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Mémoires Année : 2015

Evolution of Crohn's disease in patients who are intolerant to thiopurines

Évolution de la maladie de Crohn chez les patients intolérants aux thiopurines

Résumé

Introduction: The use of thiopurines (azathioprine and purinetol) for the treatment of Crohn's disease is today controversial because their efficacy and safety are inferior to those of anti-TNF. Approximately 10% of patients treated by thiopurines have an immuno-allergic intolerance that forbids the continuation of the treatment. The aim of his study is to assess if the intolerance to thiopurines (before and after prescription of anti-TNF) is a loss of chance in Crohn's disease. Patients and methods: We compared the evolution of 114 patients (42 women, 72 men, aged of 29 +/- 14 years) having an intolerance to thiopurines (this intolerance lead to a definitive treatment discontinuation during the year following the prescription of thiopurines) to the evolution of 228 patients matched 2/1 for age, sex, and the duration of the disease, treated by thiopurines and tolerant to this treatment. The data were obtained from the register MICISTA which listed 1805 consecutive patients who had a first prescription of thiopurines between January 1st 1994 and December 31st 2006. The patients were separated into 2 cohorts: one before the use of anti-TNF (1994-2000, n=31), and one after (2001-2006, n=83). The primary end point was the intestinal surgery (analysis with Kaplan Meier). The secondary end points were the percentage of patients-years with a clinically active disease, the use of anti-TNF, the rate of anal fistula and serious events (stomy, cancer or death). Results: Because of an intolerance, the prescription of thiopurines had to be replaced by the prescription of Methotrexate (n=56), or anti-TNF (n=25) during the year following the intolerance. During the follow-up, 46 patients / 114 intolerant to thiopurines (40,4%) had surgery vs. 67/228 controls (29,3%). The cumulative probability of surgery was at five years 28,61% (IC95=[20,89-37,82]) for patient intolerant to thiopurines, vs. 19,03% (IC95%=[14,43;24,69]) for controls (log rank p=0,012). The percentage of active years was 40,6% (527/1294) for patients intolerant to thiopurines vs. 31,6% (891/2813) for controls (p<0,0001). The percentage of anti-TNF prescription at 5 years of follow up was 44, 52% (IC95%=[35,6-53,8]) for intolerant patients vs. 29,8% (IC95%=[24,2;36]) for controls (p<0,0001). The cumulated risk of serious event after 10 years of follow up was 15,9% (IC95=[9-26,5]) for intolerant patients vs. 4,9% (IC95=[2,5-9,6]) for controls (p=0,009). There is a tendency for a higher rate of anal fistula for intolerant patients compared to controls (at 5 years 13,8% vs. 12,5%) but the difference was not significant. The analyses of the 2 calendar cohorts confirmed the significant differences between intolerant patients and tolerant patients in the cohort between 1994 and 2000 for the surgery rate at 5 years of follow-up (42,3% vs. 21%, p=0,005), the use of anti-TNF at 5 years of follow-up (23% vs. 12,9% p<0,0001), the clinical activity (43% vs. 33%, p=0,0002) and the probability of anal fistula (31,6% vs. 18,5% at 10 years, p=0,04). In the cohort between 2001 and 2006, the intolerant patients had more often an active disease (39,4% vs. 31%, p=0,0001), anti-TNF treatment (at 5 years of follow-up 52,7% vs. 36,2%, p=0,01). However, in this cohort, the cumulative probability of surgery at 5 years of follow-up was not significantly different between intolerant patients and tolerant patients (23,5% vs. 18,3%,p=0,21). Besides, the probability of anal fistula was not significantly different between the 2 groups in this cohort (13,9% for intolerant patients vs. 11,5% for tolerant patients, p=0,74). Conclusion: Patients intolerant to thiopurines have a more severe evolution of their Crohn's disease compared to patients who are tolerant to thiopurines. These results emphasize that thiopurines still have an important place in the treatment of Crohn's disease. The use of anti-TNF compensates partially this handicap.
Introduction : La place des thiopurines (TP) dans le traitement de la maladie de Crohn (MC) est discutée. Environ 10% des patients placés sous TP ont une intolérance précoce interdisant leur poursuite. Ce travail a pour but de préciser la perte de chance que représente l'intolérance aux TP avant et après l'ère des anti-TNF. Patients et Méthodes : 114 patients avec intolérance précoce aux TP (arrêt définitif dans la 1ère année de prescription) ont été comparées à 228 contrôles tolérants appariés 2/1 en âge, sexe et ancienneté de la MC (registre MICISTA). Ils ont été divisés en 2 cohortes calendaires: avant (1994-2000, n=31) et après (2001-06, n=83) l'arrivée des anti-TNF. Le critère principal de jugement était le recours à une chirurgie intestinale. Les critères accessoires étaient le pourcentage de patients-années avec maladie cliniquement active, le recours aux antiTNF, la survenue d'un événement grave (stomie, cancer ou décès). Résultats : Le risque cumulé de chirurgie à 5 ans était de 28,61% chez les intolérants vs 19,03% chez les contrôles (p=0.01). Les intolérants avaient plus recours aux anti-TNF, une maladie plus active et plus d’événements graves. Avant 2000, les intolérants avaient plus recours à la chirurgie, aux a-TNF et une maladie plus active. Dans la cohorte 2001-06, les intolérants avaient plus souvent une maladie active et recours aux anti-TNF mais n’étaient pas plus opérés. Conclusion : Les intolérants aux TP ont une MC d'évolution plus sévère, traduisant la perte de chance que représente l'impossibilité d'utiliser ce traitement. Les anti-TNF compensent en partie ce handicap. Ces résultats démontrent indirectement que les TP gardent un intérêt thérapeutique dans la MC.
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Dates et versions

dumas-01307415 , version 1 (26-04-2016)

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  • HAL Id : dumas-01307415 , version 1

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Julia Attali. Évolution de la maladie de Crohn chez les patients intolérants aux thiopurines . Médecine humaine et pathologie. 2015. ⟨dumas-01307415⟩
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