What is the role of Tofacitinib (Janus kinase inhibitor) in the treatment of ankylosing spondylitis?

Role of Tofacitinib in Ankylosing Spondylitis Treatment

Tofacitinib is considered a third-line therapy option for ankylosing spondylitis, recommended only after failure of NSAIDs, TNF inhibitors, and IL-17 inhibitors, due to its limited evidence base and less favorable safety profile. 1

Treatment Algorithm for Ankylosing Spondylitis

1. First-line therapy: NSAIDs

   • Continuous treatment with NSAIDs is conditionally recommended over on-demand treatment 1
   • Lack of response to at least 2 different NSAIDs at maximal doses over 1 month, or incomplete responses over 2 months, constitutes adequate trial before escalating therapy 1

2. Second-line therapy: TNF inhibitors (TNFi)

   • Strongly recommended for patients with active AS despite NSAID treatment 1
   • No particular TNFi is recommended as preferred choice 1

3. Alternative second-line therapy: IL-17 inhibitors

   • Secukinumab or ixekizumab are strongly recommended for patients with active AS despite NSAID treatment 1
   • TNFi are conditionally recommended over secukinumab or ixekizumab as first biologic 1, 2

4. Third-line therapy options:

   • Tofacitinib
     • Conditionally recommended only after failure of NSAIDs when other biologics are not available 1
     • TNFi are conditionally recommended over tofacitinib 1
     • Secukinumab or ixekizumab are conditionally recommended over tofacitinib 1

Efficacy of Tofacitinib in Ankylosing Spondylitis

Tofacitinib has demonstrated efficacy in clinical trials:

• In a phase II trial, tofacitinib 5mg twice daily showed significantly higher ASAS20 response rates compared to placebo (80.8% vs 41.2%; p<0.001) 3
• In a phase III trial, tofacitinib 5mg twice daily demonstrated:
  • ASAS20 response rate of 56.4% vs 29.4% with placebo (p<0.0001) 4
  • ASAS40 response rate of 40.6% vs 12.5% with placebo (p<0.0001) 4
• Efficacy was observed in both biologic-naive and TNFi-inadequate responder patients, though absolute response magnitude was generally greater in biologic-naive patients 5

Special Clinical Scenarios

1. Patients with contraindications to TNFi:

   • If contraindication is heart failure or demyelinating disease:
     • Secukinumab or ixekizumab are preferred over tofacitinib 1
   • If contraindication is tuberculosis or high infection risk:
     • Sulfasalazine is preferred over secukinumab, ixekizumab, and tofacitinib 1

2. Patients with coexisting ulcerative colitis:

   • If TNFi is not an option, tofacitinib may be considered over IL-17 inhibitors 1
   • IL-17 inhibitors have not shown efficacy in inflammatory bowel disease, while tofacitinib is approved for ulcerative colitis 1

3. Patients with primary non-response to TNFi:

   • Secukinumab or ixekizumab are conditionally recommended over switching to a different TNFi or tofacitinib 1

Safety Considerations

• In clinical trials up to 48 weeks, tofacitinib safety profile included:

  • Herpes zoster (non-serious): 2.3% of patients 4
  • Serious infections: 0.8% of patients 4
  • Adjudicated hepatic events: 2.3% of patients 4
  • No reported malignancies, major adverse cardiovascular events, thromboembolic events, or opportunistic infections in the phase III trial 4

• However, the ORAL Surveillance study showed tofacitinib to be inferior to TNFi when comparing adverse events 6, which contributes to its positioning after TNFi and IL-17 inhibitors in the treatment algorithm

Clinical Pearls and Pitfalls

• Pitfall: Using tofacitinib as first-line biologic therapy instead of TNFi or IL-17 inhibitors

  • Avoid by: Following the recommended treatment sequence (NSAIDs → TNFi → IL-17 inhibitors → tofacitinib)

• Pitfall: Overlooking comorbidities that might influence treatment choice

  • Avoid by: Considering inflammatory bowel disease (where tofacitinib may be preferred over IL-17 inhibitors) or infection risk (where tofacitinib should be avoided)

• Pitfall: Inadequate monitoring for adverse events

  • Avoid by: Regular laboratory monitoring for liver function abnormalities and vigilance for infections, particularly herpes zoster

• Pearl: Consider baseline CRP levels when evaluating potential response

  • Patients with elevated CRP (≥5 mg/L) may show numerically higher treatment effects with tofacitinib compared to those with normal CRP 7