What are the considerations for using tofacitinib (Janus kinase (JAK) inhibitor) in a child or adolescent with polyarticular juvenile idiopathic arthritis (JIA) who has failed or is intolerant to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic disease-modifying antirheumatic drugs (bDMARDs)?

Tofacitinib Use in Juvenile Idiopathic Arthritis

Primary Recommendation

Tofacitinib is recommended as a treatment option for children and adolescents with polyarticular course JIA who have failed or are intolerant to conventional synthetic DMARDs (particularly methotrexate) and biologic DMARDs, with FDA approval for patients aged 2 years and older. 1, 2

FDA-Approved Indication and Dosing

• Tofacitinib is FDA-approved for active polyarticular course JIA (pcJIA) in patients 2 years to 17 years of age who have had an inadequate response or intolerance to at least one DMARD (which could include methotrexate or biologic agents) 1

• The approved dose is 5 mg twice daily or body weight-based equivalent twice daily for pediatric patients 1

• The FDA approval encompasses RF-negative polyarthritis, RF-positive polyarthritis, extended oligoarthritis, and systemic JIA without systemic manifestations 1

Position in Treatment Algorithm

When Biologics Are Available

• The American College of Rheumatology recommends biologic DMARDs (TNF inhibitors, abatacept, or tocilizumab) as the preferred next step after inadequate response to methotrexate in patients with moderate to high disease activity 3

• For patients with moderate activity (JADAS-27 3.9–≤8.5) and poor prognostic features, or high disease activity (JADAS-27 >8.5), combination therapy with parenteral methotrexate plus a bDMARD (preferably anti-TNFα) is recommended 3

• Tofacitinib should be considered after failure of at least one biologic DMARD in settings where multiple biologic options are accessible 3

When Biologics Are Not Accessible

• The Pan-American League of Associations for Rheumatology (PANLAR) 2025 guidelines specifically recommend JAK inhibitors (tofacitinib and baricitinib) as potential treatment options when bDMARDs are not readily available due to economic constraints 3

• This recommendation acknowledges that in resource-limited settings, tofacitinib may serve as an earlier treatment option when biologics are inaccessible 3

Efficacy Data

Pivotal Trial Results

• In the phase 3 withdrawal trial, tofacitinib demonstrated a significantly lower flare rate (29%) compared to placebo (53%) at week 44 (hazard ratio 0.46,95% CI 0.27-0.79; p=0.0031) 2

• After 18 weeks of open-label tofacitinib treatment, 77% of patients achieved JIA ACR30 response, 70% achieved ACR50, and 49% achieved ACR70 1, 2

• Among 142 patients with polyarticular course JIA randomized in the withdrawal phase, the treatment effect was consistent across disease subtypes 2

Real-World Evidence

• A study from Bangladesh in refractory polyarticular course JIA showed that 70.4% of patients achieved inactive disease at 24 weeks, with all patients starting at high disease activity 4

• Significant improvement in JADAS-27 scores was observed across all JIA subtypes except oligoarticular extended type 4

• Tofacitinib enabled significant reduction in corticosteroid doses in refractory cases 4

Safety Profile

Common Adverse Events

• In the pivotal trial, adverse events occurred in 77% of tofacitinib-treated patients during the withdrawal phase, with infections or infestations being the most common (48% over the entire exposure period) 2

• Serious adverse events were rare (1% in tofacitinib group during withdrawal phase) 2

• Mild side effects including headache, vomiting, transient ALT elevation, and anemia were observed but generally improved with continued treatment 4

Critical Safety Considerations

• Tofacitinib carries increased risk of serious infections, particularly in immunocompromised patients and those with impaired renal or hepatic function 5

• Screen for tuberculosis and viral hepatitis before initiating treatment, as required for all JAK inhibitors 1

• Avoid use in patients with severe hepatic impairment; dose adjustment required for moderate hepatic impairment and moderate to severe renal impairment 1

• Monitor complete blood counts, liver function tests, and lipid profiles during treatment 1

• In adult populations, JAK inhibitors have shown increased cardiovascular and malignancy risks in patients ≥50 years with cardiovascular risk factors, though this has not been studied in pediatric populations 1

Concomitant Methotrexate Use

• Concomitant methotrexate is permitted but not required with tofacitinib therapy 1, 2

• In the pivotal trial, 65% of patients received concomitant methotrexate, demonstrating that tofacitinib can be effective both as monotherapy and combination therapy 2

• This differs from infliximab, where combination with a DMARD is strongly recommended to reduce anti-drug antibody formation 3

Advantages Over Injectable Biologics

• Tofacitinib offers the advantage of oral administration, which may be particularly relevant for children and adolescents who prefer to avoid injections 2

• The medication provides a cost-effective alternative to biologics in resource-limited settings 3, 4

• Rapid onset of action with clinical improvement observable within weeks 4

Special Populations

Refractory Systemic JIA

• Case reports demonstrate effectiveness of tofacitinib in refractory systemic JIA with complete remission achieved after 3 months in a patient who failed multiple conventional DMARDs and biologics 6

• This suggests potential utility beyond the FDA-approved indication of systemic JIA without active systemic features 6

Patients with Multiple DMARD Failures

• Tofacitinib has demonstrated efficacy in patients refractory to traditional treatments, including those who failed methotrexate and multiple biologics 5, 4

• The Bangladesh study specifically enrolled refractory cases with significant treatment success 4

Critical Pitfalls to Avoid

• Do not use tofacitinib as first-line therapy when methotrexate has not been tried or optimized (unless methotrexate is contraindicated), as conventional synthetic DMARDs remain the recommended initial approach 3

• Do not overlook the need for tuberculosis and hepatitis screening before initiation 1

• Do not use in patients with active serious infections or those with severe immunocompromise 1, 5

• Do not assume tofacitinib can replace biologics in all scenarios—in settings where biologics are accessible, they remain the preferred option after methotrexate failure per ACR guidelines 3

• Do not continue treatment without monitoring response—assess disease activity at regular intervals (6-8 weeks initially) and consider alternative therapy if inadequate response 3

Monitoring Requirements

• Baseline laboratory evaluation should include complete blood count, comprehensive metabolic panel, lipid panel, tuberculosis screening, and hepatitis B/C screening 1

• Monitor CBC, liver enzymes, and lipids at 4-8 weeks after initiation, then every 3 months during maintenance therapy 1

• Assess disease activity using validated measures (JADAS-27 or cJADAS-10) at each visit to guide treatment decisions 3