What is the role of JAK (Janus kinase) inhibitors, such as tofacitinib (Xeljanz), in the treatment of moderate to severe ulcerative colitis in patients in India?

Role of JAK Inhibitors in Treating Moderate to Severe Ulcerative Colitis in India

JAK inhibitors, particularly tofacitinib, are recommended as second-line therapy for moderate to severe ulcerative colitis patients in India who have failed or are intolerant to TNF-α antagonists, with demonstrated efficacy in achieving clinical remission in biologic-naïve Indian patients. 1

Treatment Algorithm for Moderate to Severe UC in India

First-Line Therapy

• 5-ASA compounds (mesalamine) for mild-moderate disease
• Corticosteroids for moderate-severe disease
• For steroid-dependent or steroid-refractory cases, proceed to biologics 2

Second-Line Therapy Options

1. TNF-α antagonists (first-line biologics):

   • Infliximab or vedolizumab preferred over adalimumab for induction of remission 3
   • Golimumab as an alternative option

2. JAK Inhibitors (after TNF-α failure):

   • Tofacitinib recommended specifically after failure of or intolerance to TNF-α antagonists 3
   • FDA and regulatory guidelines specifically position tofacitinib as second-line after TNF-α antagonist failure 3

Evidence for Tofacitinib in Indian Patients

Recent Indian multicenter data shows promising results for tofacitinib in biologic-naïve patients:

• 70.2% achieved clinical remission after 8 weeks of therapy
• 59.6% maintained remission at 24 weeks
• Baseline serum albumin was an independent predictor of remission at 8 weeks 1

Dosing Recommendations

• Induction phase: 10 mg twice daily for 8 weeks
• Maintenance phase: 5 mg twice daily for most patients
• Higher maintenance dose (10 mg twice daily) may be considered in patients who lose response at 5 mg, but with careful monitoring due to increased risks 3, 4
• Approximately 25-29% of patients who are de-escalated to the lower maintenance dose may not maintain remission 3

Safety Considerations in Indian Population

Infection Risks

• Higher risk of herpes zoster infection (4.1 per 100 patient-years) 5
• In Indian patients specifically, observed adverse events included:
  • Tuberculosis (4.2%)
  • CMV colitis (2.1%)
  • Herpes zoster (2.1%) 1

Cardiovascular Risks

• Increased risk of pulmonary embolism and major adverse cardiovascular events with 10 mg twice daily dosing 3, 4
• Avoid high dose in patients with risk factors: heart failure, malignancy, recent surgery, coagulation disorders, previous thromboembolism, combined contraceptive therapy 3

Monitoring Requirements

• Do not initiate if:
  • Absolute lymphocyte count <500 cells/mm³
  • Absolute neutrophil count <1000 cells/mm³
  • Hemoglobin <9 g/dL 4
• Consider TB screening and zoster vaccination before starting therapy, particularly important in the Indian setting 3, 1

Advantages of Tofacitinib in the Indian Context

• Oral administration (versus injectable biologics)
• No immunogenicity issues (unlike biologics)
• Demonstrated efficacy in Indian patients 1
• May be preferred for patients valuing convenience of oral administration 3

Limitations and Caveats

• Limited long-term safety data specific to Indian population
• Higher infection risks, particularly TB, which is endemic in India
• Regulatory positioning as second-line therapy after TNF-α antagonist failure
• Cardiovascular risk considerations with higher dosing

Conclusion

For moderate to severe UC patients in India, JAK inhibitors like tofacitinib represent an effective second-line option after TNF-α antagonist failure. Recent Indian data supports its efficacy even in biologic-naïve patients, but safety monitoring is essential, particularly for infections like TB and herpes zoster that may have higher prevalence in India.