JAK Inhibitors in Ankylosing Spondylitis
JAK inhibitors (tofacitinib and upadacitinib) are effective for active ankylosing spondylitis but should be reserved as second-line therapy after TNF inhibitors or IL-17 inhibitors are contraindicated or unavailable, due to less long-term safety data and increased cardiovascular and malignancy risks in certain populations. 1
Treatment Positioning and Algorithm
TNF inhibitors and IL-17 inhibitors should be prioritized over JAK inhibitors as first-line biologic therapy for active ankylosing spondylitis that has failed NSAIDs. 1 The rationale is straightforward: TNF and IL-17 inhibitors have substantially more evidence from large observational studies and longer follow-up data, whereas JAK inhibitor evidence comes primarily from RCTs with shorter duration. 1
JAK inhibitors are strongly recommended when biologic DMARDs are contraindicated or unavailable. 1 This includes situations where:
- TNF inhibitors and IL-17 inhibitors have failed (primary or secondary failure) 1
- Access or cost barriers prevent use of biologics 1
- Patient preference for oral administration over injectable therapy 1
Approved JAK Inhibitors and Efficacy
Tofacitinib and upadacitinib are the approved JAK inhibitors for ankylosing spondylitis. 1, 2 Upadacitinib is FDA-approved specifically for adults with active ankylosing spondylitis who have had inadequate response or intolerance to one or more TNF blockers. 2
Both agents demonstrate robust efficacy:
- Tofacitinib achieved 56.4% ASAS20 response versus 29.4% placebo at week 16 (p<0.0001) 3
- Upadacitinib achieved 52% ASAS40 response versus 26% placebo at week 16 (p=0.0003) 3
- Filgotinib (selective JAK1 inhibitor) showed mean ASDAS improvement of -1.47 versus -0.57 with placebo (p<0.0001) 4
Critical Safety Considerations
In patients ≥65 years old with smoking history or cardiovascular risk factors or malignancy risk, JAK inhibitors should only be used if no suitable alternatives exist. 1, 5 This conditional recommendation stems from the ORAL Surveillance study showing tofacitinib 10mg twice daily was associated with increased cardiovascular events and malignancies compared to TNF inhibitors in rheumatoid arthritis patients ≥50 years with at least one cardiovascular risk factor. 1
Common adverse events include:
- Infections (most common), particularly herpes zoster which occurs more frequently than with TNF inhibitors 5
- Hematologic abnormalities including lymphocytopenia and anemia 5
- Venous thromboembolism and pulmonary embolism risk (warning issued even for 5mg twice daily dose) 5
- Tuberculosis and opportunistic infections 5
Special Clinical Scenarios
For ankylosing spondylitis with inflammatory bowel disease: Monoclonal antibody TNF inhibitors are strongly recommended over JAK inhibitors. 1 However, in ulcerative colitis patients with contraindication to or lack of access to monoclonal TNF inhibitors, JAK inhibitors are conditionally recommended. 1
For ankylosing spondylitis with uveitis: Monoclonal antibody TNF inhibitors are conditionally recommended over other biologics including JAK inhibitors for recurrent/refractory uveitis. 1
Treatment Failure Management
After primary failure of a first biologic (TNF or IL-17 inhibitor), switching to a JAK inhibitor is strongly recommended as an alternative to switching biologic mechanism. 1 For secondary failure of any agent (TNF inhibitor, IL-17 inhibitor, or JAK inhibitor), cycling or switching between any of the three mechanisms is strongly recommended. 1
Monitoring Requirements
Regular monitoring must include:
- Screening for tuberculosis before initiation 5
- Complete blood counts for hematologic abnormalities 5
- Surveillance for infections, particularly herpes zoster 5
- Recognition that CRP and ESR may be reduced independently of disease activity, potentially masking infections 5
Dosing and Contraindications
Dose reduction is required in patients with creatinine clearance <30 mL/min. 5 JAK inhibitors are contraindicated in severe hepatic impairment (Child Pugh C). 5
JAK inhibitors should not be combined with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants like azathioprine and cyclosporine. 2