What is the role of upadacitinib (Rinvoq) for a patient with ulcerative colitis, anterior uveitis, and ankylosing spondylitis who has failed conventional therapy?

Upadacitinib for Ulcerative Colitis with Iridocyclitis and Ankylosing Spondylitis

Upadacitinib 15 mg once daily is the preferred JAK inhibitor for this patient after failure of conventional therapy, as it is the only agent with regulatory approval for both ulcerative colitis and ankylosing spondylitis, and unlike IL-17 inhibitors, it does not exacerbate inflammatory bowel disease. 1, 2

First-Line Treatment Strategy

TNF inhibitor monoclonal antibodies (infliximab or adalimumab) should be attempted first before considering upadacitinib, as they remain the gold standard for patients with this triple disease presentation. 3, 1

• Infliximab or adalimumab are FDA-approved for all three conditions (ulcerative colitis, ankylosing spondylitis, and anterior uveitis), providing simultaneous disease control. 3, 1
• These monoclonal antibodies have superior efficacy for anterior uveitis compared to other biologics, with observational data showing uveitis rates of 13.6 per 100 patient-years for adalimumab and 27.5 for infliximab, compared to pre-treatment rates of 36.8 and 45.5 respectively. 3
• Golimumab is approved for ulcerative colitis and ankylosing spondylitis but has less robust data for uveitis, making it a second-tier TNF inhibitor option. 3

Absolutely Contraindicated Agents

Etanercept must never be used in this patient population, as it lacks efficacy for ulcerative colitis and has been associated with new-onset or worsening inflammatory bowel disease. 3, 4

IL-17 inhibitors (secukinumab, ixekizumab) are absolutely contraindicated because they can trigger new-onset inflammatory bowel disease or cause exacerbations of existing ulcerative colitis, despite their efficacy for ankylosing spondylitis. 3, 1, 2

Role of Upadacitinib After TNF Inhibitor Failure

Primary Non-Response to First TNF Inhibitor

Switch directly to upadacitinib 15 mg once daily rather than trying another TNF inhibitor when the initial TNF inhibitor produces no primary response. 1, 2

• Upadacitinib is approved by the EMA for both ulcerative colitis and ankylosing spondylitis, making it uniquely suited for this dual-disease presentation. 1, 2
• The FDA has approved upadacitinib for moderate-to-severe ulcerative colitis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis after inadequate response or intolerance to TNF inhibitors. 5, 6
• Expert consensus supports JAK inhibitor use with 86-91% agreement after primary TNF inhibitor failure in patients with inflammatory bowel disease-associated spondyloarthritis. 3, 1, 2

Secondary Non-Response or Intolerance to First TNF Inhibitor

Attempt dose escalation of the current TNF inhibitor first, then switch to a different monoclonal antibody TNF inhibitor (e.g., infliximab to adalimumab) if escalation fails. 3, 1

Upadacitinib remains an appropriate alternative in this scenario, with expert agreement ranging from 82-100% for JAK inhibitor use after secondary TNF inhibitor failure. 3, 1

Clinical Efficacy Data for Upadacitinib

Ulcerative Colitis Outcomes

Upadacitinib demonstrates superior efficacy compared to placebo for both induction and maintenance of clinical and endoscopic remission in moderate-to-severe ulcerative colitis. 6, 7

• In real-world experience with heavily pre-treated patients (100% prior anti-TNF exposure, 89.3% with ≥2 advanced therapies), 81.5% achieved clinical remission by week 8. 8
• Clinical response occurs rapidly, with remission rates of 36% as early as week 2 in ulcerative colitis patients. 8
• Among patients who previously failed tofacitinib, 77.8% still achieved clinical remission with upadacitinib by 8 weeks, demonstrating efficacy even after prior JAK inhibitor exposure. 8
• Extended induction therapy may benefit non-responders: 59.1% of patients without clinical response at week 8 achieved response after an additional 8 weeks of upadacitinib 45 mg. 9

Ankylosing Spondylitis Outcomes

Upadacitinib is proven effective for ankylosing spondylitis and is recommended by the American College of Rheumatology and European League Against Rheumatism for active axial spondyloarthritis after inadequate response to NSAIDs or biologic DMARDs. 2

TNF inhibitors remain first-line for most patients, but upadacitinib 15 mg once daily is an appropriate alternative, particularly when TNF inhibitors are contraindicated or have failed. 2

Anterior Uveitis Considerations

There is no direct evidence for upadacitinib's efficacy in anterior uveitis, as this was not a primary endpoint in clinical trials. However, the drug's anti-inflammatory mechanism through JAK1 inhibition may provide benefit. 6, 7

If uveitis control is inadequate on upadacitinib, consultation with ophthalmology is essential, as monoclonal antibody TNF inhibitors (adalimumab, infliximab) have the strongest evidence for reducing uveitis flares. 3

Mandatory Pre-Treatment Screening

Screen all patients for latent tuberculosis with clinical risk stratification, chest X-ray, and interferon-gamma release assay before initiating upadacitinib. 3, 1, 2, 5

Test for hepatitis B surface antigen, hepatitis C, and HIV to prevent fatal reactivations under JAK inhibition. 3, 1, 2

Obtain baseline complete blood count with differential, liver enzyme panel, and lipid profile prior to therapy initiation. 1, 2, 5

Assess for active infections and treat any identified infections before starting upadacitinib. 2, 5

Monitoring Requirements During Treatment

Infection Surveillance

Monitor continuously for serious infections, especially tuberculosis and herpes zoster, as JAK inhibition markedly increases infection risk. 1, 5, 6

• Herpes zoster infection is the most common serious infection, with rates increasing with longer duration of exposure to upadacitinib. 6, 9, 7
• Discontinue upadacitinib immediately if a serious infection develops and treat according to standard protocols. 1, 5

Laboratory Monitoring

Perform serial complete blood counts to detect neutropenia, lymphopenia, or anemia during therapy. 1, 2, 5

Monitor liver enzymes regularly to identify potential hepatotoxicity. 1, 2, 5

Check cholesterol levels approximately 12 weeks after starting upadacitinib and as needed thereafter. 5

Assess inflammatory markers (ESR, CRP) and fecal calprotectin periodically to gauge disease activity and therapeutic response. 3, 8

• In real-world data, 62% of patients with elevated fecal calprotectin and 64% with elevated CRP normalized these markers by week 8 on upadacitinib. 8

Thromboembolic Risk

Monitor for signs of venous thromboembolism, as JAK inhibitors carry an FDA black box warning for increased thrombotic risk. 3, 2, 5

The FDA issued this warning based on tofacitinib data, and caution is advised in patients with acute severe ulcerative colitis, which itself is a risk factor for thrombosis. 3

Dosing Strategy

Induction therapy: Upadacitinib 45 mg once daily for 8 weeks for moderate-to-severe ulcerative colitis. 5, 9, 8

Maintenance therapy: Upadacitinib 15 mg once daily after achieving clinical response, as this dose is approved for both ulcerative colitis and ankylosing spondylitis. 1, 5, 9

• Upadacitinib 30 mg once daily may be considered for maintenance in ulcerative colitis patients requiring higher disease control, with 43.6% achieving clinical remission at week 52 compared to 26.5% with 15 mg. 9
• For ankylosing spondylitis, the standard dose is 15 mg once daily, so this dose provides optimal coverage for both conditions. 2, 5

Extended induction with upadacitinib 45 mg for an additional 8 weeks may be attempted in patients without clinical response at week 8, as 59.1% subsequently achieved response by week 16. 9

Agents to Avoid in This Population

Do not use sulfasalazine or methotrexate for axial ankylosing spondylitis, as there is no evidence for efficacy in axial disease. 3, 1, 2

• Sulfasalazine may only be considered for peripheral arthritis if present, but it provides no benefit for spinal involvement. 3

Systemic glucocorticoids have no proven benefit for axial disease and should be avoided for ankylosing spondylitis management. 3, 1

NSAIDs are contraindicated in active ulcerative colitis, though a short 2-4 week course of a selective COX-2 inhibitor is acceptable only when inflammatory bowel disease is in remission. 1

Do not use vedolizumab for this patient, as its gut-specific mechanism makes it ineffective for musculoskeletal manifestations and ankylosing spondylitis. 3

Rituximab, abatacept, and IL-6 inhibitors lack efficacy for ankylosing spondylitis and should not be used. 3, 1

Long-Term Management Strategy

Continue upadacitinib indefinitely after achieving remission, as discontinuation is associated with high risk of disease recurrence in both ulcerative colitis and ankylosing spondylitis. 1

Do not routinely taper or stop JAK inhibitor therapy once stable disease is achieved. 1

Maintain a structured physical therapy program for ankylosing spondylitis throughout treatment, as exercise and regular physiotherapy remain essential components of care. 3, 1

5-aminosalicylate compounds may be discontinued in ulcerative colitis once remission is achieved on upadacitinib, as they provide no additional benefit. 3

Common Pitfalls to Avoid

Do not switch a stable patient from an originator TNF inhibitor to its biosimilar without compelling rationale, as this is strongly discouraged. 3, 1

Do not add sulfasalazine or methotrexate to a failing TNF inhibitor for axial disease; instead, switch to upadacitinib or another biologic agent. 1, 2

Do not assume that acne is a reason to discontinue upadacitinib, as it is the most commonly reported adverse event (22.9% of patients) but is generally manageable. 7, 8

Do not delay treatment while awaiting stool culture results if acute severe ulcerative colitis is suspected; initiate corticosteroids promptly. 3

Do not use upadacitinib in pregnancy, as animal studies suggest potential harm to the unborn baby; effective contraception must be used during treatment and for 4 weeks after the last dose. 5