What are the benefits and risks of Xeljanz (Tofacitinib) compared to other treatments for conditions like rheumatoid arthritis, psoriatic arthritis, or ulcerative colitis?

Xeljanz (Tofacitinib) Benefits and Risks: Key Talking Points

Tofacitinib should be used with caution and only when other treatment options have failed, particularly in patients over 65 or with cardiovascular risk factors, due to increased risks of serious adverse events including thrombosis, malignancy, and cardiovascular events. 1, 2

Mechanism and Indications

• Tofacitinib is an oral Janus kinase (JAK) inhibitor that works by blocking the JAK/STAT pathway, inhibiting multiple cytokines involved in inflammatory processes 3
• FDA-approved for treating:
  • Rheumatoid arthritis (RA) in adults who have had inadequate response to TNF blockers
  • Psoriatic arthritis (PsA) with similar restrictions
  • Ulcerative colitis (UC) in adults who have had inadequate response to TNF blockers
  • Ankylosing spondylitis after TNF blocker failure
  • Polyarticular course juvenile idiopathic arthritis in patients 2 years and older 2

Benefits

• Efficacy in Ulcerative Colitis:

  • High certainty evidence for large benefit in maintaining remission with both 5mg and 10mg twice daily doses 1
  • Low to moderate certainty for small to moderate benefit in inducing remission 1
  • Effective for retreatment after a break in therapy, with response rates of 75.8% at 2 months 1

• Efficacy in Rheumatoid Arthritis:

  • Comparable efficacy to biologic DMARDs, including TNF inhibitors 1, 3
  • Some studies showed non-inferiority to adalimumab 1

• Administration Advantages:

  • Oral administration (unlike injectable biologics)
  • No immunogenicity issues (being a small molecule rather than a protein) 1
  • May be preferred by patients who desire oral route of administration 1

Risks and Safety Concerns

• FDA Boxed Warnings 2:

  • Serious infections leading to hospitalization or death
  • Increased all-cause mortality compared to TNF blockers in RA
  • Malignancies (higher rates of lymphomas and lung cancers)
  • Major adverse cardiovascular events (MACE)
  • Thrombosis (pulmonary embolism, venous and arterial thrombosis)

• Cardiovascular and Thrombotic Risks:

  • The ORAL surveillance study showed increased risk of major adverse cardiac events (MACE) and cancer compared to TNF inhibitors in RA patients over 50 with cardiovascular risk factors 1
  • Five-fold increase in pulmonary embolus for patients on 10mg twice daily compared to TNF inhibitor therapy 1
  • Venous thromboembolism (VTE) risk is higher in patients with risk factors such as previous history of thromboembolic events, high BMI, hormone replacement therapy, and older age 1, 4

• Infection Risks:

  • Increased risk of herpes zoster (both non-serious and serious) with IRs of 3.6,1.8,3.5 and 2.4 for RA, PsA, UC and PsO, respectively 5
  • Risk of serious infections with IRs of 2.5,1.2,1.7 and 1.3 for RA, PsA, UC and PsO, respectively 5
  • Higher rate of serious infections in patients over 65 years with cardiovascular risk factors compared to TNF inhibitors 1

• Malignancy Risks:

  • Meta-analysis showed slightly higher cancer risk compared to TNF inhibitors (RR = 1.40; 95% CI, 1.06-2.08) 6
  • In the UC clinical program, malignancy events were infrequent (IR 0.75; 95% CI, 0.46-1.16) 7

Regulatory Considerations and Recommendations

• FDA Restrictions:

  • In the US, tofacitinib requires prior failure of or contraindications to TNF antagonists before use 1
  • Recommended dose for RA and PsA is 5mg twice daily or 11mg extended-release once daily 2

• European Medicines Agency (EMA) Cautions:

  • JAK inhibitors should only be used when no suitable alternatives are available in:
    • Patients aged 65 years or above
    • Those at increased risk of cardiovascular problems
    • Current or long-term past smokers
    • Those at increased risk of cancer 1
  • Doses should be reduced in patients at risk of VTE, cancer, or cardiovascular problems 1

• Contraindications:

  • Severe active infections, acute or chronic, including latent TB and opportunistic infections 1
  • Should be avoided during pregnancy and lactation 1
  • Use with caution in patients with malignancy history 1

Comparative Positioning

• In biologic-naïve UC patients, other agents like infliximab, vedolizumab, risankizumab, and ozanimod showed superiority over adalimumab 1
• In biologic-exposed UC patients, upadacitinib demonstrated superior efficacy 1
• For patients requiring oral administration, JAK inhibitors or S1P receptor modulators may be preferred options 1
• Safety data from tofacitinib use in UC does not show the same level of risk as seen in RA studies 1

Monitoring Recommendations

• Screen for tuberculosis, hepatitis, and HIV before initiating therapy 1
• Do not initiate if absolute lymphocyte count <500 cells/mm³, absolute neutrophil count <1000 cells/mm³, or hemoglobin <9 g/dL 2
• Monitor for signs of infection, thrombosis, and cardiovascular events 2
• Consider zoster vaccination before starting therapy in those aged over 70 years and those over 50 years at high risk 1