What treatment options are available for a patient with moderate to severe Crohn's disease who has failed Upadacitinib (Rinvoq) therapy, considering combination therapy with Upadacitinib and another biologic, such as Infliximab (Remicade), Risankizumab (Skyrizi), or Ustekinumab (Stelara)?

Combination Therapy with Upadacitinib After Upadacitinib Failure: Evidence and Recommendations

Direct Answer

There is emerging evidence supporting combination therapy of upadacitinib with biologics (infliximab, risankizumab, ustekinumab, or vedolizumab) in patients with refractory Crohn's disease who have failed upadacitinib monotherapy, though this approach contradicts FDA labeling and current guidelines. 1

Critical FDA Labeling Restriction

The FDA explicitly states that upadacitinib "is not recommended for use in combination with other JAK inhibitors, biological therapies for Crohn's disease, or with potent immunosuppressants such as azathioprine and cyclosporine." 2 This represents a clear contraindication to the combination approach you are considering.

Available Research Evidence

Single Case Series Data

A 2025 descriptive case series represents the only published evidence on this specific combination strategy: 1

• 27 patients with refractory Crohn's disease received combination therapy with upadacitinib plus:
  • Risankizumab (n=17, most common)
  • Vedolizumab (n=6)
  • Ustekinumab (n=3)
  • Infliximab (n=1)

Short-term outcomes (12 weeks): 1

• Clinical response: 24/27 patients (89%)
• Steroid-free remission: 9/27 patients (33%)
• Endoscopic response: frequently observed

Longer-term outcomes (52 weeks): 1

• Clinical response: 15/20 patients (75%)
• Steroid-free remission: 11/20 patients (55%)

Safety concerns: 1

• Adverse events occurred in 13/27 patients (48%)
• Treatment discontinuation required in 3/27 patients (11%)
• Specific adverse events not detailed in available data

Alternative Evidence-Based Approaches After Upadacitinib Failure

Switch to Risankizumab (Preferred Option)

Risankizumab represents the strongest alternative after upadacitinib failure based on guideline-level evidence: 3

• Superior to ustekinumab in TNF-antagonist exposed patients (SEQUENCE trial data) 4
• Ranked highest alongside upadacitinib for biologic-exposed Crohn's disease 3
• Novel mechanism (IL-23 inhibition) provides different pathway than JAK inhibition 4

Switch to Ustekinumab

Ustekinumab shows strong persistence and efficacy data: 5

• Mean treatment duration: 27.65 months with 86.76% persistence 5
• Clinical remission rates: 54.9% at year 1,76.92% at year 4 5
• Superior persistence compared to anti-TNF: 93.2% vs 72.06% at year 1 5
• Particularly effective for perianal disease: 70% clinical remission, 40% complete fistula healing 5

Consider Infliximab (If Not Previously Failed)

Infliximab remains a guideline-recommended option: 3

• Ranked highest alongside risankizumab for biologic-naïve Crohn's disease 3
• Subcutaneous formulation now available with noninferior efficacy to IV 4

Clinical Decision Algorithm

Step 1: Verify upadacitinib failure pattern

• Primary non-response vs. secondary loss of response
• Duration of adequate dosing (45mg induction, 15-30mg maintenance) 6

Step 2: Assess prior biologic exposure

• If no prior IL-23 inhibitor exposure → Switch to risankizumab 3, 4
• If perianal disease predominates → Consider ustekinumab 5
• If limited prior biologic exposure → Consider infliximab 3

Step 3: Do NOT combine upadacitinib with biologics in routine practice

• FDA labeling explicitly prohibits this 2
• Only one small case series exists (n=27) 1
• 48% adverse event rate in combination therapy 1

Critical Pitfalls to Avoid

Regulatory violation: Combining upadacitinib with biologics violates FDA labeling and could expose you to liability 2

Immunosuppression risk: The case series showed high adverse event rates (48%) with combination therapy, though specific infections were not detailed 1

Lack of comparative data: No head-to-head trials compare combination therapy to sequential monotherapy switching 1

Insurance denial: Payers will likely deny coverage for off-label combination therapy that contradicts FDA labeling 2

When Combination Might Be Considered (Research Context Only)

If you are considering this approach despite FDA restrictions, the case series suggests: 1

• Risankizumab + upadacitinib was the most commonly used combination (17/27 patients)
• Close monitoring for adverse events is essential (occurred in 48%)
• Consider enrollment in prospective clinical trials rather than off-label use
• Obtain informed consent documenting off-label, FDA-contradicted use

However, switching to risankizumab monotherapy remains the evidence-based, guideline-supported, and FDA-compliant approach for upadacitinib failure in Crohn's disease. 3, 4