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Noninvasive Monitoring After Azathioprine Withdrawal in Patients With Inflammatory Bowel Disease in Deep Remission

      Background & Aims

      There is uncertainty regarding the optimal duration of treatment with azathioprine (AZA) in ulcerative colitis (UC) and Crohn’s disease (CD). We analyzed the clinical course and predictors of relapse after AZA withdrawal in patients in sustained deep remission.

      Methods

      A prospective study was performed on patients who stopped their treatment with AZA while being in steroid-free, extended deep remission (normal clinical, endoscopic, and histologic indexes, C-reactive protein, and fecal calprotectin [FC]). Standard biochemical tests and FC were measured at 3 and 6 months, then every 6 months. Bowel ultrasounds and ileocolonoscopy were performed every 6 and 12 months, respectively. Multivariate analysis for predictors of relapse was performed using a Cox proportional hazards model and hazard ratios were calculated. Spearman nonparametric correlation test was also used. The accuracy of significant predictors was calculated.

      Results

      Fifty-seven patients with inflammatory bowel disease stopped AZA after median 7 years (range, 5–19) and were followed up for median 50 months (range, 25–85). Twenty-six patients (18/31 UC, 8/26 CD; P = .003) relapsed, within a median 15 months (range, 2–37). FC was the only variable significantly correlated with later relapse of both diseases (UC: hazard ratio, 3.3; 95% confidence interval, 1.2–10; CD: hazard ratio, 4.5; 95% confidence interval, 1.4–12.5). The sensitivity, specificity, and positive and negative predictive values of FC were 50%, 100%, 100%, and 59% in UC and 50%, 94%, 80%, and 81% in CD.

      Conclusions

      More than half patients with UC and one-third of patients with CD relapse after AZA withdrawal despite previous deep remission. FC positivity is associated with high risk of relapse, allowing early correction of the therapeutic strategy.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      AZA (azathioprine), CD (Crohn’s disease), CDAI (Crohn’s Disease Activity Index), CRP (C-reactive protein), ESR (erythrocyte sedimentation rate), FC (fecal calprotectin), IBD (inflammatory bowel disease), UC (ulcerative colitis)
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      References

        • Harbord M.
        • Eliakim R.
        • Bettenworth D.
        • et al.
        Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management.
        J Crohns Colitis. 2017; 11: 769-784
        • Torres J.
        • Bonovas S.
        • Doherty G.
        • et al.
        ECCO guidelines on therapeutics in Crohn’s disease: medical treatment.
        J Crohns Colitis. 2020; 14: 4-22
        • Lamb C.
        • Kennedy N.
        • Raine T.
        • et al.
        British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.
        Gut. 2019; 68: s1-s106
        • Terdiman J.P.
        • Gruss C.B.
        • Heidelbaugh J.J.
        • et al.
        • AGA Institute Clinical Practice and Quality Management Committee
        American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti–TNF-a biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease.
        Gastroenterology. 2013; 145: 1459-1463
        • Campos S.
        • Portela F.
        • Sousa P.
        • et al.
        Inflammatory bowel disease: adherence to immunomodulators in a biological therapy era.
        Eur J Gastroenterol Hepatol. 2016; 28: 1313-1319
        • Annese V.
        • Beaugerie L.
        • Egan L.
        • et al.
        European evidence-based consensus: inflammatory bowel disease and malignancies.
        J Crohns Colitis. 2015; 9: 945-965
        • Doherty G.
        • Katsanos K.
        • Burisc J.
        • et al.
        European Crohn’s and Colitis Organisation topical review on treatment withdrawal [‘exit strategies’] in inflammatory bowel disease.
        J Crohns Colitis. 2018; 12: 17-31
        • Cassinotti A.
        • Actis G.C.
        • Duca P.
        • et al.
        Maintenance treatment with azathioprine in ulcerative colitis: outcome and predictive factors after drug withdrawal.
        Am J Gastroenterol. 2009; 104: 2760-2767
        • Peyrin-Biroulet L.
        • Sandborn W.
        • Sands B.
        • et al.
        Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target.
        Am J Gastroenterol. 2015; 110: 1324-1338
        • Maaser C.
        • Sturm A.
        • Vavricka S.
        • et al.
        ECCO-ESGAR guideline for diagnostic assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications.
        J Crohns Colitis. 2019; 13: 144-164
        • Zhang B.
        • Gulati A.
        • Alipour O.
        • et al.
        Relapse from deep remission after therapeutic de-escalation in inflammatory bowel disease: a systematic review and meta-analysis.
        J Crohns Colitis. 2020; 14: 1413-1423
        • Guardiola J.
        • Lobatón T.
        • Rodríguez-Alonso L.
        • et al.
        Fecal level of calprotectin identifies histologic inflammation in patients with ulcerative colitis in clinical and endoscopic remission.
        Clin Gastroenterol Hepatol. 2014; 12: 1865-1870
        • Tibble J.A.
        • Sigthorsson G.
        • Bridger S.
        • et al.
        Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease.
        Gastroenterology. 2000; 119: 15-22
        • Costa F.
        • Mumolo M.G.
        • Ceccarelli L.
        • et al.
        Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in Crohn's disease.
        Gut. 2005; 54: 364-368
        • Brignola C.
        • Campieri M.
        • Bazzocchi G.
        • et al.
        A laboratory index for predicting relapse in asymptomatic patients with Crohn's disease.
        Gastroenterology. 1986; 91: 1490-1494
        • Lasson A.
        • Öhman L.
        • Stotzer P.O.
        • et al.
        Pharmacological intervention based on fecal calprotectin levels in patients with ulcerative colitis at high risk of a relapse: a prospective, randomized, controlled study.
        United European Gastroenterol J. 2015; 3: 72-79
        • Osterman M.T.
        • Aberra F.N.
        • Cross R.
        • et al.
        Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis.
        Clin Gastroenterol Hepatol. 2014; 12: 1887-1893
        • Colombel J.F.
        • Panaccione R.
        • Bossuyt P.
        • et al.
        Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial.
        Lancet. 2018; 390: 2779-2789
        • Magro F.
        • Lopes J.
        • Borralho P.
        • et al.
        Comparison of different histological indexes in the assessment of UC activity and their accuracy regarding endoscopic outcomes and faecal calprotectin levels.
        Gut. 2019; 68: 594-603
        • Park S.
        • Abdi T.
        • Gentry M.
        • et al.
        Histological disease activity as a predictor of clinical relapse among patients with ulcerative colitis: systematic review and meta-analysis.
        Am J Gastroenterol. 2016; 111: 1692-1701
        • Lin X.
        • Qiu Y.
        • Feng R.
        • et al.
        Normalization of C-reactive protein predicts better outcome in patients with Crohn’s disease with mucosal healing and deep remission.
        Clin Transl Gastroenterol. 2020; 11: e00135
        • Ungaro R.
        • Yzet C.
        • Bossuyt P.
        • et al.
        Deep remission at 1 year prevents progression of early Crohn's disease.
        Gastroenterology. 2020; 159: 139-147
        • Turner D.
        • Ricciuto A.
        • Lewis A.
        • et al.
        STRIDE-II: an update on the selecting therapeutic targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD.
        Gastroenterology. 2021; 160: 1570-1583