What considerations should be taken when choosing between Tofacitinib (Xeljanz), Upadacitinib (Rinvoq), and biologics such as Adalimumab (Humira), Infliximab (Remicade), Vedolizumab (Entyvio), and Ustekinumab (Stelara) for Inflammatory Bowel Disease (IBD) treatment?

Considerations for Choosing Between Tofacitinib, Upadacitinib, and Biologics in IBD Treatment

For patients with moderate-to-severe IBD, treatment selection should prioritize higher efficacy medications like infliximab, vedolizumab, upadacitinib, or risankizumab over lower efficacy options like adalimumab, with JAK inhibitors (tofacitinib, upadacitinib) reserved for TNF-antagonist failures due to safety concerns. 1

Efficacy Considerations

For Biologic-Naïve Patients:

• For ulcerative colitis (UC), higher efficacy medications should be prioritized: infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab 1
• For Crohn's disease (CD), infliximab and risankizumab are favored over ustekinumab, adalimumab, vedolizumab, and certolizumab 1
• Infliximab or vedolizumab are suggested over adalimumab for induction of remission in biologic-naïve UC patients 1
• JAK inhibitors (tofacitinib, upadacitinib) should not be used as first-line therapy in biologic-naïve patients per FDA recommendations 1

For Biologic-Exposed Patients:

• For UC patients with prior TNF-antagonist exposure, higher efficacy medications are recommended: tofacitinib, upadacitinib, ustekinumab 1
• For infliximab-exposed UC patients, particularly those with primary non-response, ustekinumab or tofacitinib are suggested over vedolizumab or adalimumab 1
• For CD patients with TNF-antagonist exposure, risankizumab and upadacitinib are favored over ustekinumab, adalimumab, and vedolizumab 1
• Real-world data shows vedolizumab, infliximab, and ustekinumab have lower discontinuation rates than adalimumab as second-line biologics 2

Safety Considerations

Infection Risk:

• Ustekinumab is associated with a 32% lower risk of serious infections compared to TNF antagonists in UC patients 1
• In CD patients, ustekinumab shows a 51% lower risk of serious infections compared to TNF antagonists and 60% lower risk compared to vedolizumab 1
• JAK inhibitors (tofacitinib, upadacitinib) and TNF antagonists may have an increased risk of serious infections, though the magnitude is small for most patients 1
• Vedolizumab and anti-IL therapies (ustekinumab, risankizumab) may be preferred in patients at higher risk of immunosuppression-related infections 1

Cardiovascular and Malignancy Risk:

• JAK inhibitors may be associated with higher risk of major adverse cardiovascular events and cancer than TNF antagonists in older adults with cardiovascular risk factors 1
• FDA and EMA recommend cautious use of JAK inhibitors in patients aged 65 years or older, smokers, and those with history of cardiovascular disease or cancer 1

COVID-19 Risk Stratification:

• TNF antagonists (infliximab, adalimumab, golimumab), ustekinumab, vedolizumab, JAK inhibitors (tofacitinib), and other immunomodulators are classified as "moderate risk" during the COVID-19 pandemic 1
• Combination therapy with biologics plus immunomodulators within 6 weeks of starting treatment places patients in the "highest risk" category 1

Special Populations

Pregnancy:

• Limited data exists on the safety of JAK inhibitors and S1P receptor modulators in pregnancy; these drugs should be avoided in women of childbearing age contemplating pregnancy 1
• TNF antagonists and vedolizumab have more established safety profiles in pregnancy 1

Elderly and Comorbid Patients:

• JAK inhibitors should be used cautiously in patients ≥65 years old or with cardiovascular risk factors 1
• Vedolizumab's gut-selective mechanism may be advantageous for patients with multiple comorbidities or at higher risk of systemic immunosuppression 1

Combination Therapy Considerations

TNF Antagonists:

• Combining TNF antagonists with thiopurines or methotrexate is suggested over biologic monotherapy 1
• Patients with less severe disease who prioritize safety over efficacy may reasonably choose biologic monotherapy 1

Vedolizumab and Ustekinumab:

• Limited evidence supports routine use of thiopurines or methotrexate with vedolizumab or ustekinumab compared to monotherapy 1
• Addition of thiopurine to vedolizumab may reduce risk of treatment failure in CD 1
• Small case series suggest combining vedolizumab with other biologics or tofacitinib may be effective in refractory IBD 3

Practical Considerations

Route of Administration:

• Subcutaneous formulations of infliximab and vedolizumab show comparable efficacy to IV maintenance doses 1
• Patients with less severe disease who value convenience may prefer self-administered subcutaneous injections like adalimumab 1

Monitoring and Optimization:

• Annual review is recommended for patients on biologic therapies 1
• For patients with severe disease, extended induction regimens (up to 16 weeks) or dose escalation may be beneficial for certain agents 1
• Therapeutic drug monitoring can guide decisions about switching within or outside a drug class after loss of response 1

Algorithm for Treatment Selection

1. First-line therapy for biologic-naïve patients:

   • UC: Infliximab or vedolizumab preferred 1
   • CD: Infliximab or risankizumab preferred 1

2. After TNF-antagonist failure:

   • UC: Ustekinumab, tofacitinib, or upadacitinib 1
   • CD: Ustekinumab, risankizumab, or upadacitinib 1

3. For patients at higher infection risk:

   • Consider vedolizumab or ustekinumab due to lower infection rates 1

4. For elderly patients or those with cardiovascular risk factors:

   • Avoid JAK inhibitors; prefer TNF antagonists, vedolizumab, or ustekinumab 1

5. For women planning pregnancy:

   • Avoid JAK inhibitors and S1P receptor modulators; prefer TNF antagonists or vedolizumab 1