Efficacy and Safety of Azathioprine in Ulcerative Colitis with 5-aminosalicylic acid Intolerance: A Single-Center Retrospective Cohort Study

Technical Summary: Efficacy and Safety of Azathioprine in Ulcerative Colitis with 5-ASA Intolerance

Problem Statement
Ulcerative colitis (UC) requires long-term maintenance therapy to prevent relapse and maintain endoscopic healing. While oral 5-aminosalicylic acid (5-ASA) is the standard first-line therapy, approximately 20% of patients develop intolerance, characterized by adverse events such as worsening diarrhea, fever, or organ toxicity (e.g., interstitial nephritis, pancreatitis). This intolerance often necessitates the discontinuation of 5-ASA, forcing a transition to alternative maintenance strategies. Azathioprine is an established immunomodulator for UC maintenance; however, its specific efficacy and safety profile in patients who are intolerant to 5-ASA remains unclear. There is a lack of direct comparative data regarding whether 5-ASA intolerance predisposes patients to poorer outcomes or higher discontinuation rates when treated with azathioprine.

Methodology
The authors conducted a single-center, retrospective cohort study at Tokyo Medical University Hospital involving patients diagnosed with UC between April 2014 and December 2023.

• Cohort: 66 patients receiving azathioprine for maintenance therapy were included. They were stratified into two groups: 15 patients with 5-ASA intolerance and 51 patients with 5-ASA tolerance.
• Definitions: 5-ASA intolerance was defined as an adverse event within 6 months of initiation preventing rechallenge, or a severe initial event precluding rechallenge. Relapse was defined as the initiation of prednisolone (≥20 mg/day) or advanced therapy. Adverse events were defined as symptoms or lab abnormalities attributable to azathioprine that resolved upon discontinuation.
• Endpoints:
  • Primary: Azathioprine continuation rates (time to discontinuation due to relapse or adverse events).
  • Secondary: Risk factors for discontinuation, risk factors for azathioprine-associated adverse events, continuation rates excluding adverse event-related discontinuations, and endoscopic outcomes (Mayo Endoscopic Subscore [MES] 0–1 and MES 0) at least one year post-initiation.
• Statistical Analysis: Comparisons between groups utilized the chi-square or Fisher's exact test for categorical variables and the Mann–Whitney U test for continuous variables. Survival analysis (Kaplan–Meier and log-rank test) assessed continuation rates. Univariate Cox proportional hazards and logistic regression models evaluated risk factors. Multivariable analysis was not performed due to the limited sample size of the 5-ASA intolerant group.

Key Results

• Baseline Characteristics: The 5-ASA intolerant group initiated azathioprine significantly sooner after diagnosis (median 69 days) compared to the tolerant group (median 1,513 days) and received a lower median starting dose (50 mg/day vs. 50–100 mg/day). No other significant baseline differences were observed regarding sex, disease extent, or history of acute severe UC.
• Azathioprine Continuation: Over a median follow-up of 805 days (intolerant) and 431 days (tolerant), 41 patients discontinued azathioprine (25 due to relapse, 16 due to adverse events).
  • Cumulative continuation rates at 1 and 3 years were 60.0% and 52.5% for the intolerant group, versus 52.6% and 46.3% for the tolerant group.
  • There was no statistically significant difference between groups (log-rank p = 0.404).
  • 5-ASA intolerance was not associated with an increased risk of discontinuation (Hazard Ratio [HR] 0.71; 95% CI 0.31–1.61; p = 0.407).
• Adverse Events: Adverse events led to discontinuation in 16 patients, most commonly liver dysfunction, nausea, and myelosuppression. 5-ASA intolerance was not significantly associated with the occurrence of azathioprine-associated adverse events (Odds Ratio [OR] 1.82; 95% CI 0.51–6.44; p = 0.354). Interestingly, a lower azathioprine dose was significantly associated with adverse events (OR 0.943; p = 0.025), though the authors note this may reflect reverse causation (dose reduction prior to discontinuation).
• Endoscopic Outcomes: Among patients with follow-up data, 5-ASA intolerance was not associated with achieving MES 0–1 (p = 0.279) or MES 0 (p = 0.803). No baseline factors significantly predicted endoscopic remission in this cohort.

Key Contributions
This study provides the first direct comparison of azathioprine outcomes between UC patients with and without 5-ASA intolerance. It establishes that 5-ASA intolerance does not serve as a predictor for azathioprine failure, adverse events, or poor endoscopic healing. The data supports the clinical transition from 5-ASA to azathioprine in intolerant patients without anticipating a compromised safety or efficacy profile specific to their intolerance history.

Significance and Claims
The authors conclude that azathioprine demonstrates comparable long-term treatment continuation, safety, and endoscopic outcomes in patients with and without 5-ASA intolerance. Consequently, the study suggests that azathioprine is a viable and effective maintenance treatment option for UC patients who cannot tolerate 5-ASA. The authors emphasize that a history of 5-ASA intolerance should not preclude the use of azathioprine, as the mechanisms of adverse reactions to these two drug classes appear distinct (hypersensitivity vs. metabolic/pharmacogenetic factors).

The paper maintains a modest tone regarding its limitations, acknowledging the retrospective single-center design, the small sample size of the intolerant group (limiting statistical power and multivariable analysis), the lack of thiopurine metabolite and NUDT15 genotype data, and the non-standardized endoscopic follow-up. The authors state that larger, multicenter studies are warranted to confirm these findings.