Patients’ Preference on Advanced Therapy and Follow-Up Procedure for Inflammatory Bowel Disease in Japan: A Web-Based 3A Survey

The two inflammatory bowel diseases (IBDs), ulcerative colitis (UC), and Crohn’s disease (CD), are intractable diseases of unknown cause [1], and the number of patients with IBD continues to increase. UC and CD are associated with diarrhea, abdominal pain, fever, bloody stools, and other symptoms that greatly impair quality of life [2, 3]. Antitumor necrosis factor antibody, anti-p40 antibody, anti-α4β7 integrin antibody, and Janus kinase inhibitors are currently available for the treatment of refractory IBD. The new drugs can be administered orally, intravenously, or subcutaneously via various routes and at different frequencies [4‒7].

Shared decision-making is becoming increasingly important in the treatment of IBD. When selecting a drug, it is important to consider not only efficacy, safety, and drug information but also patient acceptability [8]. Achieving mucosal healing is associated with improved prognosis in the treatment of IBD, and in recent years, monitoring by using a combination of biomarkers along with endoscopy has been emphasized as a treat-to-target strategy [9, 10]. Fecal biomarkers, such as fecal calprotectin and fecal immunochemical test, have been found to be correlated with endoscopic activity scores [11, 12]. Recently, a blood biomarker, leucine-rich alpha-2 glycoprotein (LRG), has been reported to be a useful biomarker for patients with IBD; LRG assay is currently approved and available for use in Japan [13‒16].

We previously reported on the quality of life and acceptability of topical therapy in the 3I and 3T surveys, which were internet surveys of patients with IBD [1, 17]. In this study, we conducted the 3A survey (acceptance about usage of advanced therapy and examination for patients with IBD) to determine the acceptability of usage of drug administration and examination methods in patients with IBD.

From January 26 to February 2, 2023, 1,535 patients with IBD registered with Cross Marketing Co., Ltd. (Tokyo, Japan) were sent an email asking for cooperation in a questionnaire survey conducted via the internet. The survey items included disease (UC/CD), age, sex, area of residence, duration of disease, smoking status, history of bowel resection, occupation, treatment history, attending medical institution (university hospital, general hospital, clinic, or no attending medical institution), current degree of diarrhea and abdominal pain (none, mild, moderate, or severe), frequency of attending medical institution, and preference for each drug administration usage and examination method (on a scale of 1–10), as well as the most preferred methods.

As of August 2022, infliximab [18], adalimumab [19], golimumab [20], ustekinumab [21], vedolizumab [22], tofacitinib [23], and filgotinib [24] were available as advanced therapies for refractory IBD in Japan. The drug name or other information was not provided in the evaluation of acceptability of drug administration usage. Instead, nine comparisons were made: 8-week interval infusion, 4-week interval infusion, 12-week interval subcutaneous injection, 8-week interval subcutaneous injection, 4-week interval subcutaneous injection, 2-week interval subcutaneous injection, 1-week interval subcutaneous injection, once-daily oral administration, and twice-daily oral administration.

Additionally, three examination methods were compared: blood tests, stool tests, and endoscopy. This study was approved by the Ethics Committee of Iwate Medical University (MH2022-103), and informed consent was obtained from all patients.

The primary endpoint was the comparison of acceptability scores from 1 (least preferred) to 10 (most preferred) for nine drug administration usages and three examination methods. The secondary endpoints were the preferred drug administration usage and examination methods. In addition, the acceptability scores for drug administration usages and the most preferred drug administration usage were analyzed according to patient treatment history.

Statistical analysis was performed using Student’s t-test to compare acceptability scores, and statistical significance was set at p < 0.05.

The survey was distributed to 1,535 patients, yielding a response rate of 30.6% (470 patients: 388 with UC and 82 with CD). No responses were considered ineligible, and all patients were included in the analysis. The mean age was 52.9 ± 11.2 years; the mean disease duration was 14.8 ± 10.3 years, and 69.4% were males (Table 1). The ratio of CD to UC, sex ratio, disease duration, and status of therapeutic drugs in this survey were similar to those in the general situation in Japan [25]. The occupational statuses were full-time (49.6%), part-time (15.1%), student (0%), housework (8.9%), other (3.6%), and unemployed (22.8%). Sixty-eight (14.5%) patients received intravenous infusions, 54 (11.5%) received subcutaneous injections, and 375 (79.8%) did not receive either treatment.

Oral once daily had the highest acceptability score, with a mean of 7.9 in the 475 patients evaluated; significant differences were observed between oral twice daily, intravenous infusion at each dosing interval, and subcutaneous injection at each dosing interval (p < 0.0001) (Fig. 1). Comparison of each administration usage revealed a significant difference (p < 0.05) between all administration usages, except for intravenous infusion at 8-week intervals versus subcutaneous injection at 8-week intervals (p = 0.430) and intravenous infusion at 4-week intervals versus subcutaneous injection at 2-week intervals (p = 0.233). Patients with a history of intravenous infusion or subcutaneous injection reported a higher acceptability score for intravenous infusion and subcutaneous injection than those without a history of treatment; however, once-daily oral administration had the highest acceptability score, with a significant difference among all administration usages (p < 0.0001) (Fig. 2).

Once-daily oral administration was the most preferred usage of administration (80.4%), and when twice daily was included, 88.9% of the patients indicated oral administration as the most preferred method (Fig. 3). The proportion of patients who preferred intravenous infusion or subcutaneous injection increased among those with a history of intravenous infusion or subcutaneous injection. Oral administration was the most preferred treatment (Fig. 4).

The mean acceptability scores for blood test, stool test, and endoscopy were 7.3, 5.1, and 4.3, respectively, with significant differences among all groups (p < 0.0001) (Fig. 5).

The preferred examination methods, in descending order, were blood tests (76.0%), endoscopy (19.6%), and stool tests (4.5%) (Fig. 6).

With the development of therapeutic agents, treatment options for refractory IBD have increased in recent years [26] Although the efficacy and safety of drugs for refractory IBD has been investigated in network meta-analyses [27‒29]. these are indirect comparisons, and direct comparisons are still limited [30, 31] Hence, no clear conclusions can be drawn. Poor adherence to drugs for refractory IBD has been shown to be associated with poor prognosis [32‒36]. Patient acceptability is important for obtaining efficacy through good adherence in real-world clinical practice. Therefore, we evaluated the acceptability of nine administration usages of the following drugs available in Japan: infliximab, adalimumab, golimumab, ustekinumab, vedolizumab, tofacitinib, and filgotinib. The highest acceptability score was observed for once-daily oral administration, which was significantly different from the other administration usages. Acceptance scores decreased with increase in frequency of administration and shortening of interval between administrations. Once-daily oral administration was the preferred method of administration (80.4%). When twice-daily administration was included, 88.9% of patients indicated that oral administration was their preferred method of administration.

However, the 11.1% who preferred non-oral therapy also preferred intravenous or subcutaneous formulations, as indicated in the results. Although the reason for this preference was not confirmed, it is assumed to be due to the longer administration interval compared with that of oral formulations.

Similar acceptability assessment reports have recently been published in the UK [37] and France [38], with results similar to ours. In a French report, 12- and 8-week intervals of subcutaneous injections were more acceptable than once-daily oral administration by patients with a treatment history of intravenous or subcutaneous injections. In our study, the acceptability of intravenous infusion and subcutaneous injection increased in patients with a history of intravenous or subcutaneous treatment; however, oral administration remained the most preferred method. This may be due to the differences in medical treatment conditions, culture, and national characteristics between Western and Japanese patients.

Filgotinib, a once-daily oral drug, available in Japan since March 2022, has been shown to be effective against UC in clinical trials [24, 39‒41]. However, data have not yet been fully accumulated. In addition to the risk of herpes zoster, tofacitinib has been associated with an increased risk of cardiovascular events and malignancy in rheumatoid arthritis, and safety data in IBD are currently being accumulated [42‒45]. Although there is good safety data for filgotinib in rheumatoid arthritis treatment [46], there is a need for more safety data, especially in IBD. The results of a detailed study on abnormal spermatogenesis are also awaited [47].

Mucosal healing has been shown to be associated with improved prognosis in IBD treatment [48, 49]. To achieve mucosal healing, treat-to-target strategy using biomarkers is important [50]. As a biomarker reflecting mucosal healing, C-reactive protein is insufficient. The usefulness of fecal calprotectin and fecal immunochemical test has been reported, and they are widely used [11, 12, 51‒53]. The new blood biomarker, LRG, showed good correlation with endoscopy activity scores as well as fecal calprotectin and fecal immunochemical test. LRG assay has been available in Japan since June 2020 [13‒16, 54‒56].

The acceptability of blood test, stool test, and endoscopy was evaluated in this study. Blood tests, stool tests, and endoscopy were ranked in the descending order of acceptability; 76.0% of the respondents indicated that blood tests were the most preferred examination method. Stool testing was the least preferred examination method (4.5%). We believe that resistance to bringing stool samples and the burden of collecting stool samples and bringing them to medical institutions may have influenced these results. Comparison between endoscopy and other modalities, such as computed tomography enterography, magnetic resonance enterography, capsule endoscopy, and ultrasound, is a future challenge. The usefulness of prostaglandin E-major urinary metabolites as new biomarkers has recently been reported [57‒59] and should be compared with urinalysis.

Similar acceptability assessment reports have recently been published in New Zealand [60], where blood tests were reported as the most prescribed, completed, and comfortable tests and had the least worrying test results. Conversely, endoscopy was rated as the least comfortable and generated the most worry compared to the stool test.

This survey has several limitations. The first is the possibility of a biased population as this is an internet-based patient survey. Although there was a high proportion of males in this survey conducted by the commercial company Cross Marketing Co., Ltd., it was similar to the general sex ratio and age structure of patients with IBD in Japan and other East Asian countries [25, 61‒63] and did not differ from our two previous surveys in Japan [2, 17]. Therefore, we assume this bias to be relatively small. Second, because this was a web-based survey, there was the problem of response accuracy. Regarding consistency of web-based surveys in IBD, Randell et al. [64] reported the consistency of patient and physician ratings by CCFA partners, and Kelstrup et al. [65] reported the consistency of patient ratings and medical records in web-based surveys. Although we were unable to confirm consistency with medical records in this survey, we assume that the consistency of web-based surveys in IBD is relatively high based on these reports. The third limitation is the patients’ subjective evaluation in the comparison of drug administration usages and not the actual adherence to treatment. Nonetheless, we believe that our survey is informative because there are only a limited number of reports comparing the acceptability of each drug administration usage, which may differ between countries. Fourth, concerning examination methods, endoscopy and blood tests have different targets in the treat-to-target (T2T) strategies of Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) guidelines [10], and comparing them in the same category may, therefore, be inappropriate. However, as both are clinically important, we believe that they have considerable clinical significance.

Despite the abovementioned limitations, the web-based survey showed a high acceptance of once-daily oral administration of advanced therapies and blood tests in Japanese patients with IBD. These observations provide clues to improve the management of outpatients with IBD.

This survey was supported by the Cross Marketing Co., Ltd. (Tokyo, Japan).

All the procedures were performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. The study design was observational. This study was approved by the Ethics Committee of our institution (Institutional Review Board of Iwate Medical University). The IRB Approval No. MH2022-103. The study was performed in accordance with the ethics guidelines of Japan and was allowed to be implemented without obtaining written informed consent. The study was announced on the homepages of the participating institutions. Written informed consent to participate was not directly obtained but inferred by completion of the questionnaire. Patients who expressed unwillingness to participate in the study were excluded.

The authors do not have conflicts of interest to declare.

The authors have no funding support to declare.

Toshifumi Morishita: study design, data collection, data analysis, and writing the first draft of the manuscript; Shunichi Yanai, Yosuke Toya, and Takayuki Matsumoto: study design and data analysis. All the authors have read and approved the final version of the manuscript.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author [T.M.] upon reasonable request.