A Retrospective Claims Database Study on Drug Utilization in Japanese Patients with Crohn’s Disease Treated with Adalimumab or Infliximab

Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract belonging to the group of Inflammatory Bowel Diseases (IBD) that results in a considerably decreased quality of life. The incidence and prevalence of CD are increasing with time and in different regions around the world [1]. The highest reported prevalence rates per 100,000 persons were 322 in Europe, 318.5 in North America, and 67.9 in Asia and the Middle East [1]. In Japan, the prevalence of CD reached 26.8 per 100,000 in 2010 [2].

Given the chronic and progressive nature of the disease, the main goal of the treatment is to stop progression, reduce and control symptoms, reduce the risks of complication, and maintain nourishment to improve the quality of life of patients [3]. Therefore, the long-term management as well as treatment persistence is very important.

CD management includes drug, nutritional and surgical therapies. However, it has been shown that the standard therapies for CD patients have several limitations; treatment with immunosuppressants is associated with adverse events risk [4], and treatment with corticosteroids is not adequate for the maintenance of clinical remission [5]. Monoclonal antibodies, targeting tumor necrosis factor (TNF)-α, are considered the treatment of choice in patients with CD [6].

In Japan, the available anti-TNF treatments for CD are infliximab (IFX) and adalimumab (ADA). IFX was the first TNF-α chimeric monoclonal antibody introduced for the treatment of CD in 2002. It is administered intravenously at a dose of 5 mg/kg body weight at weeks 0, 2, and 6 for induction. The standard dose of maintenance IFX therapy is 5 mg/kg of body weight administered every 8 weeks [7]. ADA is administered subcutaneously and is prescribed at an induction dose of 160 mg at week 0 and 80 mg at week 2. The standard maintenance dose is 40 mg administered every 2 weeks [8‐10].

Clinical trials have demonstrated the efficacy and safety of ADA and IFX in the induction and maintenance of remission in patients with moderate to severe CD, in particular in Japanese patients [7, 8, 11‐13]. However, treatment outcomes in the real-world setting might differ from clinical trials, as patients’ profiles may be more diverse and patients may not strictly adhere to a regular injection schedule. Several real-world studies have demonstrated that despite the high response rate, the response to ADA or IFX is lost over time, leading the efficacy of treatment waning (and consequently dose increase) to treatment discontinuation or to treatment switch [14‐22]. However, to date, there is limited real-world Japan-specific evidence in the literature regarding loss of response and treatment persistence.

The primary objectives of this study were: (1) to estimate the probability of treatment failure in the induction phase with ADA or IFX and (2) to estimate the probability of persistence in the maintenance phase with ADA or IFX. The secondary objective was to estimate the probability of dose escalation in the maintenance phase with ADA or IFX. Exploratory objectives were to estimate the probabilities of adverse events and surgical procedures in the maintenance phase.

To the best of our knowledge, this is the first retrospective study that describes ADA and IFX treatment-related events based on Japan-specific claims data. The added value of this study is the provision of real-world data which could be seen to be of higher relevance in terms of understanding actual clinical practice compared to clinical trial or single center studies.

In the current study, patients were considered to have failed induction treatment if they switched or discontinued index treatment within 4 or 14 weeks, for ADA and IFX initiators, respectively. In the literature, failure in the induction phase was most often called primary non-response and defined as no clinical improvement at the end of the anti-TNF induction phase [22, 27]. Our data showed that ≈20% of patients did not complete induction therapy on ADA or IFX, which is in agreement with previously published clinical data on the efficacy of anti-TNFs [22, 23, 28]. A recent study by Viazis et al. (Greece) reported that among 161 CD patients treated with ADA of IFX, 29 (18%) were considered as primary non responders to induction therapy [22]. Farkas et al. (Hungary) reported that 88% of CD patients completed induction therapy with IFX [28]. In Vermeire et al. (Belgium), 74% of CD patients responded to IFX induction therapy [23]. This suggests that our definition of treatment failure, based on claims data only, provides a good proxy of primary non-response.

However, our analysis also showed that frequent changes in treatment occurred during the maintenance phases: switches, discontinuations, or dose escalations. Overall, the probability of switch or discontinuation over 12 months following the initial response to induction therapy was 20.3% (15.2% for ADA group and 25.8% for IFX group). These rates are consistent with published data on anti-TNF persistence from retrospective studies in other countries—rates of discontinuation ranged from 15% to 35% [15, 20, 29]. Gonzaga et al. (US) reported that 27% of 153 CD patients, who received maintenance therapy with IFX, discontinued their treatment within 12 months of maintenance therapy [15]. A recent multicenter retrospective study in the US by Rosh et al. showed that the 12-month probability of discontinuation after ADA initiation in IBD patients was approximately 15% (Kaplan–Meir estimate) [20]. A recent Italian administrative database study in CD adult patients treated with anti-TNFs (ADA, IFX, and etanercept) showed that treatment persistence (defined as the absence of switches or treatment interruptions after anti-TNF treatment initiation) was somewhat lower than in our study for ADA patients: 78% for IFX and 65% for ADA [29].

The secondary outcome assessed in the current study was the rate of dose escalation, which may be interpreted as a proxy of secondary loss of response. In our study, eight patients, representing 12.5% of the study population entering the maintenance phase, required dose increase and or interval reduction between ADA or IFX prescriptions during a 12-month follow-up period. This rate is lower than that obtained from previously published clinical trial data (12-month rates ranged between 23% and 46%) [30]. This wide variability in loss of response rates across studies could be explained by the diversity of definitions of this outcome. In 2011, a literature review by Ben-Horin et al. discussed the disparity in the definitions of loss of response across studies on anti-TNF efficacy; some authors defined loss of response as a quantifiable re-emergence of symptoms (for example, a change in the CD Activity Index [CDAI]), and others qualified dose escalation as a “decisive definition”, while others characterized it by switch, discontinuation, or an occurrence of a surgical intervention [30]. On the other hand, when we compared our study results to real-world published data, where authors adopted dose escalation as a definition of loss of response, we found also higher rates ranging from 23% to 55% [14, 16, 17, 19, 21, 22, 31], but the majority of those studies had a longer follow-up compared to our study. The rate of dose escalation for IFX (22.6% over 12 months) is close to the lower end of the range reported above. Under the current definition of dose escalation, patients treated with IFX who started their dosage at 10 mg/kg were not considered as dose escalated, since the weight was not available in JMDC database. For ADA group, the rate of dose escalation was found to be lower, which likely results from the fact that the higher dose has not yet been approved in Japan [32, 33].

Although treatment switches, discontinuations or dose escalations were interpreted as events of failure or non-response to the treatment and that the definition of those events took into account intercurrent infections, concomitant surgeries, or immunostimulant therapies, it should be noted that a proportion of these events could have occurred for other factors, such as patient compliance, medication reactions, choices made by practitioners, or patient preference.

In the current study, a minority of patients had immunosuppressant prescriptions after anti-TNF treatment initiation (32% approximately in both groups). Several studies suggested that the risk–benefit profile of immunosuppressants therapy is different in Japanese patients compared to Western patients [24, 25, 34], and thus, in the real-world setting, physicians may be cautious on adding immunosuppressant. Furthermore, the results showed that among patients treated with IFX, there was a significantly higher probability of dose escalation in patients who were prescribed immunosuppressant therapy compared to those without immunosuppressants. The addition of immunosuppressants, such as azathioprine, is expected to reduce the risk of loss of response [35]. However, the higher rate of dose escalation in our study, interpreted as proxy of loss of response, in patients treated with the combination could be explained by the fact that physicians may have prescribed immunosuppressants before increasing the IFX dose in patients with worsening symptoms (in other words, patients treated with the combination and IFX only were not comparable). In addition, IFX patients not treated with immunosuppressants could have been switched to other treatments instead of having their IFX dose increased.

The male-to-female ratio was 4:1 in our JMDC extract, and 5:1 in the 133 patients meeting selection criteria. This ratio is higher than those reported by Japan-specific epidemiological studies (2.6:1–2.3:1) [36, 37]. However, given that the JMDC data contain 26% more males compared to Japan census, we would expect to have a 3-to-1 male-to-female ratio approximately. The higher proportion of males in our sample is probably attributable to sampling variability.

Besides the small sample size, several limitations of our study should be noted. First, the sensitivity analysis demonstrated that the results were sensitive to a change in the definition of discontinuation during maintenance phase. As expected, the probability of discontinuation increased in both the groups when the time window decreased. However, the difference in discontinuation rate between the treatment groups remained non-significant.

Second, given the nature of the data available in the JMDC database, we did not have any clinical record, such as CDAI or physician’s assessment of severity, and could only develop proxies of treatment failure in induction phase or loss of response in maintenance phase. However, the comparison of results to the literature suggests that those proxies were actually informative. Besides, although surgeries might indicate a loss of response [38], it was not possible to make the distinction between surgeries performed for treating intestinal complications due to loss of response or for treating lesion which pre-existed before the index date. Although the rate of pre-index date surgical treatments was similar to both the groups (Table S4, Supplementary Material), these factors may have led to an underestimation of loss of response rates observed in this study compared to other studies showing higher rates of loss of response [14, 16‐19, 21, 22, 30, 31].

In the current study, the probability of adverse events was investigated in an exploratory manner, based on the claims database. Due to the nature of the JMDC data, the oldest reported diagnosis of an adverse event did not necessarily correspond the first date of the symptoms appearance, which would have led an overestimation of adverse events. Nevertheless, further evaluation of this outcome is required based on data from prospective studies or chart reviews.

Another limitation of this study is that the results were based on crude comparison between ADA and IFX groups. The possibility of performing a matched comparison was considered, but the sample size was too small. Although the clinical status of patients could not be obtained, patients’ demographic and clinical characteristics were similar between treatment groups (Table 1 and Table S4). In addition, given the retrospective nature of the study and the small sample size, the results should be interpreted with caution.

Finally, some limitations related to the nature of claims databases should also be mentioned; diagnostic codes are for a reimbursement purpose which may be different from diagnosis in a chart. Only the month and the year of medical and claims data were available. The full dates were missing for 6% of the prescriptions and 9% of the procedures, respectively. These issues, however, were unlikely to differ across groups or outcomes.

This is the first retrospective study that describes ADA and IFX treatment-related events based on a real-life claims database in Japan. The current study demonstrated that Japanese CD patients have a high primary response to ADA and IFX therapy in the real-world setting, and suggests that outcomes achieved in the real world are comparable to those observed in clinical trials. However, response can be lost during the maintenance phase in a certain number of patients, leading to treatment switch, discontinuation, or dose escalation. This study further suggests that treatment persistence was similar to patients treated with ADA compared to those treated with IFX. However, the results should be considered with caution due to the retrospective nature and small size of the study. Given that CD is a chronic and a progressive disease, further research on the causes of discontinuations and ways to improve persistence are recommended for the future.