The Use of Anti-Mycobacterial Therapy for Treatment of Crohn’s Disease
Another argument against the role of MAP in Crohn’s disease is that anti-mycobacterial therapies are ineffective at treating patients with Crohn’s disease. This argument primarily stems from the results of a double-blind randomized control trial conducted in 2007, where 213 Crohn’s disease patients were treated with anti-mycobacterial drugs or placebo (Selby et al., 2007).
The authors reported an absolute benefit of 16% at week 16, but no evidence of a sustained benefit through the remainder of the 2-year study. However, an intention-to-treat reanalysis of the data later revealed that the benefit observed at 16 weeks was maintained at weeks 52 and 104 (Behr and Hanley, 2008). Notwithstanding the duration of the observed benefit, a major constraint of this trial was the lack of evaluation of MAP status prior to inclusion in the study. The study evaluated whether patients got better, which is a clinically valid outcome, but could not provide insights into a pathogenic role of MAP.The varying interpretations of these data has left the potential efficacy of antimycobac- terial therapy unresolved. A systematic review conducted by Feller et al. (2010) evaluated the outcomes of Crohn’s disease remission and relapse for patients treated with antibiotics vs placebo. This study found a significant benefit in studies treating patients with clofazimine, an antibiotic known to be active against mycobacteria, but no benefit was observed in studies involving classic anti-tuberculosis drugs. A second systematic review conducted in 2011 evaluated the effect of antibiotic therapy in IBD treatment using only randomized control trials. The authors found a statistically significant effect of antibiotics over placebo in treating both active and quiescent Crohn’s disease (Khan et al., 2011). It is important to note however, that these systematic reviews included a variety of antibiotics, including those active and those inactive against mycobacteria.
In 2013, RedHill Biopharma began a phase III double-blind placebo-controlled randomized control trial to assess the effect of RHB-104 vs placebo for treatment of moderate to severe active Crohn’s disease. An important difference from the 2007 study is that the changes in MAP blood status would be evaluated by PCR, although MAP positivity was not a requirement for inclusion in the trial (clinicaltrials.gov NCT01951326). RHB- 104 is a formulation of rifabutin, clofazimine, and clarithromycin shown to be effective against MAP strains isolated from Crohn’s disease patients (Alcedo et al., 2016; Qasem et al., 2016). RedHill Biopharma has announced that the treatment group was superior to placebo in achieving remission at week 26 (3 7% vs 23%) with statistically greater responses. They also reported those receiving RHB-104 experienced a significant benefit in attaining an earlier remission and in maintaining remission to week 52 (RedHill Biopharma, 2018a). Additionally, the company stated that RHB-104 was shown to have a greater calculated maintenance of remission over other standard-of-care therapies for Crohn’s disease such as Infliximab (RedHill Biopharma, 2018b). At the time of writing, the RedHill study remains unpublished.
Overall, these results indicate a statistically significant, although clinically modest benefit of antimycobacterial therapy in the treatment of Crohn’s disease. More data are required to determine whether this clinical benefit supports a direct involvement of MAP in development of Crohn’s disease.
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