Introduction: 5-aminosalicylic acid (5-ASA) is the first-line drug for the treatment of mild-to-moderate ulcerative colitis (UC). Three oral sustained-release formulations are often used. However, no unified view of their actual use in routine medical practice has been presented to date. Methods: Using a health insurance claims database, we extracted patients with an initial diagnosis of mild-to-moderate UC during the period from December 1, 2017, to March 31, 2022. For the three types of oral 5-ASA formulation, we calculated and compared descriptive statistics of medication persistence rates (MPR), proportions of days covered (PDC), and adherence proportion (PDC ≥80%) in the extracted population. Results: An oral 5-ASA formulation was used in combination with a topical preparation (cohort 1) in 899 patients, and oral 5-ASA was used alone (cohort 2) in 1,829 patients. In cohort 1, MPR at days 151–180 with concomitant use of topical formulation was significantly higher for the Multi Matrix System™ (MMX) formulation (65.2%) compared with that for pH-dependent formulation (51.7%, p < 0.025), while MPR tended to be higher for MMX than for the time-dependent formulation (56.4%, not significant). During days 151–180 after starting the oral formulation, MPR for MMX (66.7% and 65.8%) was higher than for pH-dependent (55.9% and 55.3%) and time-dependent (57.6% and 55.9%) formulations in cohorts 1 + 2 and 2, respectively. In cohort 1, there was a significant difference between MMX (68.3%) and pH-dependent (57.1%) formulations, but no significant difference was seen with time-dependent formulations (61.8%). In terms of the proportion of adherence until day 180, MMX was significantly better than the other formulations. Conclusion: The analyses of the three oral 5-ASA formulations suggested that both MPR and medication adherence were better for the MMX formulation than for time-dependent or pH-dependent formulations.

Ulcerative colitis (UC) is a diffuse, nonspecific inflammatory bowel disease that primarily involves the large intestinal mucosa and causes symptoms including abdominal pain, diarrhea, bloody stool, and bowel urgency. There are chronic, repeated cycles of flares and remissions [1]. In Japan, the number of UC patients has grown in recent years [2]. According to an epidemiological survey in 2014, at least 220,000 people are estimated to be affected by UC [3]. Most patients with UC have mild-to-moderate disease activity [4]. In mild-to-moderate UC, five-aminosalicylic acid (5-ASA) preparations with an anti-inflammatory effect and their prodrug, oral salazosulfapyridine (SASP), are commonly used as first-line drugs for both induction and maintenance therapy [5]. As there is currently no definitive treatment for UC, it is important to continue taking medication to prevent relapse.

Mucosal 5-ASA or acetyl-5-ASA concentrations in the large intestine have been shown to correlate inversely with disease activity in UC patients [6]. In order to inhibit absorption in the upper gastrointestinal tract and increase exposure in the lower gastrointestinal tract, some oral sustained-release formulations have been developed to adequately deliver 5-ASA to the large intestinal mucosa, utilizing drug delivery systems. In Japan, three types of oral sustained-release formulations are currently marketed: (1) time-dependent, (2) pH-dependent, and (3) Multi Matrix System™ (MMX) formulations. In addition to these oral drugs, topical preparations of 5-ASA are also used, such as suppositories and enemas. Combination therapy with oral and topical preparations is commonly used due to good efficacy for induction and maintenance in mild-to-moderate UC [7, 8].

There are differences in the approved dose and dosage regimens between these three types of oral formulation; therefore, it cannot be concluded which is generally better. Conversely, a study measuring mucosal 5-ASA concentrations in the large intestine of UC patients showed that the MMX formulation provided the highest 5-ASA levels among these three formulations [9]. In a randomized controlled trial conducted in patients with active UC, the group taking the MMX formulation had a significantly greater decrease from baseline in the Disease Activity Index for Ulcerative Colitis (UC-DAI) and greater remission rate than those on the pH-dependent formulation [10]. Furthermore, a retrospective study reported a significant decrease in partial Mayo scores when patients with active UC switched to the MMX formulation after an inadequate response to the other formulations [11]. These reports suggest that therapeutic effects in UC patients may differ among the three types of oral 5-ASA formulation.

Oral 5-ASA formulations require continued regular administration to maintain remission; therefore, persistence is one of the principal behaviors required for treatment of UC with 5-ASA [12]. A study using a healthcare database in Canada reported a significantly higher persistence rate for MMX formulation than for the other formulations [13]. However, it is desirable to conduct a Japanese survey of the persistence of these three oral formulations with or without concomitant use of topical preparations (enemas and suppositories) for two reasons: (1) the concomitant use of topical preparations, which shows favorable efficacy for induction and maintenance, was not investigated in the Canadian study [13] and (2) the positioning of topical preparations in overseas guidelines varies from that in Japan [1, 14]. Indeed, Kane reported that rectal 5-ASA use was one of the significant predictors of increased persistent use of the medication [15]. In our previous retrospective cohort study using the National Health Insurance (NHI) claims database, established and managed by the Japan Medical Database Center (JMDC) Inc, our exploration suggested that the persistence rate with oral 5-ASA formulations, after concomitant use of topical preparations, tended to be greater for the MMX formulation than for the other formulations [16].

In addition to persistence, adherence is known to be another important factor for remission maintenance [12]. Nonadherence to 5-ASA in UC patients not only increases the risk of relapse but also leads to an increased risk of colorectal cancer and reduced quality of life [17, 18]. Moreover, lack of adherence to UC treatments has been associated with a significant increase in overall costs related to treatment of UC [19]. Some reports from foreign databases show that adherence was higher with use of the MMX formulation than with other oral treatments [13, 20].

In this study, we conducted a survey using the same health insurance claims database (JMDC), with extension of the study period and an increased sample size, to assess whether the rate of persistence with medication consisting of oral 5-ASA would be higher for the MMX formulation than for time-dependent or pH-dependent formulations, after starting concomitant use of topical preparations. In addition, the persistence rate for oral 5-ASA preparations in patients not receiving topical preparations, as well as medication adherence to each oral formulation were examined in an exploratory manner.

Data Source and Study Design

This is a retrospective cohort study using the JMDC Claims Database (that includes all medical expense payment systems throughout Japan) integrating multiple databases. This database enables follow-up of each patient even if patients are transferred to another institution or treated at two or more institutions; this allows the flow of medical examinations and treatment to be ascertained in chronological order. All personal information has been processed using sophisticated encryption with an irreversible anonymization technique. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000048318).

Extraction of the Target Population

Data on prescription claims were obtained for subjects who had their first prescription of an oral 5-ASA formulation together with a diagnosis of UC (International Classification of Diseases [ICD]-10) between December 1, 2017, and March 31, 2022, and who also met eligibility criteria. We defined the index date as the first day on which the oral 5-ASA formulation was prescribed during the study period. The follow-up period was set at 360 days from the index date.

The inclusion criteria were as follows: (1) being available for observation for 6 months retrospectively from the month preceding the index date; (2) being available for observation for the next 13 months including the index date; (3) no treatment for UC for 6 months retrospectively from the month preceding the index date; (4) no treatment for UC other than an oral 5-ASA formulation, or topical preparation of 5-ASA or steroid (hereinafter referred to as topical preparations) in the next 13 months including the index date; and (5) aged 16 years or older on the index date. These inclusion criteria were specified in order to include patients with mild-to-moderate UC in the study.

Exclusion criteria were as follows: (1) a diagnosis of Crohn’s disease, colorectal cancer, or the implementation of total or subtotal colectomy during the 6 months retrospectively from the month preceding the index date and in the next 13 months including the index date; (2) prescription of an oral 5-ASA preparation out of the approved dose range in the next 13 months, including the index date; (3) records of unknown prescription dates for oral 5-ASA and topical preparations in the next 13 months, including the index date; and (4) prescription of an unknown drug name or standard for oral 5-ASA or topical preparations in the next 13 months, including the index date. These exclusion criteria were specified to exclude data that were out of the approved dose range and where the amount required for summarizing was insufficient because the objective of this study was to evaluate the actual treatment conditions of therapies approved in Japan.

From the patients included in the study, we excluded those who were prescribed topical preparations during the 6 months prior to the index date, patients who were prescribed two or more oral 5-ASA or topical preparations on the index date due to data handling challenges, and patients who were not prescribed an oral 5-ASA preparation within 30 days from the index date excluding the index date; the Japanese treatment guidelines recommend follow-up within 2 weeks for initial treatment, and the absence of a refill within 30 days may suggest a possibility that the patient does not have UC, the remaining patients were included in the analyses. The analyses were performed on the following three populations according to the status of concomitant use of topical preparations: cohort 1, a population of patients who received topical preparations in combination; cohort 2, a population of patients who did not receive topical preparations in combination; and the entire population (cohort 1 + 2).

For analyses by formulation in each cohort, we classified three different formulations (Table 1) as time-dependent, pH-dependent, and MMX formulations. SASP preparations were excluded from the analyses because there were few patients to whom this was applicable. In addition, patients whose 5-ASA formulations were changed during the follow-up period were excluded from the analyses.

Table 1.

Summary of 3 types of 5-ASA sustained-release oral formulations in Japan

Type of formulation
time-dependentpH-dependentMMX
Indication approved in Japan UC (except severe), CD UC (except severe) UC (except severe) 
Regimen TID, BID, OD TID, OD OD 
Maximum dose, mg/day 4,000 3,600 4,800 
Tablets 250 mg, 500 mg 400 mg 1,200 mg 
Granules 94% None None 
Type of formulation
time-dependentpH-dependentMMX
Indication approved in Japan UC (except severe), CD UC (except severe) UC (except severe) 
Regimen TID, BID, OD TID, OD OD 
Maximum dose, mg/day 4,000 3,600 4,800 
Tablets 250 mg, 500 mg 400 mg 1,200 mg 
Granules 94% None None 

Endpoints and Data Analyses

Patient background characteristics were tabulated according to gender, age, and disease extent. The disease extent was summarized if a diagnosis based on the disease extent was available during the follow-up period.

Medication persistence was analyzed as duration from the index date or the start date of topical preparations in combination with oral formulation (cohort 1 only), until cessation of oral 5-ASA treatment. Treatment cessation was determined if the patient did not receive 5-ASA oral treatment for a period of 14 days or more. As with the prior studies [16], medication persistence rates (MPR) were summarized for each formulation, every 30 days after the index date. The primary endpoint was MPR for the three types of oral formulation between days 151–180 after the concomitant use of topical preparations. In addition, daily persistence rates for the three formulations were calculated using the Kaplan-Meier method.

With topical preparations, the proportion of days covered (PDC) was evaluated for every 30 days based on the following calculation: “(number of days covered by a topical preparation/30 days) × 100.” PDC for topical preparations was classified into quartiles: <25%, 25% to <50%, 50% to <75%, and ≥75%. Patients with a PDC of <25% were assumed to have “practically discontinued” concomitant use of topical preparations. Patients with a PDC of ≥75% were considered to be “practically continuing” concomitant use of topical preparations. Proportions of patients classified into the quartiles in these 2 patient groups were compared among the three formulations. During the process of summarizing the data, the concomitant use of topical preparations was deemed “discontinued” when there was a refill interval of 12 consecutive weeks (84 days) or more.

Regarding medication adherence with oral formulations, we calculated the PDC for the oral 5-ASA formulation from the index date or the initiation of concomitant use of topical preparations (cohort 1) to day 180. As with the prior studies, patients with a PDC of ≥80% were defined as adherent patients [13], and the proportions of adherent patients were compared among formulations.

Statistical Analyses

As descriptive statistics, the number of patients/cases (n), arithmetic mean, proportion (%), and standard deviation (SD) or 95% confidence interval (CI) were calculated. Patients using SASP, who had been excluded due to the small number of patients compared with those using other 5-ASA preparations in the previous study [16], were also excluded from evaluation in this study. MPR was compared among the three formulations using the χ2 test. The primary endpoint was MPR, and this was compared for pH-dependent or time-dependent formulations against the MMX formulation. Multiplicity was adjusted for using the Bonferroni method. No adjustment for multiplicity was performed in comparisons of other endpoints, apart from that for the primary endpoint. A post hoc comparison of the proportion of adherent patients among the three formulations was performed using the χ2 test. The significance level was set to 2.5% (two-sided) with multiplicity adjustment for the primary endpoint and 5% (two-sided) for the other endpoints. The software and system environment version used for statistical analyses were Amazon Redshift 1.0.44126 and SAS 9.4 (TS1M6).

Ethical Considerations

This study used anonymized, processed information, and is thus outside the scope of the “Ethical Guidelines for Medical and Biological Research Involving Human Subjects;” therefore, no Ethics Committee review was conducted.

Study Sample

The process of patient extraction is illustrated in Figure 1. Of the 4,290 patients with UC who were identified, an oral 5-ASA preparation was used in combination with topical preparations (cohort 1) in 899 patients, and oral 5-ASA formulations were used alone (cohort 2) in 1829 patients. Time-dependent, pH-dependent, and MMX formulation were prescribed to 204, 203, and 328 patients in cohort 1, and 517, 459, and 609 patients in cohort 2, respectively. The number of patients using SASP was minute: 3 patients in cohort 1 and 46 patients in cohort 2, so they were excluded from the subsequent evaluation among the formulations.

Fig. 1.

Description of patient numbers extracted from the JMDC claims database. 5-ASA, 5-aminosalicylic acid; SASP, salazosulfapyridine; MMX, Multi Matrix System.

Fig. 1.

Description of patient numbers extracted from the JMDC claims database. 5-ASA, 5-aminosalicylic acid; SASP, salazosulfapyridine; MMX, Multi Matrix System.

Close modal

The background characteristics of the analysis populations are shown by cohort in Table 2. The mean age of the entire population (cohorts 1 + 2) was 40.1 years, and the most common age group was 40 to <50 years (28.9%), whereas the proportion of patients aged ≥60 and <20 years was small: 4.8% and 4.2%, respectively. Male patients accounted for 63.5%, and the disease extent of UC could be identified in 16.3% of all patients. In both cohorts 1 and 2, the composition of patient background characteristics was very similar; there were no substantial differences among the three oral formulations either, except for the average dose and average number of pills.

Table 2.

Summary of patients’ background by cohort (age, sex, disease type, dose, pill burden)

Total: cohorts 1 + 2Cohort 1: with topical formulationCohort 2: without topical formulation
totaltime-dependentpH-dependentMMXtotaltime-dependentpH-dependentMMXtotaltime-dependentpH-dependentMMX
(n = 2,728)(n = 721)(n = 662)(n = 937)(n = 899)(n = 204)(n = 203)(n = 328)(n = 1,829)(n = 517)(n = 459)(n = 609)
Age, mean (SD), years 40.1 (12.0) 40.8 (12.2) 40.4 (11.6) 40.0 (11.8) 38.8 (11.7) 38.9 (11.8) 39.4 (11.8) 38.7 (11.6) 40.7 (12.1) 41.6 (12.3) 40.9 (11.5) 40.7 (11.8) 
Age group, n (%) 
 ≥16, <20 y. o. 115 (4.2) 35 (4.9) 20 (3.0) 37 (3.9) 44 (4.9) 11 (5.4) 7 (3.4) 15 (4.6) 71 (3.9) 24 (4.6) 13 (2.8) 22 (3.6) 
 ≥20, <30 y. o. 468 (17.2) 110 (15.3) 110 (16.6) 164 (17.5) 174 (19.4) 40 (19.6) 42 (20.7) 66 (20.1) 294 (16.1) 70 (13.5) 68 (14.8) 98 (16.1) 
 ≥30, <40 y. o. 705 (25.8) 182 (25.2) 171 (25.8) 231 (24.7) 249 (27.7) 49 (24.0) 51 (25.1) 95 (29.0) 456 (24.9) 133 (25.7) 120 (26.1) 136 (22.3) 
 ≥40, <50 y. o. 788 (28.9) 211 (29.3) 200 (30.2) 285 (30.4) 254 (28.3) 63 (30.9) 65 (32.0) 85 (25.9) 534 (29.2) 148 (28.6) 135 (29.4) 200 (32.8) 
 ≥50, <60 y. o. 521 (19.1) 133 (18.4) 137 (20.7) 181 (19.3) 147 (16.4) 32 (15.7) 30 (14.8) 56 (17.1) 374 (20.4) 101 (19.5) 107 (23.3) 125 (20.5) 
 ≥60 y. o. 131 (4.8) 50 (6.9) 24 (3.6) 39 (4.2) 31 (3.4) 9 (4.4) 8 (3.9) 11 (3.4) 100 (5.5) 41 (7.9) 16 (3.5) 28 (4.6) 
Male n (%) 1,733 (63.5) 454 (63.0) 413 (62.4) 604 (64.5) 550 (61.2) 131 (64.2) 116 (57.1) 198 (60.4) 1,183 (64.7) 323 (62.5) 297 (64.7) 406 (66.7) 
Disease type, n (%) 
 Classified 444 (16.3) 104 (14.4) 90 (13.6) 182 (19.4) 172 (19.1) 32 (15.7) 34 (16.7) 70 (21.3) 272 (14.9) 72 (13.9) 56 (12.2) 112 (18.4) 
 Pancolitis 167 (6.1) 47 (6.5) 29 (4.4) 64 (6.8) 36 (4.0) 9 (4.4) 5 (2.5) 11 (3.4) 131 (7.2) 38 (7.4) 24 (5.2) 53 (8.7) 
 Left-sided colitis 86 (3.2) 19 (2.6) 19 (2.9) 34 (3.6) 39 (4.3) 6 (2.9) 8 (3.9) 16 (4.9) 47 (2.6) 13 (2.5) 11 (2.4) 18 (3.0) 
 Proctitis 164 (6.0) 29 (4.0) 38 (5.7) 75 (8.0) 83 (9.2) 11 (5.4) 19 (9.4) 38 (11.6) 81 (4.4) 18 (3.5) 19 (4.1) 37 (6.1) 
 Segmental colitis 36 (1.3) 11 (1.5) 5 (0.8) 14 (1.5) 20 (2.2) 7 (3.4) 2 (1.0) 9 (2.7) 16 (0.9) 4 (0.8) 3 (0.7) 5 (0.8) 
5-ASA dose, g/day, mean (SD) 2.9 (1.0) 3.0 (0.5) 3.8 (1.0) 3.0 (0.9) 3.1 (0.5) 4.0 (0.9) 2.8 (1.0) 2.9 (0.5) 3.8 (1.0) 
5-ASA pill burden, pills/day, mean (SD) 4.6 (2.0) 7.4 (1.3) 3.2 (0.8) 4.6 (2.1) 7.7 (1.3) 3.3 (0.8) 4.5 (2.0) 7.3 (1.4) 3.1 (0.9) 
Total: cohorts 1 + 2Cohort 1: with topical formulationCohort 2: without topical formulation
totaltime-dependentpH-dependentMMXtotaltime-dependentpH-dependentMMXtotaltime-dependentpH-dependentMMX
(n = 2,728)(n = 721)(n = 662)(n = 937)(n = 899)(n = 204)(n = 203)(n = 328)(n = 1,829)(n = 517)(n = 459)(n = 609)
Age, mean (SD), years 40.1 (12.0) 40.8 (12.2) 40.4 (11.6) 40.0 (11.8) 38.8 (11.7) 38.9 (11.8) 39.4 (11.8) 38.7 (11.6) 40.7 (12.1) 41.6 (12.3) 40.9 (11.5) 40.7 (11.8) 
Age group, n (%) 
 ≥16, <20 y. o. 115 (4.2) 35 (4.9) 20 (3.0) 37 (3.9) 44 (4.9) 11 (5.4) 7 (3.4) 15 (4.6) 71 (3.9) 24 (4.6) 13 (2.8) 22 (3.6) 
 ≥20, <30 y. o. 468 (17.2) 110 (15.3) 110 (16.6) 164 (17.5) 174 (19.4) 40 (19.6) 42 (20.7) 66 (20.1) 294 (16.1) 70 (13.5) 68 (14.8) 98 (16.1) 
 ≥30, <40 y. o. 705 (25.8) 182 (25.2) 171 (25.8) 231 (24.7) 249 (27.7) 49 (24.0) 51 (25.1) 95 (29.0) 456 (24.9) 133 (25.7) 120 (26.1) 136 (22.3) 
 ≥40, <50 y. o. 788 (28.9) 211 (29.3) 200 (30.2) 285 (30.4) 254 (28.3) 63 (30.9) 65 (32.0) 85 (25.9) 534 (29.2) 148 (28.6) 135 (29.4) 200 (32.8) 
 ≥50, <60 y. o. 521 (19.1) 133 (18.4) 137 (20.7) 181 (19.3) 147 (16.4) 32 (15.7) 30 (14.8) 56 (17.1) 374 (20.4) 101 (19.5) 107 (23.3) 125 (20.5) 
 ≥60 y. o. 131 (4.8) 50 (6.9) 24 (3.6) 39 (4.2) 31 (3.4) 9 (4.4) 8 (3.9) 11 (3.4) 100 (5.5) 41 (7.9) 16 (3.5) 28 (4.6) 
Male n (%) 1,733 (63.5) 454 (63.0) 413 (62.4) 604 (64.5) 550 (61.2) 131 (64.2) 116 (57.1) 198 (60.4) 1,183 (64.7) 323 (62.5) 297 (64.7) 406 (66.7) 
Disease type, n (%) 
 Classified 444 (16.3) 104 (14.4) 90 (13.6) 182 (19.4) 172 (19.1) 32 (15.7) 34 (16.7) 70 (21.3) 272 (14.9) 72 (13.9) 56 (12.2) 112 (18.4) 
 Pancolitis 167 (6.1) 47 (6.5) 29 (4.4) 64 (6.8) 36 (4.0) 9 (4.4) 5 (2.5) 11 (3.4) 131 (7.2) 38 (7.4) 24 (5.2) 53 (8.7) 
 Left-sided colitis 86 (3.2) 19 (2.6) 19 (2.9) 34 (3.6) 39 (4.3) 6 (2.9) 8 (3.9) 16 (4.9) 47 (2.6) 13 (2.5) 11 (2.4) 18 (3.0) 
 Proctitis 164 (6.0) 29 (4.0) 38 (5.7) 75 (8.0) 83 (9.2) 11 (5.4) 19 (9.4) 38 (11.6) 81 (4.4) 18 (3.5) 19 (4.1) 37 (6.1) 
 Segmental colitis 36 (1.3) 11 (1.5) 5 (0.8) 14 (1.5) 20 (2.2) 7 (3.4) 2 (1.0) 9 (2.7) 16 (0.9) 4 (0.8) 3 (0.7) 5 (0.8) 
5-ASA dose, g/day, mean (SD) 2.9 (1.0) 3.0 (0.5) 3.8 (1.0) 3.0 (0.9) 3.1 (0.5) 4.0 (0.9) 2.8 (1.0) 2.9 (0.5) 3.8 (1.0) 
5-ASA pill burden, pills/day, mean (SD) 4.6 (2.0) 7.4 (1.3) 3.2 (0.8) 4.6 (2.1) 7.7 (1.3) 3.3 (0.8) 4.5 (2.0) 7.3 (1.4) 3.1 (0.9) 

y. o., years old.

Persistence Rate by Three Types of Oral Formulation

The primary endpoint was defined as MPR (cohort 1) for the three types of oral formulation at days 151–180, after the concomitant use of topical preparations. MPRs for the three types of oral formulation are summarized in Table 3. The MPR at days 151–180 after the concomitant use of topical preparations was higher for the MMX formulation at 65.2%, compared with that for the pH-dependent formulation, at 51.7% (p < 0.025). On comparing the MMX formulation and time-dependent formulation, there was no significant difference, but MPR tended to be higher for the MMX formulation than for the time-dependent formulation, where the value was 56.4% (p = 0.04).

Table 3.

Medication persistence in treatment with 5-ASA oral formulations between 151 and 180 days

Persistence: % (95% CI)5-ASA oral formulations
totaltime-dependentpH-dependentMMX
151–180 days after the concomitant use of topical preparation Cohort 1 59.1 (55.4–62.5) 56.4 (48.6–64.2) 51.7 (43.9–59.6)* 65.2 (59.4–71.1) 
151–180 days after the index date Total (cohort 1 + 2) 60.1 (58.1–62.0) 57.6 (54.0–61.2) 55.9 (52.1–59.7)a 66.7 (63.7–69.7) 
 Cohort 1 63.4 (59.8–66.8) 61.8 (55.1–68.4) 57.1 (50.3–64.0)a 68.3 (63.3–73.3) 
 Cohort 2 58.6 (56.1–60.9) 55.9 (51.6–60.2)a 55.3 (50.8–59.9)a 65.8 (62.1–69.6) 
Persistence: % (95% CI)5-ASA oral formulations
totaltime-dependentpH-dependentMMX
151–180 days after the concomitant use of topical preparation Cohort 1 59.1 (55.4–62.5) 56.4 (48.6–64.2) 51.7 (43.9–59.6)* 65.2 (59.4–71.1) 
151–180 days after the index date Total (cohort 1 + 2) 60.1 (58.1–62.0) 57.6 (54.0–61.2) 55.9 (52.1–59.7)a 66.7 (63.7–69.7) 
 Cohort 1 63.4 (59.8–66.8) 61.8 (55.1–68.4) 57.1 (50.3–64.0)a 68.3 (63.3–73.3) 
 Cohort 2 58.6 (56.1–60.9) 55.9 (51.6–60.2)a 55.3 (50.8–59.9)a 65.8 (62.1–69.6) 

Data: % (95% CI).

*p < 0.025 versus MMX.

ap < 0.05 versus MMX, χ2 test.

MPR at days 151–180 after the index date was also analyzed in each population. In the entire population (cohorts 1 + 2) and cohort 2, the MPR was significantly higher for the MMX formulation (66.7% and 65.8%) than for the time-dependent formulation (57.6% and 55.9%) and pH-dependent formulation (55.9% and 55.3%, p < 0.05 in both populations). In cohort 1, there was a significant difference between MMX formulation (68.3%) and pH-dependent formulation (57.1%, p < 0.05), whereas no significance difference was shown on comparing the time-dependent formulation (61.8%, p = 0.12).

Kaplan-Meier curves were drawn to assess the time-course of persistence. The persistence rates of each formulation decreased over time, showing similar trends regardless of population or study period (Fig. 2).

Fig. 2.

Medication persistence in treatment with 5-ASA oral formulations – Kaplan-Meier curve. a From the concomitant use of topical preparation, cohort 1. b From the index date, total (cohort 1 + cohort 2). c From the index date, cohort 1. d From the index date, cohort 2. 5-ASA, 5-aminosalicylic acid; MMX, Multi Matrix System.

Fig. 2.

Medication persistence in treatment with 5-ASA oral formulations – Kaplan-Meier curve. a From the concomitant use of topical preparation, cohort 1. b From the index date, total (cohort 1 + cohort 2). c From the index date, cohort 1. d From the index date, cohort 2. 5-ASA, 5-aminosalicylic acid; MMX, Multi Matrix System.

Close modal

Table 4 shows MPR for the three oral formulations at 180 days from the index date or concomitant use of topical preparations (cohort 1 only), the last evaluation time point. The MPR with the concomitant use of topical preparations was significantly higher for the MMX formulation at 59.1% compared with those for time-dependent and pH-dependent formulations at 49.0% and 45.8%, respectively (p < 0.05 in both formulations) (Table 4). On analysis from the index date, MPR in the entire population (cohorts 1 + 2), and cohort 2 was significantly higher for the MMX formulation (61.2% and 60.6%) than for the time-dependent formulation (50.6% and 48.9%, p < 0.05 in both populations) and pH-dependent formulation (49.2% and 48.8%, p < 0.05 in both populations). In cohort 1, there was a significant difference between the MMX formulation (62.2%) and pH-dependent formulation (50.2%, p < 0.05), whereas no significant difference was shown compared with the time-dependent formulation (54.9%, p = 0.10).

Table 4.

Medication persistence in treatment with 5-ASA oral formulations at the last observation

Persistence: % (95% CI)5-ASA oral formulations
totaltime-dependentpH-dependentMMX
At 180 days after the concomitant use of topical preparation Cohort 1 52.7 (49.1–56.3) 49.0 (42.2–55.9)* 45.8 (39.0–52.7)* 59.1 (53.8–64.5) 
At 180 days after the index date Total (cohorts 1 + 2) 53.9 (51.9–55.9) 50.6 (47.0–54.3)* 49.2 (45.4–53.1)* 61.2 (58.0–64.3) 
 Cohort 1 56.9 (53.3–60.5) 54.9 (48.1–61.7) 50.2 (43.4–57.1)* 62.2 (56.9–67.4) 
 Cohort 2 52.5 (50.1–54.9) 48.9 (44.6–53.2)* 48.8 (44.2–53.4)* 60.6 (56.7–64.5) 
Persistence: % (95% CI)5-ASA oral formulations
totaltime-dependentpH-dependentMMX
At 180 days after the concomitant use of topical preparation Cohort 1 52.7 (49.1–56.3) 49.0 (42.2–55.9)* 45.8 (39.0–52.7)* 59.1 (53.8–64.5) 
At 180 days after the index date Total (cohorts 1 + 2) 53.9 (51.9–55.9) 50.6 (47.0–54.3)* 49.2 (45.4–53.1)* 61.2 (58.0–64.3) 
 Cohort 1 56.9 (53.3–60.5) 54.9 (48.1–61.7) 50.2 (43.4–57.1)* 62.2 (56.9–67.4) 
 Cohort 2 52.5 (50.1–54.9) 48.9 (44.6–53.2)* 48.8 (44.2–53.4)* 60.6 (56.7–64.5) 

Data: % (95% CI).

*p < 0.05 versus MMX, χ2 test.

Trends in Concomitant Use of Topical Preparations

The time-course of the concomitant use of topical preparations is shown in Table 5. The proportion of patients practically continuing use (PDC ≥75%) was similar among the three oral formulations and decreased over time until day 180. The proportion of patients practically discontinuing treatment (PDC <25%) increased to 32.4–43.3% over time (days 61–90) and was maintained at almost the same rate (29.4–40.9%) for days 151–180 with the MMX and time-dependent formulations, in contrast to the pH-dependent formulation, where the rate decreased to 28.1%. As with the prior study [16], the proportion of patients who practically discontinued treatment at days 151–180 was highest for the MMX formulation (40.9%).

Table 5.

Trends in concomitant use of topical formulation from initiation to 180 days

Days after the concomitant use of topical preparationPDC <25%PDC ≥75%
totaltime-dependentpH-dependentMMXtotaltime-dependentpH-dependentMMX
1–30 6.5 (4.8–8.1) 4.4 (1.6–7.2) 6.9 (3.4–10.4) 5.5 (3.0–8.0) 68.9 (65.8–71.9) 72.1 (65.9–78.2) 68.5 (62.1–74.9) 68.0 (62.9–73.0) 
31–60 31.7 (28.7–34.7) 26.0 (20.0–32.0) 35.0 (28.4–41.5) 31.7 (26.7–36.7) 39.9 (36.7–43.1) 41.2 (34.4–47.9) 37.4 (30.8–44.1) 43.0 (37.6–48.3) 
61–90 40.2 (37.0–43.4) 32.4 (25.9–38.8) 39.9 (33.2–46.6) 43.3 (37.9–48.7) 31.6 (28.6–34.6) 33.8 (27.3–40.3) 29.6 (23.3–35.8) 32.6 (27.5–37.7) 
91–120 38.3 (35.1–41.4) 32.8 (26.4–39.3) 33.0 (26.5–39.5) 42.7 (37.3–48.0) 24.5 (21.7–27.3) 28.4 (22.2–34.6) 21.2 (15.6–26.8) 22.9 (18.3–27.4) 
121–150 36.9 (33.8–40.1) 32.4 (25.9–38.8) 33.0 (26.5–39.5) 40.2 (34.9–45.6) 18.7 (16.1–21.2) 19.1 (13.7–24.5) 15.8 (10.8–20.8) 19.2 (14.9–23.5) 
151–180 34.4 (31.3–37.5) 29.4 (23.2–35.7) 28.1 (21.9–34.3) 40.9 (35.5–46.2) 18.2 (15.7–20.8) 19.1 (13.7–24.5) 15.8 (10.8–20.8) 17.4 (13.3–21.5) 
Days after the concomitant use of topical preparationPDC <25%PDC ≥75%
totaltime-dependentpH-dependentMMXtotaltime-dependentpH-dependentMMX
1–30 6.5 (4.8–8.1) 4.4 (1.6–7.2) 6.9 (3.4–10.4) 5.5 (3.0–8.0) 68.9 (65.8–71.9) 72.1 (65.9–78.2) 68.5 (62.1–74.9) 68.0 (62.9–73.0) 
31–60 31.7 (28.7–34.7) 26.0 (20.0–32.0) 35.0 (28.4–41.5) 31.7 (26.7–36.7) 39.9 (36.7–43.1) 41.2 (34.4–47.9) 37.4 (30.8–44.1) 43.0 (37.6–48.3) 
61–90 40.2 (37.0–43.4) 32.4 (25.9–38.8) 39.9 (33.2–46.6) 43.3 (37.9–48.7) 31.6 (28.6–34.6) 33.8 (27.3–40.3) 29.6 (23.3–35.8) 32.6 (27.5–37.7) 
91–120 38.3 (35.1–41.4) 32.8 (26.4–39.3) 33.0 (26.5–39.5) 42.7 (37.3–48.0) 24.5 (21.7–27.3) 28.4 (22.2–34.6) 21.2 (15.6–26.8) 22.9 (18.3–27.4) 
121–150 36.9 (33.8–40.1) 32.4 (25.9–38.8) 33.0 (26.5–39.5) 40.2 (34.9–45.6) 18.7 (16.1–21.2) 19.1 (13.7–24.5) 15.8 (10.8–20.8) 19.2 (14.9–23.5) 
151–180 34.4 (31.3–37.5) 29.4 (23.2–35.7) 28.1 (21.9–34.3) 40.9 (35.5–46.2) 18.2 (15.7–20.8) 19.1 (13.7–24.5) 15.8 (10.8–20.8) 17.4 (13.3–21.5) 

Data: % (95% CI).

Adherence to Oral 5-ASA Treatment

The proportions of adherent patients (PDC ≥80%) are shown in Table 6. In the analysis of concomitant use of topical preparations, the MMX formulation group showed a significantly higher adherent population (77.1%) than was the case with the time-dependent and pH-dependent formulations (64.7% and 68.5%, p < 0.05 for both formulations). The proportion of adherent patients, analyzed from the index date, was also evaluated. For the MMX formulation (78.2% in cohorts 1 + 2, 80.2% in cohort 1, 77.2% in cohort 2), this was significantly greater than for the time-dependent formulation (67.5% in cohorts 1 + 2, 68.1% in cohort 1, 67.3% in cohort 2) and pH-dependent formulation (68.7% in cohorts 1 + 2, 72.4% in cohort 1, 67.1% in cohort 2) (p < 0.05 for all comparisons).

Table 6.

Proportion of good adherence (≥80%) to 5-ASA oral treatments

Adherence: % (95% CI)5-ASA oral formulations
totaltime-dependentpH-dependentMMX
At 180 days after the concomitant use of topical preparation Cohort 1 72.6 (69.7–75.6) 64.7 (58.1–71.3)* 68.5 (62.1–74.9)* 77.1 (72.6–81.7) 
At 180 days after the index date Total (cohorts 1 + 2) 72.5 (70.8–74.2) 67.5 (64.1–71.0)* 68.7 (65.2–72.3)* 78.2 (75.6–80.9) 
 Cohort 1 76.2 (73.4–79.0) 68.1 (61.7–74.5)* 72.4 (66.3–78.6)* 80.2 (75.9–84.5) 
 Cohort 2 70.7 (68.6–72.8) 67.3 (63.3–71.4)* 67.1 (62.8–71.4)* 77.2 (73.8–80.5) 
Adherence: % (95% CI)5-ASA oral formulations
totaltime-dependentpH-dependentMMX
At 180 days after the concomitant use of topical preparation Cohort 1 72.6 (69.7–75.6) 64.7 (58.1–71.3)* 68.5 (62.1–74.9)* 77.1 (72.6–81.7) 
At 180 days after the index date Total (cohorts 1 + 2) 72.5 (70.8–74.2) 67.5 (64.1–71.0)* 68.7 (65.2–72.3)* 78.2 (75.6–80.9) 
 Cohort 1 76.2 (73.4–79.0) 68.1 (61.7–74.5)* 72.4 (66.3–78.6)* 80.2 (75.9–84.5) 
 Cohort 2 70.7 (68.6–72.8) 67.3 (63.3–71.4)* 67.1 (62.8–71.4)* 77.2 (73.8–80.5) 

Data: % (95% CI).

*p < 0.05 versus MMX, χ2 test.

This study investigated MPR for and medication adherence to oral sustained-release formulations of 5-ASA in UC patients, using the JMDC Claims Database as a source of real-world data. The number of UC patients in Japan has grown rapidly over the past few decades [2], so it has been difficult to treat these patients at specialized, core hospitals alone. As a result, a medical care framework has been established at collaborating regional healthcare institutions. The JMDC Claims Database aggregates all health insurance claims from authorized medical insurance institutions and allows vertical investigation of the details of medical care, even when patients are treated at two or more medical institutions. Because the treating institutions vary according to the stage and severity of UC, this database, which covers information from multiple treating institutions, is considered suitable for a study involving UC patients. This database is limited to health insurance and has little data from older people aged 65 years or more as the medical care services of this group are mainly covered by national health insurance. Hence, the results may not directly generalize to Japanese society overall. Nevertheless, even taking into consideration the increasing incidence of UC over-time – the mean age of initial onset was 30.8 years before 2000 and rose over time to 36.9 years from 2001 to 2013 [21] – the mean age of patients in this study with an initial diagnosis of UC (40.1 years) was similar to that in a prior study [21].

The current study showed that the MPR for oral 5-ASA preparations at days 151–180 after the concomitant use of topical preparations was significantly higher for the MMX formulation than for the pH-dependent formulation, and tended to be higher than that of the time-dependent formulation (no significant difference). Our prior study [16] showed a difference in the MPR: 65.9% for MMX formulation, 44.9% for pH-dependent formulation, and 46.9% for time-dependent formulation. This study revealed increases in MPR for pH-dependent and time-dependent formulations, which may have prevented us from demonstrating a difference in the persistence rate between MMX and time-dependent formulation. During the study period, which was an extension from the prior study, the work environment changed substantially, for example, initiation of telework due to the COVID-19 pandemic. Since the database used for this study mainly consists of data from workers, the change in the work environment might have affected treatment compliance, especially by facilitating consumption of pH-dependent and/or time-dependent formulations, which require administration of multiple doses per day, resulting in the increases in their persistence rates. Longer follow-up may allow detection of significant differences between MMX and time-dependent formulation because the differences in MPR increased over time (Fig. 2), and there was a significant difference in the MPR at day 180, after the concomitant use of topical preparations (Table 3).

In this study, MPR at day 180 after the index date was 53.9% in the entire population; the result was similar to that of prior studies [12, 13, 20, 22], despite differences in the analytical methods such as the study period and sample size. In the respect of adherence, the proportion of patient adherence was high in the entire population analyzed from index date. Prior studies reported that the annual proportion of patients who adhered was 21.0% [20] or 27.7% [13]. The difference in medication adherence between this study and prior studies was assumed to be largely due to the effect of differences in analytical methods, particularly the period of analysis.

The analyses of each oral formulation of 5-ASA suggested that both MPR and medication adherence were higher for the MMX formulation than for time-dependent or pH-dependent formulations, as seen in prior studies [12, 13, 20]. The clinical efficacy of oral 5-ASA preparations is known to be dose-dependent [23], and the persistence rate has been reported to be higher for patients prescribed high-dose 5-ASA [22]. Because the MMX formulation was prescribed at the highest dose and the fewest tables among three oral formulations, this might have resulted in a higher MPR for the MMX formulation. Time-dependent or pH-dependent formulations can be administered once daily if needed during the maintenance phase, while multiple doses need to be taken during the active phase of the disease. In contrast, the dosage regimen of the MMX formulation is just once daily, during both the active and maintenance phases. Daily dosing is known to greatly affect medication adherence [24, 25], and medication adherence has been reported to be better with once-daily dosing than with multiple dosing [25]; this might therefore have contributed to high adherence to the MMX formulation. Moreover, medication nonadherence has been reported to increase the risk of clinical relapse for UC [16], so medication adherence might have affected the MPR.

In terms of the concomitant use of topical preparations, MMX formulation showed the highest proportion of PDC <25%, indicating that topical formulations are practically unnecessary. This result may imply that MMX formulation is the most effective in treating distal lesion compared to other formulations, which is consistent with the higher efficacy of MMX formulation in treating proctitis compared to pH-dependent formulation [10]. However, it should be noted that the differences in the proportion of topical steroid use among the formulations may affect the result.

There are some inherent limitations as in other studies based on health insurance claims. The data set used for the analyses might contain coding errors. Similarly, because the diagnosis of UC was detected only when it was identified by the relevant ICD codes, there might be data errors. In the future, there is room to improve diagnostic accuracy by conducting an additional study that includes the presence or absence of large bowel endoscopy. In this study, patients who received systemic steroid or advanced therapy to control severity were not included. However, as there was no information on severity in the database, the severity of the analysis population for each formulation might be different. The persistence rates from prescription data were used for the medication adherence analysis in this study. It is thus possible that the drugs might not have been taken as specified in the health insurance claims, so that the derived MPR and medication adherence might be higher than actual rates. In this study, patients without the refill of oral 5-ASA within 30 days from the index date were excluded from the analyses due to the possibility that the patient does not have UC; patients who were prescribed 30 or more days of oral 5-ASA formulation on the index date were also excluded from the analyses, regardless of whether they continued their prescription or not. As a side note, we confirmed that analyses including those patients did not yield clinically meaningful differences from the results of this study (data not shown). In conclusion, both MPR and medication adherence were higher for the MMX formulation than for time-dependent or pH-dependent formulations, regardless of the concomitant use of topical preparations.

The authors acknowledge Yuji Honma of JMDC Inc. for writing the protocol and analysis of the study methodology and supervision of the assessment of the data, and Takanori Sakamoto of SRD Co., Ltd. for writing the first draft of the manuscript based on input from the authors.

This is a retrospective cohort study using the JMDC Claims Database (that includes all medical expense payment systems throughout Japan) integrating multiple databases established and managed by the JMDC Inc. This database enables follow-up on a patient basis even if patients are transferred to another institution or treated at two or more institutions and to exhaustively ascertain the flow of medical examinations and treatment in chronological order. All personal information has been processed using sophisticated encryption with an irreversible anonymization technique. Therefore, ethical approval and consent were not required as this study was based on publicly available data.

Shiro Nakamura has received honoraria from AbbVie G.K, EA Pharma Co., Ltd, Kyorin Pharmaceutical Co., Ltd, Mochida Pharmaceutical Co., Ltd, Pfizer Co., Ltd, Takeda Pharmaceutical Co., Ltd, Tanabe Mitsubishi Pharma Corporation and Janssen Pharmaceutical K.K. Takumi Ota, Takahiro Takebe, Yutaka Shimizu, Takashi Orido, and Hiroyuki Tanaka are employees of Mochida Pharmaceutical Co. Ltd., Tokyo, Japan. This study was funded by Mochida Pharmaceutical Co. Ltd.

Mochida Pharmaceutical Co. Ltd. (Tokyo, Japan/https://www.mochida.co.jp/) funded this study and played a role in designing the study, collecting/analyzing data, deciding to publish, and preparing the manuscript. Services provided by JMDC (data analysis) and SRD (medical writing) were funded by Mochida Pharmaceutical Co. Ltd.

Takumi Ota: study design, interpretation, and drafting manuscript; Takahiro Takebe and Shiro Nakamura: study design, interpretation, and manuscript writing; Yutaka Shimizu and Takashi Orido: conception, study design, interpretation, and manuscript writing; and Hiroyuki Tanaka: conception, interpretation, and manuscript writing.

The data that support the findings of this study are available from JMDC Inc. but were used under license for the current study; therefore, restrictions apply, and the data are not publicly available. For inquiries about access to the data set used in this study, contact JMDC (https://www.jmdc.co.jp).

1.
Nakase
H
,
Uchino
M
,
Shinzaki
S
,
Matsuura
M
,
Matsuoka
K
,
Kobayashi
T
, et al
.
Evidence-based clinical practice guidelines for inflammatory bowel disease 2020
.
J Gastroenterol
.
2021
;
56
(
6
):
489
526
.
2.
Yamazaki
M
,
Chung
H
,
Xu
Y
,
Qiu
H
.
Trends in the prevalence and incidence of ulcerative colitis in Japan and the US
.
Int J Colorectal Dis
.
2023
;
38
(
1
):
135
.
3.
Murakami
Y
,
Nishiwaki
Y
,
Oba
MS
,
Asakura
K
,
Ohfuji
S
,
Fukushima
W
, et al
.
Estimated prevalence of ulcerative colitis and Crohn’s disease in Japan in 2014: an analysis of a nationwide survey
.
J Gastroenterol
.
2019
;
54
(
12
):
1070
7
.
4.
Singh
S
,
Feuerstein
JD
,
Binion
DG
,
Tremaine
WJ
.
AGA technical review on the management of mild-to-moderate ulcerative colitis
.
Gastroenterology
.
2019
;
156
(
3
):
769
808.e29
.
5.
Ko
CW
,
Singh
S
,
Feuerstein
JD
,
Falck-Ytter
C
,
Falck-Ytter
Y
,
Cross
RK
, et al
.
AGA clinical practice guidelines on the management of mild-to-moderate ulcerative colitis
.
Gastroenterology
.
2019
;
156
(
3
):
748
64
.
6.
Naganuma
M
,
Iwao
Y
,
Ogata
H
,
Inoue
N
,
Funakoshi
S
,
Yamamoto
S
, et al
.
Measurement of colonic mucosal concentrations of 5-aminosalicylic acid is useful for estimating its therapeutic efficacy in distal ulcerative colitis: comparison of orally administered mesalamine and sulfasalazine
.
Inflamm Bowel Dis
.
2001
;
7
(
3
):
221
5
.
7.
Nguyen
NH
,
Fumery
M
,
Dulai
PS
,
Prokop
LJ
,
Sandborn
WJ
,
Murad
MH
, et al
.
Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses
.
Lancet Gastroenterol Hepatol
.
2018
;
3
(
11
):
742
53
.
8.
Ford
AC
,
Khan
KJ
,
Achkar
JP
,
Moayyedi
P
.
Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic review and meta-analysis
.
Am J Gastroenterol
.
2012
;
107
(
2
):
167
77
.
9.
Olaisen
M
,
Spigset
O
,
Flatberg
A
,
Granlund
AB
,
Brede
WR
,
Albrektsen
G
, et al
.
Mucosal 5-aminosalicylic acid concentration, drug formulation and mucosal microbiome in patients with quiescent ulcerative colitis
.
Aliment Pharmacol Ther
.
2019
;
49
(
10
):
1301
13
.
10.
Ogata
H
,
Aoyama
N
,
Mizushima
S
,
Hagino
A
,
Hibi
T
.
Comparison of efficacy of multimatrix mesalazine 4.8 g/day once-daily with other high-dose mesalazine in active ulcerative colitis: a randomized, double-blind study
.
Intest Res
.
2017
;
15
(
3
):
368
79
.
11.
Kato
M
,
Sugiyama
K
,
Miyakawa
M
,
Nasuno
M
,
Tanaka
H
,
Motoya
S
.
Efficacy of Multi Matrix system mesalazine for the induction of remission in patients with ulcerative colitis who insufficiently respond toother mesalazine formulations: a Japanese single-center study
.
J Jpn Soc Coloproctol
.
2021
;
74
(
6
):
357
63
.
12.
Kane
SV
,
Sumner
M
,
Solomon
D
,
Jenkins
M
.
Twelve-month persistency with oral 5-aminosalicylic acid therapy for ulcerative colitis: results from a large pharmacy prescriptions database
.
Dig Dis Sci
.
2011
;
56
(
12
):
3463
70
.
13.
Lachaine
J
,
Yen
L
,
Beauchemin
C
,
Hodgkins
P
.
Medication adherence and persistence in the treatment of Canadian ulcerative colitis patients: analyses with the RAMQ database
.
BMC Gastroenterol
.
2013
;
13
:
23
.
14.
Raine
T
,
Bonovas
S
,
Burisch
J
,
Kucharzik
T
,
Adamina
M
,
Annese
V
, et al
.
ECCO guidelines on therapeutics in ulcerative colitis: medical treatment
.
J Crohns Colitis
.
2022
;
16
(
1
):
2
17
.
15.
Kane
SV
,
Accortt
NA
,
Magowan
S
,
Brixner
D
.
Predictors of persistence with 5-aminosalicylic acid therapy for ulcerative colitis
.
Aliment Pharmacol Ther
.
2009
;
29
(
8
):
855
62
.
16.
Nitta
T
,
Shimizu
Y
,
Notsu
T
,
Orido
T
,
Nagao
H
,
Nakamura
S
.
Combination with topical therapy and continuation proportion of oral therapy with 5-aminosalicylic acid for patients with ulcerative colitis: database study using Japanese claims data
.
Ther Res
.
2022
;
43
(
5
):
429
41
.
17.
Kane
SV
,
Huo
D
,
Aikens
J
,
Hanauer
S
.
Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis
.
Am J Med
.
2003
;
114
(
1
):
39
43
.
18.
Kane
SV
.
Systematic review: adherence issues in the treatment of ulcerative colitis
.
Aliment Pharmacol Ther
.
2006
;
23
(
5
):
577
85
.
19.
Hawthorne
AB
,
Rubin
G
,
Ghosh
S
.
Review article: medication non-adherence in ulcerative colitis—strategies to improve adherence with mesalazine and other maintenance therapies
.
Aliment Pharmacol Ther
.
2008
;
27
(
12
):
1157
66
.
20.
Yen
L
,
Wu
J
,
Hodgkins
PL
,
Cohen
RD
,
Nichol
MB
.
Medication use patterns and predictors of nonpersistence and nonadherence with oral 5-aminosalicylic acid therapy in patients with ulcerative colitis
.
J Manag Care Pharm
.
2012 Nov-Dec
;
18
(
9
):
701
12
.
21.
Takahashi
H
,
Matsui
T
,
Hisabe
T
,
Hirai
F
,
Takatsu
N
,
Tsurumi
K
, et al
.
Second peak in the distribution of age at onset of ulcerative colitis in relation to smoking cessation
.
J Gastroenterol Hepatol
.
2014
;
29
(
8
):
1603
8
.
22.
Fossmark
R
,
Olaisen
M
,
Martinsen
TC
,
Melberg
HO
.
Factors associated with the persistence of oral 5-aminosalicylic acid monotherapy in ulcerative colitis: a nationwide Norwegian cohort study
.
Ther Adv Gastroenterol
.
2021
;
14
:
17562848211021760
.
23.
Schroeder
KW
,
Tremaine
WJ
,
Ilstrup
DM
.
Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study
.
N Engl J Med
.
1987
;
317
(
26
):
1625
9
.
24.
Shale
MJ
,
Riley
SA
.
Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease
.
Aliment Pharmacol Ther
.
2003
;
18
(
2
):
191
8
.
25.
Kato
S
,
Kani
K
,
Kobayashi
T
,
Yamamoto
R
,
Nagoshi
S
,
Yakabi
K
.
Adherence to oral 5-aminosalicylic acid by patients with quiescent ulcerative colitis: a questionnaire survey
.
Nihon Shokakibyo Gakkai Zasshi
.
2015
;
112
(
10
):
1819
29
.