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

Tofacitinib in Spondyloarthritis

Tofacitinib is a lower-tier treatment option for ankylosing spondylitis that should only be used after TNF inhibitors and IL-17 inhibitors have been tried, or in the specific scenario of coexisting ulcerative colitis when TNF inhibitors are not an option. 1

Treatment Hierarchy for Ankylosing Spondylitis

The American College of Rheumatology establishes a clear treatment algorithm that places tofacitinib well down the therapeutic ladder:

First-Line Therapy

• NSAIDs remain the initial treatment for active ankylosing spondylitis, with patients requiring inadequate response to at least 2 different NSAIDs at maximal doses over 1 month before escalating therapy 1

Second-Line Therapy

• TNF inhibitors are strongly recommended as the preferred biologic therapy after NSAID failure 1, 2
• IL-17 inhibitors (secukinumab or ixekizumab) are strongly recommended as alternatives, though TNF inhibitors are conditionally preferred over IL-17 inhibitors based on greater clinical experience and long-term safety data 1

Third-Line Therapy

• Tofacitinib ranks below both TNF inhibitors AND IL-17 inhibitors in the treatment hierarchy 1
• The ACR conditionally recommends TNF inhibitors over tofacitinib (PICO 60) 1
• The ACR conditionally recommends IL-17 inhibitors over tofacitinib (PICO 61) 1
• This lower ranking is justified by the smaller evidence base for tofacitinib compared to TNF inhibitors and IL-17 inhibitors 1

Evidence Supporting Tofacitinib Efficacy

Despite its lower position in treatment algorithms, tofacitinib does demonstrate clinical efficacy:

• Phase III data show significant benefit: ASAS20 response rate of 56.4% with tofacitinib versus 29.4% with placebo at week 16 (p<0.0001) 3
• ASAS40 response rates: 40.6% with tofacitinib versus 12.5% with placebo at week 16 (p<0.0001) 3
• Dose-response relationship: The 5 mg twice daily dose demonstrated 80.8% ASAS20 response versus 41.2% placebo in phase II trials 4
• Sustained efficacy: Clinical responses were maintained through 48 weeks of open-label treatment 3

Specific Clinical Scenarios Where Tofacitinib May Be Preferred

Coexisting Ulcerative Colitis

This is the most important exception to the treatment hierarchy. When patients have both ankylosing spondylitis and ulcerative colitis, and TNF inhibitors are not an option, tofacitinib should be considered over IL-17 inhibitors 1. The rationale:

• IL-17 inhibitors have not shown efficacy in inflammatory bowel disease 1
• Tofacitinib is FDA-approved for ulcerative colitis treatment 1

Contraindications to TNF Inhibitors

When TNF inhibitors are contraindicated (tuberculosis, chronic infection, high infection risk), the ACR conditionally recommends IL-17 inhibitors over tofacitinib 1. However, if IL-17 inhibitors are also not suitable, tofacitinib becomes a consideration 2

Performance in TNF Inhibitor-Inadequate Responders

Tofacitinib shows efficacy in patients who have failed TNF inhibitors, though responses are attenuated:

• bDMARD-naive patients: ASAS20 treatment difference of 30.8% (95% CI: 19.1%-42.6%) 5
• TNF inhibitor-inadequate responders: ASAS20 treatment difference of 19.4% (95% CI: 1.7%-37.0%) 5
• The absolute magnitude of responses is generally greater in biologic-naive patients compared to TNF inhibitor-experienced patients 5
• Higher discontinuation rates in TNF inhibitor-inadequate responders (12.9%) versus biologic-naive patients (3.9%) 5

Baseline CRP and Treatment Response

Baseline inflammatory markers influence treatment outcomes:

• Elevated CRP (≥5 mg/L) is associated with numerically higher placebo-adjusted efficacy responses compared to normal CRP (<5 mg/L) 6
• Patients with CRP ≥10 mg/L show similar patterns of enhanced treatment effect 6
• However, tofacitinib demonstrates efficacy versus placebo regardless of baseline CRP level 6

Safety Profile

The safety profile of tofacitinib in ankylosing spondylitis is consistent with its use in other indications:

• Adverse event rates: 54.9% with tofacitinib versus 51.5% with placebo through week 16 3
• Serious adverse events: 1.5% with tofacitinib versus 0.7% with placebo through week 16 3
• Herpes zoster: 2.3% non-serious cases through week 48 3
• Hepatic events: 2.3% adjudicated hepatic events through week 48 3
• No deaths, malignancies, major adverse cardiovascular events, or thromboembolic events were reported in the phase III trial 3

Critical Pitfalls to Avoid

Do Not Use Tofacitinib as First-Line Therapy

• Never initiate tofacitinib before trying NSAIDs 2
• Never use tofacitinib before TNF inhibitors or IL-17 inhibitors unless specifically indicated (e.g., coexisting ulcerative colitis) 2

Do Not Overlook the Treatment Algorithm

• The conditional recommendations against tofacitinib as early therapy reflect both limited evidence base and established efficacy of other agents 1
• When patients with contraindications to TNF inhibitors exist, IL-17 inhibitors should still be prioritized over tofacitinib in most cases 1

Consider Concomitant Medications

• In patients with high infection risk, sulfasalazine may be preferred over tofacitinib, IL-17 inhibitors, and TNF inhibitors 1
• Efforts should be made to mitigate infectious contraindications to allow use of more effective biologics 1