Adalimumab Is More Effective Than Azathioprine and Mesalamine at Preventing Postoperative Recurrence of Crohn's Disease

A Randomized Controlled Trial

Edoardo Savarino MD; PhD; Giorgia Bodini MD; Pietro Dulbecco MD; Lorenzo Assandri MD; Linda Bruzzone MD; Fabrizio Mazza MD; Anna Chiara Frigo MSc; Valentina Fazio MD; Elisa Marabotto MD; Vincenzo Savarino MD

Disclosures

Am J Gastroenterol. 2013;8(11):1731-1742. 

In This Article

Results

Baseline Demographics

In all, 51 patients were included in the study: 16 in the ADA group, 17 in the AZA group, and 18 in the mesalamine group. Of these, 5 patients withdrew before 2 years of follow-up evaluation; 2 patients in the mesalamine group, 2 patients in the AZA group, and 1 in the ADA group. All patients had end-of-study colonoscopic evaluation and were included in the intention-to-treat analysis. Figure 1 shows the CONSORT flow diagram of the progress through the phases of this randomized trial.

Figure 1.

CONSORT flow diagram of the progress through the phases of the randomized trial with three groups (patients within the study, combined clinical/endoscopic remission, and recurrence). ADA, adalimumab; AZA, azathioprine.

The baseline characteristics of the three groups are summarized in Table 1. Characteristics were similar for sex, age, smoking, duration of CD, disease behavior, disease location, prior medication exposure, including IFX, and prior surgical resection. The 12 patients with prior IFX exposure had received between 1 and 6 doses before surgery. The indication for surgery in these patients included small-bowel obstruction and penetrating complications related to intraabdominal abscess formation. None of the patients received antibiotics (for a cumulative duration of >10 days) in the postoperative follow-up period.

Endoscopic Recurrence

A total of 46 patients underwent ileocolonoscopy with biopsy within 2–3 weeks after the 2-year study period (Table 2). Five patients had ileocolonoscopies before this period because of early withdrawal. One of the 16 (6.3%) patients treated with ADA had endoscopic recurrence, defined as a score of i2, i3, or i4, compared with 11 of 17 (64.7%) patients in the AZA group (OR=0.036 (95% CI 0.004–0.347); Figure 2) and 15 of 18 (83.3%) patients in the mesalamine group (OR=0.013 (95% CI 0.001–0.143); Figure 2). Moreover, no differences were observed in AZA-treated patients as compared with mesalamine-treated patients (OR=0.367 (95% CI 0.075–1.797); Figure 2). The only one ADA-treated patient who experienced recurrence had an endoscopic grade score of i2. Among the AZA-treated patients who experienced recurrence, 3 had the maximum endoscopic grade score of i4 (Figure 3), and among the mesalamine-treated patients, 4 had the maximum endoscopic grade score of i4 (Figure 3). Endoscopic and radiological findings at 1-year follow-up period are reported in Table 3, whereas radiological findings at 2-year follow-up period are reported in Table 2.

Figure 2.

Percentage of patients in remission (endoscopic grade score of i0 or i1) and with recurrence (endoscopic grade score of i2, i3, or i4) of Crohn's disease at the 2-year endoscopic evaluation by random assignment to adalimumab (ADA) or azathioprine (AZA) or mesalamine.

Figure 3.

Endoscopic grade and percentage of patients with endoscopic recurrence of Crohn's disease at 2-year follow-up evaluation by random assignment to adalimumab (ADA) or azathioprine (AZA) or mesalamine.

Clinical Recurrence

The clinical recurrence grading scale proposed by Hanauer et al.[9] was used to determine clinical recurrence on 46 patients (Table 2 and Figure 4). Two out of 16 (12.5%) patients in the ADA group had a clinical recurrence (score of 2 on the clinical recurrence grading scale) compared with 11 of 17 (OR=0.078 (95% CI 0.013–0.464)) in the AZA group and 9 of 18 (OR=0.143 (95% CI 0.025–0.819)) in the mesalamine group. Similar results were observed considering CDAI >200 for identifying clinical recurrence (6.3% vs. 70.6%, OR=0.028 (95% CI 0.003–0.271) and 6.3% vs. 50%, OR=0.067 (95% CI 0.007–0.617), respectively). No differences were found in the AZA-treated patients as compared with the mesalamine-treated patients in terms of clinical relapse assessed by both clinical recurrence grading scale or CDAI scores (OR=1.833 (95% CI 0.472–7.126) and OR=2.400 (95% CI 0.569–9.670), respectively). The clinical recurrence assessed with the grading scale correlated with endoscopic recurrence and serologic evidence of inflammation in 1 out of 2 ADA-treated, 9 out of 11 AZA-treated, and 9 out of 9 mesalamine-treated patients, whereas the clinical recurrence assessed with CDAI score correlated with endoscopic recurrence and serologic evidence of inflammation in all ADA-treated, 10 out of 12 AZA-treated, and 9 out of 9 mesalamine-treated patients. Based on the CDAI score (<150), there were 15 of 16 (93.8%) patients in the ADA group with a clinical remission compared with 4 of 17 (OR=0.021 (95% CI 0.002–0.207)) patients in the AZA group and 6 of 18 patients in the mesalamine group (OR=0.033 (95% CI 0.004–0.316)). Again, no differences were observed in the AZA-treated patients as compared with the mesalamine-treated patients in terms of clinical remission assessed by CDAI scores (OR=1.625 (95% CI 0.367–7.201)). Only 1 patient in the AZA group and 2 patients in the mesalamine group had a CD exacerbation that was clinically significant and required treatment. These patients withdrew from the study at weeks 50, 59, and 64, respectively. The data were included in the intention-to-treat analysis.

Figure 4.

Clinical grade and percentage of patients with endoscopic recurrence of Crohn's disease at 2-year follow-up evaluation by random assignment to adalimumab (ADA) or azathioprine (AZA) or mesalamine.

Safety of Therapy

The occurrence of adverse events was similar among our groups (Table 4). One patient in the ADA group discontinued therapy at week 36 because of developing a form of atopic dermatitis involving the whole body. After suspension of ADA administration the cutaneous disease disappeared. In addition, two patients in the AZA group interrupted treatments because of adverse events. One patient at week 50 had a severe CD exacerbation with diarrhea, weight loss, and abdominal pain, whereas the second patient at week 36 developed severe abdominal pain with concomitant increase of pancreatic enzymes. Both patients were admitted to the hospital and were elected to withdraw from the study. The first patient had been treated with steroids and antibiotics. Then, he received ADA at 160/80 mg for induction doses and at 40 mg for maintenance dose, every 2 weeks, with clinical remission and normalization of CRP and ESR levels for all the study period. The second patient after withdrawal of AZA had complete relief of symptoms and normalization of blood testing. He was given mesalamine as maintenance therapy and had endoscopic and clinical CD recurrence after 8 months. Two patients in the mesalamine group developed severe exacerbation of CD at weeks 59 and 64 with diarrhea, weight loss, abdominal pain, and, in one case, perianal fistula. Because of the severity of the CD recurrence, both patients were withdrawn from the study and admitted to the hospital. One patient had been treated with IFX and quickly improved with complete resolution of CD symptoms and normalization of CRP and ESR levels. The second patient received ADA at 160/80 mg for induction doses and 40 mg for maintenance dose, every 2 weeks, with clinical remission and normalization of CRP and ESR levels for all the study period.

Quality-of-Life Assessment

Quality of life was measured by means of the validated IBD-Q that patients completed before surgery and at 1 and 2 years after surgery. Mean value of IBD-Q was similar among the groups before surgery (71 vs. 75 vs. 68), whereas at 2 years after surgery, mean IBD-Q value was higher in the ADA group that in the AZA (OR=0.028 (95% CI 0.004–0.196)) and mesalamine groups (OR=0.015 (95% CI 0.002–0.134)). In particular, at 2 years of follow-up, 14/16 (87.5%) ADA-treated patients reported a score >170 compared with 2/17 (87.5 vs. 11.8%) AZA-treated patients and 3/18 (87.5 vs. 16.7%) mesalamine-treated patients. No differences were observed in AZA-treated patients as compared with mesalamine-treated patients in terms of quality of life (OR=0.531 (95% CI 0.059–4.779)).

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