, maximum 1000 mg/day

OR

meloxicam: children and adolescents (≥60 kg body weight): 7.5 mg orally once daily

Consider – intra-articular corticosteroid

Back
ONGOING
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polyarticular JIA: 5 or more joints ever involved
Consider – 

intra-articular corticosteroid

Treatment recommended for SOME patients in selected patient group

Intra-articular corticosteroid injections are used to relieve pain and/or swelling while systemic therapies take effect.[61] 

Radiographic assistance may be necessary for injecting some joints. The procedure can be undertaken with the administration of entonox or general anesthetic to the child. Adverse effects from intra-articular injections are uncommon.

Relief is expected to last for at least 4 months.[62] Injections can be repeated every 4 months as needed. A shorter duration of relief may imply a need to escalate systemic therapy.[62] 

Intra-articular corticosteroid injections may not be a suitable treatment for large numbers of joints that have been injected multiple times. Escalation of systemic therapy may be more appropriate.[61]

Primary options

triamcinolone acetonide: children and adolescents: consult specialist for guidance on intra-articular dose

OR

methylprednisolone acetate: children and adolescents: consult specialist for guidance on intra-articular dose

Consider – oral corticosteroid

Back
ONGOING
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polyarticular JIA: 5 or more joints ever involved
Consider – 

oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Used to relieve symptoms for up to 3 months in patients with high or moderate disease activity, while disease-modifying antirheumatic drugs or biologic therapies take effect.[61]

Primary options

prednisone: children and adolescents: 0.05 to 2 mg/kg/day orally given in 1-4 divided doses

oligoarticular JIA: 4 or fewer joints ever involved

1st line – intra-articular corticosteroid

Back
ONGOING
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oligoarticular JIA: 4 or fewer joints ever involved
1st line – 

intra-articular corticosteroid

Patients with JIA should be managed by a specialist pediatric rheumatology multidisciplinary team.[60] 

Corticosteroid injections alone may be appropriate for children with oligoarticular arthritis.[62]

Radiographic assistance may be necessary for injecting some joints. The procedure can be undertaken with the administration of entonox or general anesthetic to the child. Adverse effects from intra-articular injections are uncommon.

Relief is expected to last for at least 4 months.[62] Injections can be repeated every 4 months as needed. A shorter duration of relief may imply a need to escalate systemic therapy.[62]

Primary options

triamcinolone acetonide: children and adolescents: consult specialist for guidance on intra-articular dose

OR

methylprednisolone acetate: children and adolescents: consult specialist for guidance on intra-articular dose

Plus – supportive care

Back
ONGOING
|
oligoarticular JIA: 4 or fewer joints ever involved
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[60] Ongoing input from physical therapists and occupational therapists is required.[60] 

Patients with JIA have an increased risk of psychiatric morbidity.[70] Support and strategies for managing any difficulties should be provided.[60]

Consider – NSAID

Back
ONGOING
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oligoarticular JIA: 4 or fewer joints ever involved
Consider – 

NSAID

Treatment recommended for SOME patients in selected patient group

Used for relief of joint pain and/or swelling. NSAID monotherapy may be given for 2 months if the child has low disease activity, no contractures, and no poor prognostic features.[62] Poor prognostic features are: arthritis of the hip or cervical spine, arthritis of the ankle or wrist plus prolonged or marked inflammatory marker elevation, or radiographic evidence of erosions or joint space narrowing.[62] If there is any residual disease activity after 2 months’ treatment, therapy should be escalated to intra-articular corticosteroid injections.[62] 

Specific NSAIDs are approved for children with JIA (e.g., ibuprofen, naproxen, meloxicam). Others are commonly used off-label. No specific NSAID is superior to another.[92] Sequential trials of different NSAIDs are used to identify the most effective medicine for individual patients. 

Possible adverse effects include renal impairment, gastrointestinal symptoms (nausea, constipation, diarrhea, abdominal pain), headache, and rash.[92]

Primary options

ibuprofen: children and adolescents: 30-50 mg/kg/day orally given in 3-4 divided doses, maximum 3200 mg/day

OR

naproxen: children ≥2 years of age and adolescents: 5 mg/kg orally twice daily, maximum 1000 mg/day

OR

meloxicam: children and adolescents (≥60 kg body weight): 7.5 mg orally once daily

Consider – methotrexate

Back
ONGOING
|
oligoarticular JIA: 4 or fewer joints ever involved
Consider – 

methotrexate

Treatment recommended for SOME patients in selected patient group

Started initially for patients who have high disease activity and poor prognostic features.[62] Poor prognostic features are: arthritis of the hip or cervical spine, arthritis of the ankle or wrist plus prolonged or marked inflammatory marker elevation, or radiographic evidence of erosions or joint space narrowing.[62]

Recommended after initial corticosteroid injections for patients with high disease activity but without poor prognostic features, and patients with moderate disease activity and poor prognostic features.[62] Also recommended after repeated corticosteroid injections for patients with moderate disease activity but no poor prognostic features, and patients with low disease activity and poor prognostic features.[62]

Folic acid is usually given concomitantly to decrease the side effects of methotrexate, and antiemetics may be used to reduce nausea. Patients should be counseled to avoid alcohol and pregnancy while taking methotrexate.

Before starting methotrexate, a complete blood count, serum creatinine, and liver enzymes should be checked. Measurements should be repeated every 3 to 4 months during treatment.[73] Patients at risk of hepatitis B or hepatitis C infection should have a screening antibody test before starting methotrexate.[62] Elevation of aspartate aminotransferase or alanine aminotransferase above 2 times the upper limit justifies temporary suspension of methotrexate, which can be re-started following normalization of serum liver enzyme levels.[62]

Primary options

methotrexate: children ≥2 years of age and adolescents: 10-15 mg/square meter of body surface area orally/subcutaneously/intramuscularly once weekly on the same day of each week, adjust dose according to response, maximum 25 mg/week

More

2nd line – tumor necrosis factor (TNF)-alpha inhibitor

Back
ONGOING
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oligoarticular JIA: 4 or fewer joints ever involved
2nd line – 

tumor necrosis factor (TNF)-alpha inhibitor

TNF-alpha inhibitors are rarely needed for patients with oligoarticular JIA. They should be considered in patients with moderate or high disease activity and poor prognostic features after 3 months’ treatment with methotrexate at maximum tolerated dose and intra-articular corticosteroids, and in patients with high disease activity but without poor prognostic features after 6 months’ treatment with methotrexate and intra-articular corticosteroids.[62] Poor prognostic features are: arthritis of the hip or cervical spine, arthritis of the ankle or wrist plus prolonged or marked inflammatory marker elevation, or radiographic evidence of erosions or joint space narrowing.[62] 

If the patient has had a partial clinical response to methotrexate, this should be continued after initiating a TNF-alpha inhibitor.[62] 

When treatment with a TNF-alpha inhibitor is needed, etanercept or adalimumab are preferred to infliximab. Infliximab carries a risk of infusion-associated reactions and is not approved for the treatment of any form of JIA.

Caution is advised in patients with recurrent infections, conditions predisposing to infections, preexisting demyelinating disorders, or hematologic diseases, due to the immunosuppressive nature of these medicines.[84] A study evaluating etanercept and adalimumab showed an increase in number of infections but no clear evidence that the overall malignancy risk was increased.[79] Chronic carriers of tuberculosis and hepatitis B are susceptible to disease reactivation. Tuberculosis skin tests, and viral hepatitis screening for patients with risk factors for infection, are recommended prior to treatment.[62][84] Live vaccines should be avoided during treatment.[85] 

Primary options

adalimumab: children ≥2 years of age and adolescents (10-14 kg body weight): 10 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (15-29 kg body weight): 20 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (≥30 kg body weight): 40 mg subcutaneously every 2 weeks

OR

etanercept: children ≥2 years of age and adolescents (<63 kg body weight): 0.8 mg/kg subcutaneously once weekly, maximum 50 mg/week; children ≥2 years of age and adolescents (≥63 kg body weight): 50 mg subcutaneously once weekly

Secondary options

infliximab: children and adolescents: consult specialist for guidance on dose

Plus – supportive care

Back
ONGOING
|
oligoarticular JIA: 4 or fewer joints ever involved
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[60] Ongoing input from physical therapists and occupational therapists is required.[60] 

Patients with JIA have an increased risk of psychiatric morbidity.[70] Support and strategies for managing any difficulties should be provided.[60]

Consider – intra-articular corticosteroid

Back
ONGOING
|
oligoarticular JIA: 4 or fewer joints ever involved
Consider – 

intra-articular corticosteroid

Treatment recommended for SOME patients in selected patient group

Injection of corticosteroids into the affected joints is recommended for all patients with active arthritis, in addition to any systemic therapy.[62] 

Radiographic assistance may be necessary for injecting some joints. The procedure can be undertaken with the administration of entonox or general anesthetic to the child. Adverse effects from intra-articular injections are uncommon.

Relief is expected to last for at least 4 months.[62] A shorter duration of relief may imply a need to escalate therapy.[62]

Primary options

triamcinolone acetonide: children and adolescents: consult specialist for guidance on intra-articular dose

OR

methylprednisolone acetate: children and adolescents: consult specialist for guidance on intra-articular dose

Consider – NSAID

Back
ONGOING
|
oligoarticular JIA: 4 or fewer joints ever involved
Consider – 

NSAID

Treatment recommended for SOME patients in selected patient group

Used for relief of joint pain and/or swelling.

Specific NSAIDs are approved for children with JIA (e.g., ibuprofen, naproxen, meloxicam). Others are commonly used off-label. No specific NSAID is superior to another.[92] Sequential trials of different NSAIDs are used to identify the most effective medicine for individual patients.

Possible adverse effects include renal impairment, gastrointestinal symptoms (nausea, constipation, diarrhea, abdominal pain), headache, and rash.[92]

Primary options

ibuprofen: children and adolescents: 30-50 mg/kg/day orally given in 3-4 divided doses, maximum 3200 mg/day

OR

naproxen: children ≥2 years of age and adolescents: 5 mg/kg orally twice daily, maximum 1000 mg/day

OR

meloxicam: children and adolescents (≥60 kg body weight): 7.5 mg orally once daily

active sacroiliitis

1st line – NSAID

Back
ONGOING
|
active sacroiliitis
1st line – 

NSAID

Patients with JIA should be managed by a specialist pediatric rheumatology multidisciplinary team.[60] 

NSAIDs are first-line for children and adolescents with active sacroiliitis.[61] 

Specific NSAIDs are approved for children with JIA (e.g., ibuprofen, naproxen, meloxicam). Others are commonly used off-label. No specific NSAID is superior to another.[92] Sequential trials of different NSAIDs are used to identify the most effective medicine for individual patients. 

Possible adverse effects include renal impairment, gastrointestinal symptoms (nausea, constipation, diarrhea, abdominal pain), headache, and rash.[92]

Primary options

ibuprofen: children and adolescents: 30-50 mg/kg/day orally given in 3-4 divided doses, maximum 3200 mg/day

OR

naproxen: children ≥2 years of age and adolescents: 5 mg/kg orally twice daily, maximum 1000 mg/day

OR

meloxicam: children and adolescents (≥60 kg body weight): 7.5 mg orally once daily

Plus – supportive care

Back
ONGOING
|
active sacroiliitis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[60] Ongoing input from physical therapists and occupational therapists is required.[60] 

Patients with JIA have an increased risk of psychiatric morbidity.[70] Support and strategies for managing any difficulties should be provided.[60]

Consider – oral corticosteroid

Back
ONGOING
|
active sacroiliitis
Consider – 

oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Used to relieve symptoms for up to 3 months during initiation or escalation of systemic therapy.[61]

Primary options

prednisone: children and adolescents: 0.05 to 2 mg/kg/day orally given in 1-4 divided doses

2nd line – TNF-alpha inhibitor or sulfasalazine

Back
ONGOING
|
active sacroiliitis
2nd line – 

TNF-alpha inhibitor or sulfasalazine

Treatment should be escalated if there is active sacroiliitis despite NSAID monotherapy. Use of TNF-alpha inhibitors is associated with decreased disease activity, compared with placebo.[93][94][95] Treatment with etanercept or adalimumab is preferred to treatment with infliximab. Infliximab carries a risk of infusion-associated reactions and is not approved for the treatment of any form of JIA.

Sulfasalazine may also be used, particularly for children in whom TNF-alpha inhibitors are contraindicated or not tolerated.[61]

Primary options

adalimumab: children ≥2 years of age and adolescents (10-14 kg body weight): 10 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (15-29 kg body weight): 20 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (≥30 kg body weight): 40 mg subcutaneously every 2 weeks

OR

etanercept: children ≥2 years of age and adolescents (<63 kg body weight): 0.8 mg/kg subcutaneously once weekly, maximum 50 mg/week; children ≥2 years of age and adolescents (≥63 kg body weight): 50 mg subcutaneously once weekly

Secondary options

sulfasalazine: children ≥6 years of age and adolescents: 30-50 mg/kg/day orally given in 2 divided doses, maximum 2000 mg/day

OR

infliximab: children and adolescents: consult specialist for guidance on dose

Plus – supportive care

Back
ONGOING
|
active sacroiliitis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[60] Ongoing input from physical therapists and occupational therapists is required.[60] 

Patients with JIA have an increased risk of psychiatric morbidity.[70] Support and strategies for managing any difficulties should be provided.[60]

Consider – oral corticosteroid

Back
ONGOING
|
active sacroiliitis
Consider – 

oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Used to relieve symptoms for up to 3 months during initiation or escalation of systemic therapy.[61]

Primary options

prednisone: children and adolescents: 0.05 to 2 mg/kg/day orally given in 1-4 divided doses

active enthesitis

1st line – NSAID

Back
ONGOING
|
active enthesitis
1st line – 

NSAID

Patients with JIA should be managed by a specialist pediatric rheumatology multidisciplinary team.[60] 

NSAIDs are first-line for children and adolescents with active enthesitis.[61] 

Specific NSAIDs are approved for children with JIA (e.g., ibuprofen, naproxen, meloxicam). Others are commonly used off-label. No specific NSAID is superior to another.[92] Sequential trials of different NSAIDs are used to identify the most effective medicine for individual patients. 

Possible adverse effects include renal impairment, gastrointestinal symptoms (nausea, constipation, diarrhea, abdominal pain), headache, and rash.[92]

Primary options

ibuprofen: children and adolescents: 30-50 mg/kg/day orally given in 3-4 divided doses, maximum 3200 mg/day

OR

naproxen: children ≥2 years of age and adolescents: 5 mg/kg orally twice daily, maximum 1000 mg/day

OR

meloxicam: children and adolescents (≥60 kg body weight): 7.5 mg orally once daily

Plus – supportive care

Back
ONGOING
|
active enthesitis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[60] Ongoing input from physical therapists and occupational therapists is required.[60] 

Patients with JIA have an increased risk of psychiatric morbidity.[70] Support and strategies for managing any difficulties should be provided.[60]

Consider – oral corticosteroid

Back
ONGOING
|
active enthesitis
Consider – 

oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Used to relieve symptoms for up to 3 months during initiation or escalation of systemic therapy.[61]

Primary options

prednisone: children and adolescents: 0.05 to 2 mg/kg/day orally given in 1-4 divided doses

2nd line – methotrexate or sulfasalazine or TNF-alpha inhibitor

Back
ONGOING
|
active enthesitis
2nd line – 

methotrexate or sulfasalazine or TNF-alpha inhibitor

Treatment should be escalated if there is active enthesitis despite NSAID monotherapy.[61]

Typically methotrexate or sulfasalazine are used first, with escalation to a TNF-alpha inhibitor if the child doesn’t respond.[96] When treatment with a TNF-alpha inhibitor is required, etanercept or adalimumab are preferred to infliximab. Infliximab carries a risk of infusion-associated reactions and is not approved for the treatment of any form of JIA. 

However, American College of Rheumatology guidelines recommend that children with active enthesitis despite NSAID monotherapy should escalate to TNF-alpha inhibitors, rather than methotrexate or sulfasalazine, and noted that the level of evidence for this recommendation was low.[61] One observational study reported a greater improvement in pain and disease activity after 12 months in children with enthesitis who received a TNF-alpha inhibitor, compared with those who received a disease-modifying antirheumatic drug alone.[97]

Before starting methotrexate, a complete blood count, serum creatinine, and liver enzymes should be checked. Measurements should be repeated every 3 to 4 months during treatment.[73] Patients at risk of hepatitis B or hepatitis C infection should have a screening antibody test before starting methotrexate.[62] Elevation of aspartate aminotransferase or alanine aminotransferase above 2 times the upper limit justifies temporary suspension of methotrexate, which can be re-started following normalization of serum liver enzyme levels.[62] Folic acid is usually given concomitantly to decrease the side effects of methotrexate, and antiemetics may be used to reduce nausea. 

For TNF-alpha inhibitors, caution is advised in patients with recurrent infections, conditions predisposing to infections, preexisting demyelinating disorders, or hematologic diseases, due to the immunosuppressive nature of these medicines.[84] A study evaluating etanercept and adalimumab showed an increase in number of infections but no clear evidence that the overall malignancy risk was increased.[79] Chronic carriers of tuberculosis and hepatitis B are susceptible to disease reactivation. Tuberculosis skin tests, and viral hepatitis screening for patients with risk factors for infection, are recommended prior to treatment.[62][84] Live vaccines should be avoided during treatment.[85] 

Primary options

methotrexate: children ≥2 years of age and adolescents: 10-15 mg/square meter of body surface area orally/subcutaneously/intramuscularly once weekly on the same day of each week, maximum 25 mg/week

More

OR

sulfasalazine: children ≥6 years of age and adolescents: 30-50 mg/kg/day orally given in 2 divided doses, maximum 2000 mg/day

OR

adalimumab: children ≥2 years of age and adolescents (10-14 kg body weight): 10 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (15-29 kg body weight): 20 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (≥30 kg body weight): 40 mg subcutaneously every 2 weeks

OR

etanercept: children ≥2 years of age and adolescents (<63 kg body weight): 0.8 mg/kg subcutaneously once weekly, maximum 50 mg/week; children ≥2 years of age and adolescents (≥63 kg body weight): 50 mg subcutaneously once weekly

Secondary options

infliximab: children and adolescents: consult specialist for guidance on dose

Plus – supportive care

Back
ONGOING
|
active enthesitis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[60] Ongoing input from physical therapists and occupational therapists is required.[60] 

Patients with JIA have an increased risk of psychiatric morbidity.[70] Support and strategies for managing any difficulties should be provided.[60]

Consider – oral corticosteroid

Back
ONGOING
|
active enthesitis
Consider – 

oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Used to relieve symptoms for up to 3 months during initiation or escalation of systemic therapy.[61]

Primary options

prednisone: children and adolescents: 0.05 to 2 mg/kg/day orally given in 1-4 divided doses

systemic-onset JIA

1st line – brief trial of NSAID

Back
ONGOING
|
systemic-onset JIA
|
without macrophage activation syndrome (MAS)
1st line – 

brief trial of NSAID

An initial trial of NSAID monotherapy is a first-line option.[98]

There is some evidence that those with systemic JIA without MAS will respond to NSAIDs alone and even have clinically inactive disease.[98]

Patients who undergo an initial trial of NSAID monotherapy should be followed up within 2 weeks for evaluation of a possible need for drug escalation.[101] If a response occurs and inactive disease occurs, then NSAIDs should be tapered and discontinued. If clinical response is not rapid and complete, rapid escalation of therapy is recommended.

Several NSAIDs are approved for children with JIA (e.g., ibuprofen, naproxen, meloxicam). Others are commonly used off-label. No specific NSAID is superior to another.[92] Sequential trials of different NSAIDs are used to identify the most effective drug for individual patients.

Possible adverse effects include renal impairment, gastrointestinal symptoms, headache, and rash.[92] 

Primary options

ibuprofen: children and adolescents: 30-50 mg/kg/day orally given in 3-4 divided doses, maximum 3200 mg/day

OR

naproxen: children ≥2 years of age and adolescents: 5 mg/kg orally twice daily, maximum 1000 mg/day

OR

meloxicam: children and adolescents (≥60 kg body weight): 7.5 mg orally once daily

Plus – supportive care

Back
ONGOING
|
systemic-onset JIA
|
without macrophage activation syndrome (MAS)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[60] Ongoing input from physical therapists and occupational therapists is required.[60] 

Patients with JIA have an increased risk of psychiatric morbidity.[70] Support and strategies for managing any difficulties should be provided.[60]

Consider – biologic agent

Back
ONGOING
|
systemic-onset JIA
|
without macrophage activation syndrome (MAS)
Consider – 

biologic agent

Treatment recommended for SOME patients in selected patient group

Biologic agents can be given in combination with an NSAID for initial treatment or after a trial period of an NSAID.[98] Biologic agents can also be used as monotherapy (i.e., interleukin [IL]-1 or IL-6 inhibitor) first-line option.

The American College of Rheumatology (ACR) does not recommend any one preferred agent, but indicates that IL-1 inhibitors (e.g., anakinra, canakinumab) and IL-6 inhibitors (e.g., tocilizumab) are extremely effective and well-tolerated options. The choice should be based on discussions between the practitioner and patient as routes of administration and frequency vary. The ACR recommends switching between IL-1 and IL-6 inhibitors when needed due to a lack of efficacy or poor tolerability as individual response varies significantly.[98][102][103][104]

Biologic agents used in systemic JIA appear safe and comparable with respect to adverse effect risk in the short term.[102] Anakinra has a short half-life, meaning its dose can be adjusted or it can be withdrawn quickly. One randomized controlled trial reported a response rate of 66% to 1 month's treatment with anakinra, compared with 8% to placebo, in children with systemic JIA. After 1 month, 83% of the children receiving placebo were switched to anakinra; 90% of children who switched from placebo responded to anakinra.[105] Canakinumab is effective for treating active systemic JIA.[103][106] Treatment with canakinumab significantly reduces fever and disease activity, compared with placebo.[103] One randomized trial showed a significant reduction in fever and active arthritis in children with systemic JIA refractory to corticosteroids and NSAIDs who were treated with tocilizumab, compared with placebo.[107] Meta-analysis has shown similar efficacy between tocilizumab, canakinumab, and anakinra.[102] One meta analysis of randomized controlled trials found that canakinumab had the highest probability of being the best treatment, in terms of the modified ACR Pediatric 30 (ACRpedi30) response rate, followed by anakinra and tocilizumab.[108]

Serious hepatotoxicity (including acute liver failure, hepatitis, and jaundice) has been identified with tocilizumab. The ACR recommends monitoring alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at initiation of treatment, within 4 to 8 weeks of treatment and every 3 to 4 months thereafter.[73] Be cautious when considering starting tocilizumab treatment in patients with ALT or AST levels higher than 1.5 times the upper limit of normal. Tocilizumab is not recommended if ALT or AST levels are higher than 5 times the upper limit of normal. If liver enzyme abnormalities are identified, consider a dose modification (reduction, interruption, or discontinuation) according to the manufacturer’s recommendations.[87]

A range of small-scale trials demonstrated resolution of systemic signs following the use of biologic agents.[105][107][109][110] With prolonged use, some patients suffered from adverse effects (e.g., infection, neutropenia, and increased aminotransferase levels).[107]

The ACR recommends considering tapering and discontinuing biologic therapies when the disease is deemed inactive.[98]

Primary options

tocilizumab: children ≥2 years of age and adolescents (<30 kg body weight): 12 mg/kg intravenously every 2 weeks, or 162 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (≥30 kg body weight): 8 mg/kg intravenously every 2 weeks, or 162 mg subcutaneously once weekly

OR

canakinumab: children ≥2 years of age and adolescents (≥7.5 kg body weight): 4 mg/kg subcutaneously every 4 weeks, maximum 300 mg/dose

OR

anakinra: children and adolescents: consult specialist for guidance on dose

Consider – conventional synthetic DMARD

Back
ONGOING
|
systemic-onset JIA
|
without macrophage activation syndrome (MAS)
Consider – 

conventional synthetic DMARD

Treatment recommended for SOME patients in selected patient group

A conventional synthetic DMARD may be added if there is residual arthritis after initial treatment.[98] There is no preferred agent.

The primary conventional synthetic DMARD used for the treatment of systemic JIA is methotrexate. Methotrexate has been commonly used in children with systemic JIA due to its corticosteroid-sparing effect.[115] Although it is used less frequently, it can be given alone or alongside a biologic agent to control symptoms. Leflunomide is another conventional synthetic DMARD that can be used in JIA to manage the inflammatory response when methotrexate is not tolerated.[74][116] 

Primary options

methotrexate: children ≥2 years of age and adolescents: 10-15 mg/square meter of body surface area orally/subcutaneously/intramuscularly once weekly on the same day of each week, maximum 25 mg/week

More

Secondary options

leflunomide: consult specialist for guidance on dose

1st line – biologic agent

Back
ONGOING
|
systemic-onset JIA
|
with MAS
1st line – 

biologic agent

MAS is a life-threatening complication of systemic-onset JIA. MAS is present if the following criteria are met in a febrile patient with known or suspected systemic-onset JIA: ferritin >684 ng/mL and any two of platelet count ≤181 x 10⁹/L, aspartate aminotransferase >48 U/L, triglycerides >156 mg/dL, or fibrinogen ≤360 mg/dL.[100] If a patient has a normal ferritin level, but there is ongoing clinical suspicion of MAS, serial ferritin testing should be considered.[58]

Consult a pediatric rheumatology specialist urgently if features of MAS are present. Patients with MAS can deteriorate rapidly and may require intensive care admission. For patients with suspected MAS, initiating treatment while diagnostic testing is in progress should be considered.[58]​ Monitoring initial treatment response by assessing clinical and laboratory markers of organ involvement should be assessed at least daily, and markers of systemic inflammation at least twice weekly. Worsening or lack of improvement in laboratory parameters of systemic inflammation, particularly ferritin, may indicate disease progression and a need to reassess diagnosis and/or treatment.[58]​ 

Biologic agent monotherapy (i.e., interleukin [IL]-1 or IL-6 inhibitor) is a first-line option.[98]

The American College of Rheumatology (ACR) does not recommend any one preferred agent, but indicates that IL-1 inhibitors (e.g., anakinra, canakinumab) and IL-6 inhibitors (e.g., tocilizumab) are extremely effective and well-tolerated options. The choice should be based on discussions between the practitioner and patient as routes of administration and frequency vary. The ACR recommends switching between IL-1 and IL-6 inhibitors when needed due to a lack of efficacy or poor tolerability as individual response varies significantly.[98][102][103][104]

Biologic agents used in systemic JIA appear safe and comparable with respect to adverse effect risk in the short term.[102] Anakinra has a short half-life, meaning its dose can be adjusted or it can be withdrawn quickly. One randomized controlled trial reported a response rate of 66% to 1 month's treatment with anakinra, compared with 8% to placebo, in children with systemic JIA. After 1 month, 83% of the children receiving placebo were switched to anakinra; 90% of children who switched from placebo responded to anakinra.[105] Canakinumab is effective for treating active systemic JIA.[103][106] Treatment with canakinumab significantly reduces fever and disease activity, compared with placebo.[103] One randomized trial showed a significant reduction in fever and active arthritis in children with systemic JIA refractory to corticosteroids and NSAIDs who were treated with tocilizumab, compared with placebo.[107] Meta-analysis has shown similar efficacy between tocilizumab, canakinumab, and anakinra.[102] One meta analysis of randomized controlled trials found that canakinumab had the highest probability of being the best treatment, in terms of the modified ACR Pediatric 30 (ACRpedi30) response rate, followed by anakinra and tocilizumab.[108]

Serious hepatotoxicity (including acute liver failure, hepatitis, and jaundice) has been identified with tocilizumab. The ACR recommends monitoring alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at initiation of treatment, within 4 to 8 weeks of treatment and every 3 to 4 months thereafter.[73] Be cautious when considering starting tocilizumab treatment in patients with ALT or AST levels higher than 1.5 times the upper limit of normal. Tocilizumab is not recommended if ALT or AST levels are higher than 5 times the upper limit of normal. If liver enzyme abnormalities are identified, consider a dose modification (reduction, interruption, or discontinuation) according to the manufacturer’s recommendations.[87]

A range of small-scale trials demonstrated resolution of systemic signs following the use of biologic agents.[105][107][109][110] With prolonged use, some patients suffered from adverse effects (e.g., infection, neutropenia, and increased aminotransferase levels).[107]

In children with systemic JIA whose disease is inactive, it may be possible to maintain this inactive disease state with lower doses of, or discontinuation of, biologic agents.[113][114] It is unclear how soon after achievement of inactive disease these can be tapered.[98]

Primary options

tocilizumab: children ≥2 years of age and adolescents (<30 kg body weight): 12 mg/kg intravenously every 2 weeks, or 162 mg subcutaneously every 2 weeks; children ≥2 years of age and adolescents (≥30 kg body weight): 8 mg/kg intravenously every 2 weeks, or 162 mg subcutaneously once weekly

OR

canakinumab: children ≥2 years of age and adolescents (≥7.5 kg body weight): 4 mg/kg subcutaneously every 4 weeks, maximum 300 mg/dose

OR

anakinra: children and adolescents: consult specialist for guidance on dose

Plus – supportive care

Back
ONGOING
|
systemic-onset JIA
|
with MAS
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[60] Ongoing input from physical therapists and occupational therapists is required.[60] 

Patients with JIA have an increased risk of psychiatric morbidity.[70] Support and strategies for managing any difficulties should be provided.[60]

Consider – systemic corticosteroid

Back
ONGOING
|
systemic-onset JIA
|
with MAS
Consider – 

systemic corticosteroid

Treatment recommended for SOME patients in selected patient group

Corticosteroids may be used in combination with a biologic agent. Biologic agent monotherapy may not be sufficient for severely sick patients.[98]

Glucocorticoid therapy should be limited to the lowest effective dose for the shortest duration possible, although treatment with high-dose corticosteroids may be required for initial disease control.[98] Long-term corticosteroid therapy in children is not appropriate because of its potential side effects on bone health and growth.[111] Tapering and discontinuing corticosteroids is strongly recommended after inactive disease has been attained in systemic JIA.[98]

Primary options

methylprednisolone sodium succinate: children and adolescents: consult specialist for guidance on intravenous dose

OR

prednisone: children and adolescents: consult specialist for guidance on oral dose

Consider – conventional synthetic DMARD

Back
ONGOING
|
systemic-onset JIA
|
with MAS
Consider – 

conventional synthetic DMARD

Treatment recommended for SOME patients in selected patient group

Biologic agents combined with a corticosteroid and a conventional synthetic DMARD may be necessary to control MAS in some patients.[98]

A conventional synthetic DMARD may be added if there is residual arthritis after initial treatment.[98] There is no preferred agent.[98]

The primary conventional synthetic DMARD used for the treatment of systemic JIA is methotrexate. Methotrexate has been commonly used in children with systemic JIA due to its corticosteroid-sparing effect.[115] Although it is used less frequently, it can be given alone or alongside a biologic agent to control symptoms. Leflunomide is another conventional synthetic DMARD that can be used in JIA to manage the inflammatory response when methotrexate is not tolerated.[74][116] 

If a patient is receiving both a biologic agent and a corticosteroid, the corticosteroid should be tapered and discontinued first before attempting to taper the biologic agent. It is unclear how soon or rapidly these can be safely discontinued in patients with inactive systemic JIA.[98]

Primary options

methotrexate: children ≥2 years of age and adolescents: 10-15 mg/square meter of body surface area orally/subcutaneously/intramuscularly once weekly on the same day of each week, maximum 25 mg/week

More

Secondary options

leflunomide: consult specialist for guidance on dose

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