Abstract
The combination therapy of thalidomide and azathioprine (AZA) offers an alternative in clinical practice for Crohn's disease (CD) patients experiencing a loss of response to AZA monotherapy. However, little is known about the efficacy and safety of this combination therapy for patients with CD. This was a retrospective study of 122 consecutive CD patients who lost response to AZA therapy and had switched to a combination therapy of thalidomide and AZA. The primary outcomes were clinical response and clinical remission rates at week 24. Patients who had an initial response to combination therapy were continued on the treatment for remission maintenance. The secondary outcomes were the proportion of clinical relapse throughout maintenance. The Kaplan–Meier method was used to calculate cumulative rates, and Cox regression analysis was used for multivariate analysis. During induction, 80.3% (98/122) patients achieved clinical response within a median duration of 6.5 weeks, (interquartile range, 4.3–8.1 weeks). The rate of clinical remission at 24 weeks was 70.5%. During follow-up, 22.4% (22/98) of the patients that were maintained on combination therapy experienced clinical relapse. The proportions of patients in remission status at 12, 24, and 36 months were 85.1, 78.3, and 70.1%, respectively. Multivariate analysis revealed C-reactive protein >10 mg/L at disease relapse on AZA monotherapy [adjusted hazard ratio (HR), 4.72; 95% CI, 1.19–18.75, P = 0.027] and 6-thioguanine nucleotides level ≥235 pmol/8 × 108 erythrocytes at AZA monotherapy (adjusted HR, 5.32; 95% CI, 1.40–20.14, P = 0.014) were associated with disease relapse on combination therapy. The endoscopic remission rate was 63.6%. Mucosal healing was achieved in 23.6% of the patients. Both Crohn's Disease Endoscopic Index of Severity (13.4 ± 4.92 vs. 6.12 ± 5.24, P < 0.001) and Rutgeerts scores (3.23 ± 0.73 vs. 1.77 ± 1.59, P = 0.003) were significantly decreased with the use of combination therapy. Adverse events occurred in 62 (50.8%) patients, but only 13 (10.7%) necessitated therapy discontinuation. Thalidomide combined with AZA was effective in inducing clinical remission and sustaining long-term steroid-free remission in CD patients who lost response to AZA monotherapy.
Highlights
Crohn’s disease (CD), an inflammatory bowel disease (IBD) with unknown etiology, may involve any part of the gastrointestinal (GI) tract
We reviewed the medical charts of 1499 patients with CD referred to our department between 2004 and 2019
The median duration of AZA monotherapy was 18.2 months (IQR, 11.2– 35.2 months). 6-TGN levels were measured at a median time of 3.1 months (IQR 0.5–7.8 months) before losing response to AZA, with a median level of 282.2 pmol/8 × 108 erythrocytes, which is within the target therapeutic window [>235 pmol/8 × 108 erythrocytes [26]]
Summary
Crohn’s disease (CD), an inflammatory bowel disease (IBD) with unknown etiology, may involve any part of the gastrointestinal (GI) tract. The clinical course of CD is characterized by its propensity to relapse [1, 2]. Thiopurines, comprising azathioprine (AZA) and mercaptopurine, are the established first-line immunosuppressive therapies with confirmed efficacy for the maintenance of CD remission [3]. Despite the widespread use of thiopurines, 20–40% of CD patients under AZA monotherapy experience a loss of response, requiring optimization or switch to another medication [4, 5]. Riello et al [6] investigated 103 pediatric CD patients on AZA monotherapy and found that the steroid-free remission rates at 6, 12, 18, and 24 months were 60.2, 39.8, 33.3, and 31.2%, respectively. The management of CD patients that are refractory to thiopurines still represents a major concern to GI clinicians
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