What are the considerations for prolonged combination therapy with anti-Tumor Necrosis Factor (anti-TNF) agents and azathioprine in patients with Crohn's disease?

From the Guidelines

Prolonged combination therapy with anti-TNF agents and azathioprine in Crohn's disease should be considered for patients who have achieved long-term remission, but monotherapy with anti-TNF agents like infliximab can be suggested due to similar relapse rates and uncertain safety profiles of combination therapy 1. When evaluating the need for prolonged combination therapy, several factors should be considered, including:

• Disease severity and response to initial combination therapy
• Presence of complex disease phenotypes, such as fistulizing or perianal disease
• High-risk features like young age at diagnosis or extensive disease
• Previous loss of response to monotherapy Potential risks of prolonged combination therapy include:
• Increased infection risk, particularly for opportunistic infections
• A small but significant increased risk of lymphoma, especially hepatosplenic T-cell lymphoma in young males, with an estimated absolute rate of 1.9 per 10,000 patient-years 1 Laboratory monitoring should be performed regularly, including:
• Complete blood counts
• Liver function tests
• Metabolite testing for azathioprine (6-TGN levels) every 3-6 months Typical dosing for combination therapy includes:
• Infliximab (5 mg/kg every 8 weeks)
• Adalimumab (40 mg every 2 weeks)
• Certolizumab pegol (400 mg every 4 weeks)
• Azathioprine (2-2.5 mg/kg/day) Additionally, annual skin examinations and vaccination updates are recommended to minimize potential risks associated with immunosuppression. The decision to continue combination therapy or transition to monotherapy should be made on a case-by-case basis, taking into account the individual patient's response to treatment, disease characteristics, and potential risks 1.

From the FDA Drug Label

Patients receiving immunosuppressants, including AZASAN, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with AZASAN. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Some of the patients were treated with AZASAN as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis Serious Infections: Patients receiving immunosuppressants, including AZASAN, are at increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections.

The considerations for prolonged combination therapy with anti-TNF agents and azathioprine in patients with Crohn's disease include:

• Increased risk of malignancy, particularly lymphoma and skin cancer
• Risk of hepatosplenic T-cell lymphoma (HSTCL), a rare and aggressive type of lymphoma
• Increased risk of serious infections, including bacterial, viral, fungal, protozoal, and opportunistic infections These risks should be carefully weighed against the potential benefits of combination therapy, and patients should be closely monitored for signs of malignancy or infection 2.

From the Research

Considerations for Prolonged Combination Therapy

• The decision to prolong combination therapy with anti-TNF agents and azathioprine in patients with Crohn's disease should be based on individual patient factors, including disease severity and response to treatment 3, 4.
• Azathioprine discontinuation earlier than 6 months is associated with loss of response and the need for anti-TNF dose escalation 3.
• Combination therapy has been shown to be superior to monotherapy for decreasing the risk of inflammatory bowel disease-related complications 5.
• The choice of immunomodulator or biologic may impact the effectiveness of combination therapy, with azathioprine being superior to methotrexate in ulcerative colitis 5.

Benefits of Combination Therapy

• Combination therapy can reduce the reliance on corticosteroid-based therapies and avoid corticosteroid-associated adverse events 6.
• Anti-TNF agents have been shown to be superior to azathioprine for minimizing exposure to corticosteroids 6.
• Combination therapy can decrease the likelihood of treatment failure in both Crohn's disease and ulcerative colitis 5.

Disease Severity and Prognostic Factors

• Patients with complicated disease or bowel damage, and with poor prognostic factors and/or severe disease, may benefit from anti-TNF treatment as first-line therapy 7.
• Treatment of Crohn's disease should be based on disease stages, including mild, moderate, and severe 7.
• Patients with mild-to-moderate Crohn's disease without poor prognostic factors and with uncomplicated disease may be treated with steroids and thiopurine as first-line therapy 7.