Clinical efficacy of adalimumab in Crohn’s disease: a real practice observational study in Japan

Crohn's disease (CD), an inflammatory bowel disease (IBD), is an intractable disease of unknown etiology [1]. CD is progressive and markedly impairs patient quality of life due to its associated symptoms such as diarrhea, abdominal pain, fever, and surgery [2‐4]. Although there is currently no cure for CD, the inflammatory cytokine tumor necrosis factor-α (TNF-α) is involved in clinical condition [5], against which anti-TNF-α monoclonal antibody (anti-TNF-α antibody) is highly effective [6, 7]. For the treatment of CD, infliximab (IFX), a chimeric antibody and infusion drug, first appeared as an anti-TNF-α antibody, followed by adalimumab (ADA), a fully humanized antibody and subcutaneous drug. IFX and ADA were highly effective in large-scale studies and have already been widely used worldwide [8‐15].

Although the clinical features of CD in Asia is relatively similar to that of North America or Europe, there are some differences such as a higher prevalence of males and ileo-colonic type, less familial clustering, extra-intestinal manifestations, and surgical rates. As for genetics, nucleotide oligomerization domain-2 (NOD2) variants and autophagy-related 16-like 1(ATG16L1) variants, which have been firmly associated with CD in the West have not been detected in the patients with CD in Asia [16]. Taking account of these differences, the data from Asia is important in spite of the numerous data from West. However, ADA received approval later in Asian countries including Japan than in the Europe and US; therefore, there are limited reports on its efficacy in Asian real practice settings [17‐20]. Watanabe et al. reported that clinical remission rate at week 4 in the induction therapy was 33.3 %. Seventy percentage of patients achieved decrease in CDAI ≥ 70 points and the rest was unresponsive at week 4 in the induction therapy [17]. Furthermore, intestinal resection is commonly required in patients with CD and often leads to repeated surgery; thus, it is important to prevent postoperative recurrence [21, 22]. Recent reports indicated that IFX and ADA effectively prevent postoperative recurrence [23‐26]. However, no report to date has demonstrated the ability of ADA to prevent postoperative recurrence in Asia. Under these circumstances, we conducted a multicenter observational study in Japan to evaluate ADA efficacy and safety as well as its ability to prevent postoperative recurrence in patients with CD in real practice settings.

ADA has been demonstrated effective against CD in the CLASSIC I [11], CLASSIC II [13], GAIN [12], CHARM [14], and EXTEND [15] placebo-controlled double-blind studies. In Japan, its clinical efficacy was also demonstrated in a placebo-controlled double-blind study [17], and ADA has been available for clinical use since October 2010. However, limited reports to date are available on usage data in real practice settings in Japan and other Asian countries. Ishida, et al. [19] and Miyoshi, et al. [20] reported results from a single center study with limited sample sizes of 28 and 45 subjects, respectively. Therefore, we investigated the results of ADA treatment for CD in real practice settings in this multicenter observational study. The remission rates from 4 to 52 weeks were similar to those reported by Ishida, et al. [19] and Miyoshi, et al [20]. ADA was more effective in real practice settings than in a clinical study with limited patients based on various exclusion criteria and a CDAI of 220–450 [17].

This study identified CD location and baseline CDAI as factors associated with ADA efficacy at 52 weeks. A study by Cohen, et al. [30] also indicated a slightly higher nonresponse rate in patients with the colonic type but with no significant difference. To our knowledge, only the current study demonstrated lower ADA efficacy in patients with the colonic type. We believe that the effects of TNF-α may be greater in patients with lesions in the small intestine, but no significant difference was detected on multivariate analysis, so this issue requires further investigation. Other factors including previous IFX treatment [31, 32] and disease duration [33, 34] are reportedly associated with ADA efficacy, but this study did not show a significant difference in these factors. This may be due to an insufficient sample size and the fact that more patients had fewer disease activity events such as intolerance with previous IFX treatment. The combined effect of immunomodulator and ADA has yet to be confirmed because of conflicting reports [35‐38], and no difference was noted in this study either. Thus, prospective comparative studies of ADA like the IFX SONIC study [39, 40] are needed. The combined effect of an elemental diet and IFX has also been reported [41‐43], but no difference was observed in this study. Serum ADA concentration and involvement in efficacy of anti-adalimumab antibody (AAA) have been highly reported recently [44‐49], but we could not evaluate these parameters in the current study.

We also investigated the ability of ADA to prevent postoperative recurrence. Several reports have been published to date in Europe or the US [25, 50‐52], but there are few reports from Asian countries. This study confirmed that ADA effectively prevented postoperative recurrence in a small sample of 16 patients. While a meta-analysis indicated the efficacy of anti-TNF-α antibody for preventing postoperative recurrence [26], the use of anti-TNF-α antibody has a cost-benefit performance issue [53] and is recommended for patients at high risk and those in whom relapse was observed in postoperative monitoring [54]. The POCER study recently reported on the usefulness of postoperative risk factor–based therapeutic stratification, endoscopic monitoring, and therapeutic intensification [55]. However, in the POCER study, thiopurine was used as the first-line treatment even for high-risk patients, while the active care group with endoscopic evaluation and therapeutic intensification had a relatively high recurrence rate. A greater number of risk factors was associated with a higher relapse rate. Our study also indicated more risk factors in patients who showed endoscopic recurrence with a Rutgeerts score of i3 or i4. Therefore, positive use of anti-TNF-α antibody may require consideration for high-risk patients. Recent studies reported the usefulness of fecal calprotectin as a parameter in postoperative monitoring [56, 57]. Postoperative monitoring and therapeutic optimization as considerations of the burden of examination and cost-benefit relationship are required.

This study has several limitations. First, it had an insufficient sample size of unselected patients with heterogeneous baseline characteristics in a real practice setting. Therefore, it was difficult to determine the efficacy-associated factors. Second, the assessment of prevention of postoperative recurrence was made only in a small group of 16 patients, the timing of ADA introduction and endoscopic examination was inconsistent, and endoscopy was not performed for some patients. Therefore, further larger-scale studies with strict evaluation methods are required to validate our results.

Even with the above-mentioned limitations, we concluded in this study that ADA effectively provided clinical remission and prevented postoperative recurrence of CD in real practice settings.

AAA, anti-adalimumab antibody; ADA, adalimumab; anti-TNF-α antibody, anti-TNF-α monoclonal antibody; CD, Crohn's disease; CDAI, CD Activity Index; CRP, C-reactive protein; IBD, inflammatory bowel disease; IFX, infliximab; PNR, primary nonresponse; SNR, secondary nonresponse; TNF-α, tumor necrosis factor-α.