Introduction

Ulcerative colitis (UC) is a chronic immune-mediated inflammatory disease of the colon characterised by a relapsing-remitting course and substantial heterogeneity in disease extent, severity, and therapeutic response [1]. Although the therapeutic landscape of UC has expanded rapidly with biologic agents and small molecules, oral and topical mesalazine remain the cornerstone of treatment for mild-to-moderate disease, particularly in biologic-naïve patients [2–5]. Current European and national guidelines continue to recommend mesalazine as first-line therapy, with emphasis on adequate dosing, topical optimisation, and tailoring treatment to disease distribution to improve clinical remission and mucosal healing [2, 3].

The key clinical question is therefore no longer whether mesalazine is effective, but how it should be optimised in everyday practice. Randomised trials and meta-analyses support a dose-response relationship for remission induction, with daily doses of at least 3 g associated with superior clinical and endoscopic outcomes compared with lower doses [4, 5]. Combined oral and rectal mesalazine is also more effective than oral monotherapy, particularly in left-sided colitis (E2), highlighting the importance of adequate local mucosal drug exposure [5]. However, uncertainty remains regarding the incremental value of higher oral doses, especially in extensive colitis (E3), where controlled trial data may not fully capture real-world prescribing patterns, disease heterogeneity, and adherence-related factors [6, 7].

Formulation choice represents another clinically relevant but insufficiently explored determinant of treatment success. Prolonged-release, time-dependent mesalazine granules allow once-daily administration and may provide more consistent colonic drug delivery, potentially improving adherence and long-term outcomes compared with conventional pH-dependent tablets [8]. This is important because non-adherence is a well-established driver of relapse and treatment failure in UC [8, 9]. Real-world evidence is therefore essential to complement randomised trials by evaluating how dose, formulation, and combined topical therapy perform in unselected patients managed in routine care [6, 7].

Aim

The UC-INCREASE study was designed to assess whether mesalazine dose and formulation influence clinical, biochemical, and endoscopic outcomes in patients with mild-to-moderate UC treated in daily gastroenterology practice.

Material and methods

Study design, setting, and objectives

UC-INCREASE was a retrospective, multicentre, non-interventional observational study of mesalazine optimisation in adults with mild-to-moderate UC treated in routine practice. It was conducted at three tertiary inflammatory bowel disease (IBD) centres in Warsaw, Poznan, and Lodz, Poland. Data were collected from 1 January 2018 to 30 November 2025. All diagnostic and therapeutic decisions, including oral dose, formulation, and rectal treatment, were made by treating physicians independently of the study. No experimental intervention, random allocation, protocol-mandated treatment change, or additional diagnostic procedure was introduced. Reporting followed the STROBE statement.

The prespecified objectives were to compare oral mesalazine 3 versus 4 g/day combined with rectal mesalazine enemas in E2, compare 3 versus 4 g/day in E3, and compare prolonged-release mesalazine granules with other oral tablets.

Study population

Eligible patients were aged ≥ 18 years, had established UC, and presented with a mild-to-moderate flare defined as a Total Mayo Score (TMS) of 2–10 or Partial Mayo Score (PMS) of 2–6. Inflammation had to extend at least 10 cm proximally beyond the rectum, corresponding to E2 or E3 according to the Montreal classification. Isolated proctitis was excluded. Background treatment had to remain unchanged in type and dose during the preceding 12 weeks.

Additional exclusion criteria were initiation, escalation, or addition of any UC therapy within 12 weeks before the index optimisation visit; participation in an interventional trial; antibiotic use or coronavirus disease 2019 within 8 weeks; microbiota-modifying supplements or major dietary or lifestyle changes within 12 weeks; an infectious flare; another severe gastrointestinal disorder affecting response assessment; or an indication for UC-related surgery. These events occurring after the index visit were recorded as intercurrent events and did not result in post-baseline exclusion.

Study procedures and follow-up

Data were collected at baseline and 12 ±4 weeks after optimisation. Baseline assessment included previous mesalazine treatment, haemoglobin (Hgb), C-reactive protein (CRP), faecal calprotectin (FC), medical history, physical examination, PMS, TMS, and endoscopic Mayo subscore (eMayo). All patients underwent flexible sigmoidoscopy or colonoscopy at baseline and follow-up, allowing calculation of TMS and eMayo at both visits. Treatment was optimised according to disease extent, activity, previous therapy, clinical judgement, and applicable guidelines.

Assessments conducted within weeks 8–16 were treated as the protocol-defined follow-up visit. Further treatment escalation because of an inadequate response occurred only after this assessment and was not included in the evaluated mesalazine exposure.

Treatment exposure and comparison groups

The optimised oral dose was classified as 3 or 4 g/day. The daily dose was derived from the recorded frequency and amount. Quantities documented in grams were used directly, whereas tablet or granule counts were converted using the relevant product strength. For abbreviated tablet entries without documented strength, 0.5 g per unit was assumed according to the prespecified database convention. Rectal mesalazine was classified separately and excluded from oral-dose calculations.

The E2 strategy comprised optimised oral mesalazine plus a rectal enema, whereas the E3 strategy comprised optimised oral mesalazine without rectal mesalazine. Prolonged-release granules were defined as Pentasa-coded granules. The comparator comprised Pentasa, Asamax, Salaza, and Salofalk tablets. The formulation analysis therefore represented a combined product-and-pharmaceutical-form comparison rather than an isolated effect of the release mechanism.

The final population comprised 243 patients: 152 with E2, including 59 receiving 3 g/day and 93 receiving 4 g/day, and 91 with E3, including 41 receiving 3 g/day and 50 receiving 4 g/day. The formulation comparison included 133 patients receiving prolonged-release granules and 110 receiving other tablets.

Outcome and safety assessment

The analysed clinical, biochemical, haematological, and endoscopic outcomes were Hgb, CRP, FC, PMS, TMS, and eMayo. Hgb, CRP, FC, PMS, TMS, and eMayo data were available for all 243 patients at baseline and follow-up. The following prespecified endpoints were assessed at follow-up:

• PMS-defined clinical remission: PMS ≤ 2, no individual component > 1, and rectal bleeding subscore of 0;

• TMS-defined clinical remission: TMS ≤ 2, no individual component >1, and rectal bleeding subscore of 0;

• endoscopic remission: eMayo = 0;

• FC-based biochemical remission: FC < 250 µg/g.

All four follow-up endpoints were prespecified and were analysed as complementary exploratory outcomes. Component-level Mayo criteria were available for all patients. Because elevated FC was not required at inclusion, biochemical remission was evaluated categorically at follow-up; FC was also analysed as a continuous before-and-after outcome. No single primary endpoint was designated. All four follow-up endpoints were prespecified and were analysed as complementary exploratory outcomes. Component-level Mayo criteria were available for all patients. Because elevated FC was not required at inclusion, biochemical remission was evaluated categorically at follow-up; FC was also analysed as a continuous before-and-after outcome.

Safety was explored in the formulation comparison. Adverse events (AEs) were identified from routine database entries and summarised by organ-system category, individual event, and occurrence of any recorded AE. Data on onset, duration, severity, seriousness, management, and causal relationship to mesalazine were incomplete. Safety analyses were exploratory and hypothesis-generating. Recorded AE frequencies were summarised descriptively and compared between formulation groups using unadjusted ORs with 95% CIs.

Data completeness and statistical analysis

Age, body mass index (BMI), and Hgb were reported as mean with standard deviation. Year of diagnosis, CRP, FC, PMS, TMS, and eMayo were reported as median with interquartile range, and categorical variables as n (%). Between-group comparisons used Welch’s t test for approximately normally distributed continuous variables, the Mann–Whitney U test for non-normally distributed or ordinal variables, Pearson’s c² test for categorical variables, and Fisher’s exact test when any expected cell count was < 5. Paired changes were assessed using the paired t test or Wilcoxon signed-rank test, as appropriate. Changes in treatment components were reported descriptively because several analytical groups were defined by the optimised regimen.

Binary endpoints were compared using unadjusted odds ratios (ORs) with 95% confidence intervals (CIs). An OR > 1 indicated higher odds of attaining the endpoint in the first group named. A 0.5 correction was applied to zero cells for OR and CI estimation. All tests were two-sided, and p < 0.05 was considered statistically significant. No adjustment was made for multiple comparisons; all between-group, subgroup, formulation, and safety findings were therefore considered exploratory observational associations rather than causal effects. Analyses were performed using R version 4.5.2.

Results

The final analysis included 243 adults, comprising 152 patients with E2 and 91 with E3. After optimisation, patients with E2 received oral mesalazine 3 g/day (n = 59) or 4 g/day (n = 93), in both cases combined with a rectal mesalazine enema. Patients with E3 received oral mesalazine 3 g/day (n = 41) or 4 g/day (n = 50) without rectal treatment. The formulation comparison included 133 patients receiving prolonged-release granules and 110 receiving other oral tablets. Selected baseline characteristics are presented in Table I. No statistically significant baseline differences were detected within either dose comparison. In the formulation analysis, baseline eMayo was modestly higher in the tablet group, whereas the remaining selected characteristics were similar. Within E2, baseline eMayo was numerically lower in the 4 g/day group than in the 3 g/day group, although the between-group difference was not statistically significant.

All overall outcomes improved significantly after optimisation. Median CRP decreased from 16.8 to 4.5 mg/l, FC from 516 to 111 µg/g, TMS from 6 to 2, and PMS from 5 to 1. The eMayo distribution shifted from an interquartile range of 1–2 to 1–1, and mean Hgb increased from 13.2 to 13.6 g/dL (all p < 0.001; Figure 1). At follow-up, component-verified PMS-defined clinical remission, component-verified TMS-defined clinical remission, endoscopic remission, and FC-based biochemical remission were achieved by 86%, 57%, 24%, and 81% of patients, respectively.

Within E2, endoscopic remission was more frequent with 4 g/day plus rectal mesalazine than with 3 g/day plus rectal 5-ASA (45% vs. 8%; OR = 8.89, 95% CI: 3.26–24.25; p < 0.001), whereas PMS-defined, TMS-defined, and FC-based remission did not differ significantly. Within E3, none of the four endpoints differed significantly between 4 and 3 g/day; endoscopic remission was numerically more frequent with 4 g/day (18% vs. 5%; OR = 4.28, 95% CI: 0.87–21.07; p = 0.103). No direct statistical comparison between E2 and E3 was included (Figure 2).

Prolonged-release granules were associated with higher attainment of all four follow-up endpoints than other oral tablets: PMS-defined remission, 97% versus 74%; TMS-defined remission, 89% versus 18%; endoscopic remission, 38% versus 6%; and FC-based biochemical remission, 96% versus 64% (all p < 0.001; Figure 2). At least one adverse event was recorded in 25.6% of patients receiving granules and 61.8% receiving other tablets (OR = 0.21, 95% CI: 0.12–0.37; p < 0.001). Nervous-system and gastrointestinal event categories, headache, nausea, and abdominal pain were also recorded less frequently with granules (Figure 3).

All between-group odds ratios were unadjusted, no multiplicity correction was applied, and the comparative findings should be regarded as exploratory.

Discussion

In this multicentre real-world study of 243 patients with mild-to-moderate UC, mesalazine optimisation was followed by significant improvement across clinical, biochemical, haematological, and endoscopic domains. Median CRP and FC decreased markedly, PMS and TMS improved, and Hgb increased. At follow-up, component-verified PMS-defined clinical remission was achieved by 86% of patients, component-verified TMS-defined clinical remission by 57%, endoscopic remission by 24%, and FC-based biochemical remission by 81%. These findings are consistent with previous evidence supporting adequately optimised mesalazine as an effective first-line strategy and with pooled data demonstrating high rates of endoscopic healing during appropriately selected oral, topical, and combined treatment [10–14]. Nevertheless, because this was a single-arm before-and-after study in which several treatment components could change concurrently, the overall improvement should be attributed to the complete optimisation strategy rather than to any individual intervention.

The oral-dose analyses demonstrated a more nuanced pattern than a uniform dose-response relationship. Within E2, endoscopic remission was substantially more frequent among patients receiving oral mesalazine 4 g/day plus a rectal enema than among those receiving 3 g/day plus a rectal enema (45% vs. 8%; OR = 8.89, 95% CI: 3.26–24.25). In contrast, PMS-defined clinical remission, TMS-defined clinical remission, and FC-based biochemical remission did not differ significantly between the E2 dose groups. Within E3, none of the evaluated endpoints differed significantly between 4 and 3 g/day. Endoscopic remission was numerically more frequent with 4 g/day (18% vs. 5%; OR = 4.28, 95% CI: 0.87–21.07), but the confidence interval was wide and the difference did not reach statistical significance. Randomised studies suggest that higher mesalazine doses may provide additional benefit in selected patients, particularly when residual endoscopic activity persists, although pooled evidence indicates that the average incremental benefit beyond an adequately optimised dose is generally modest [13, 15]. The present findings therefore suggest a possible endoscopic dose signal, particularly in E2, but do not demonstrate consistent superiority of 4 g/day across clinical, biochemical, and endoscopic outcomes.

The dose findings require cautious interpretation because the oral dose was selected by treating physicians rather than assigned randomly. Although no statistically significant baseline differences were identified between the dose groups within E2 or E3, residual differences in inflammatory burden, previous treatment response, anticipated adherence, tolerability, or physician preference may have influenced treatment selection. In E2, the baseline eMayo distribution was numerically more favourable in the 4 g/day group, despite the absence of a statistically significant between-group difference, and this may have contributed to the higher endoscopic-remission rate. Confounding by indication may also operate in either direction: physicians may preferentially prescribe a higher dose to patients perceived as having more active disease, but they may also select it for patients expected to adhere well or tolerate a more intensive regimen [16]. Moreover, no adjustment for potential confounders or multiple comparisons was performed. The strong E2 endoscopic association should therefore be regarded as exploratory and requires prospective confirmation. Because all patients with E2 received concomitant rectal mesalazine, the E2 dose findings should be interpreted within a combined oral–rectal treatment strategy, consistent with previous evidence supporting topical add-on therapy in distal and left-sided UC [14, 17, 18].

A particularly strong association was observed between prolonged-release granules and all evaluated follow-up endpoints. Compared with other oral tablets, granules were associated with higher rates of PMS-defined clinical remission (97% vs. 74%), TMS-defined clinical remission (89% vs. 18%), endoscopic remission (38% vs. 6%), and FC-based biochemical remission (96% vs. 64%). Differences in release timing, pharmaceutical form, and intraluminal distribution may influence mesalazine availability and mucosal exposure throughout the colon [10–12]. These characteristics may therefore contribute to real-world treatment effectiveness, particularly when an optimised dose must be delivered consistently across an inflamed colonic segment.

The magnitude of the observed formulation associations, however, is unlikely to result from the release mechanism alone. Oral mesalazine preparations differ not only in drug-delivery characteristics but also in administration requirements, pill burden, convenience, and patient acceptability [12]. In the present study, the comparison simultaneously reflected product, pharmaceutical form, treatment burden, adherence-related factors, and physician-driven selection. The tablet comparator was heterogeneous and included several products, while the granule group represented a more uniform treatment pattern. Baseline eMayo was also modestly higher in the tablet group, indicating greater baseline endoscopic activity and introducing the possibility of residual confounding.

Previous comparative studies and pooled analyses have generally shown smaller and less uniform differences between oral mesalazine preparations than those observed in the present cohort [10–13]. Accordingly, the very large ORs for the formulation comparison should not be interpreted as proof of causal superiority of a specific brand or release system. Rather, they indicate that an overall product-and-pharmaceutical-form strategy was strongly associated with treatment outcomes in this dataset. Prospective head-to-head studies with adjustment for baseline activity, disease extent, adherence, pill burden, and concomitant rectal therapy are required to determine how much of this association is pharmacological and how much reflects behavioural or prescribing factors.

Adherence is a plausible mediator of the observed formulation-related findings. Simplified regimens and reduced pill burden may improve persistence and correct medication use, whereas non-adherence is a well-established risk factor for relapse and adverse outcomes in UC [17]. The apparent advantage of granules may consequently reflect an interaction between drug-delivery characteristics, convenience, acceptability, adherence, and prescribing behaviour. Because adherence was not directly measured, its independent contribution could not be distinguished from pharmacological differences between formulations.

Recorded AEs were also less frequent among patients receiving prolonged-release granules than among those receiving other tablets (25.6% vs. 61.8%). Headache, nausea, abdominal pain, and broader nervous-system and gastrointestinal event categories were recorded less frequently in the granule group. This finding may indicate better tolerability, but several alternative explanations should be considered. AE ascertainment was retrospective, and information on onset, duration, severity, seriousness, management, and causal relationship to mesalazine was incomplete. Gastrointestinal symptoms may also have reflected active UC rather than treatment-related adverse reactions. Differences in disease activity, patient selection, and documentation practices may therefore have contributed to the observed association. The appropriate interpretation is that fewer AEs were recorded with granules, not that their causal safety profile was definitively superior.

The divergence between the remission endpoints is clinically relevant. PMS-defined clinical remission was achieved by 86% of patients, compared with 57% for TMS-defined clinical remission and 24% for endoscopic remission. Both Mayo-based clinical endpoints were verified using the individual component subscores, including the requirement for a rectal bleeding subscore of 0. The lower TMS-defined remission rate reflects the addition of the endoscopic component, whereas endoscopic remission required the particularly stringent endpoint of eMayo = 0. These findings demonstrate that symptomatic improvement does not necessarily indicate complete resolution of mucosal inflammation, even when FC-based biochemical remission is achieved. They therefore support the treat-to-target principle that clinical assessment should be complemented by biomarkers and endoscopy when evaluating the depth of response [19].

Contemporary expert consensus and practical reviews continue to support mesalazine as first-line treatment for mild-to-moderate UC while emphasising individualisation according to disease activity, disease extent, therapeutic targets, tolerability, formulation characteristics, and patient preference [20, 21]. The present results are consistent with this approach. Dose escalation may be appropriate in selected patients with persistent endoscopic activity, but nominal dose alone did not consistently determine treatment success. Similarly, formulation choice may be clinically relevant, but it should be considered within the broader context of adherence, treatment burden, disease distribution, and concomitant topical therapy.

Recent studies addressing dose escalation, real-world adherence, shared decision-making, and mesalazine effectiveness across adult age groups likewise suggest that treatment outcomes depend on how therapy is prescribed and used rather than solely on the selected daily dose [22–25]. This is particularly relevant in routine practice, where treatment convenience, patient preferences, and previous experience may influence adherence as strongly as pharmacological characteristics.

The overall improvement observed after optimisation accords with systematic reviews, network meta-analyses, and international guidelines supporting oral, topical, and combined mesalazine strategies for induction and maintenance of remission in mild-to-moderate UC [26–38]. The E2 findings are particularly consistent with evidence favouring combined oral and rectal mesalazine when inflammation involves the distal or left colon. However, the present study cannot determine the independent contributions of oral dose, oral formulation, and rectal treatment because these components were not assigned independently.

The potential importance of treatment convenience is further supported by studies showing that simplified and once-daily regimens can maintain efficacy while reducing treatment burden [39–42]. This is clinically important because long-term adherence remains a major determinant of relapse prevention, and poor adherence has consistently been associated with disease flare and treatment failure [43–47]. Future comparative studies should therefore include validated adherence measures, pill burden, treatment satisfaction, patient preference, and standardised tolerability assessment alongside clinical, biochemical, and endoscopic outcomes.

The study also reflects the value of structured specialist inflammatory bowel disease care and objective monitoring in routine clinical practice. Polish and regional experience has emphasised the importance of coordinated care pathways and integration of biomarkers and endoscopic targets into treatment assessment [48, 49]. Contemporary practical recommendations similarly favour an integrated approach incorporating dose, formulation, disease extent, topical treatment, adherence, and treat-to-target monitoring rather than relying on dose escalation as an isolated intervention [50].

Several limitations should be acknowledged. First, the retrospective observational design precludes causal inference and is susceptible to residual confounding, confounding by indication, regression to the mean, and differences in documentation. There was no unchanged-treatment or untreated comparator. Second, oral dose, formulation, and route were selected by treating physicians rather than assigned randomly. Third, the final analytical groups were partly defined by the optimised regimen, which may have introduced post-treatment selection bias, and it limits generalisability to other mesalazine strategies. Fourth, the formulation analysis combined differences in product, pharmaceutical form, release characteristics, treatment burden, and potentially adherence, while the comparator group was heterogeneous. Fifth, all ORs were unadjusted, no correction was applied for multiple comparisons, and some estimates were imprecise because of small event numbers, particularly for endoscopic remission in E3. Sixth, the follow-up period was appropriate for induction assessment but did not permit evaluation of long-term durability, relapse, or maintenance outcomes. Finally, AE data were obtained retrospectively without standardised grading or causality assessment.

The study also has relevant strengths. It included a relatively large multicentre cohort managed in specialist gastroenterology and IBD centres, used component-verified definitions of PMS- and TMS-defined clinical remission, and assessed response across complementary clinical, biochemical, haematological, and endoscopic domains. TMS/PMS and endoscopic assessments were available for the final cohort, and the predefined analytical frameworks allowed separate evaluation of oral dose within E2 and E3 and of oral product pattern in routine clinical practice.

Conclusions

Mesalazine optimisation was associated with significant clinical, biochemical, haematological, and endoscopic improvement in adults with mild-to-moderate ulcerative colitis. Within E2, oral mesalazine 4 g/day combined with a rectal enema was associated with more frequent endoscopic remission than 3 g/day plus a rectal enema, although clinical and biochemical remission rates were similar. Within E3, no statistically significant advantage of 4 g/day over 3 g/day was demonstrated for any evaluated endpoint. Prolonged-release granules were associated with higher attainment of all four remission endpoints and fewer recorded adverse events than other tablet formulations; however, these large unadjusted associations likely reflected an overall product-and-formulation pattern rather than the release mechanism alone. All comparative findings should be considered exploratory and require confirmation in prospective studies incorporating adjustment for baseline disease activity, adherence, treatment burden, and concomitant topical therapy.

Funding

No external funding.

Ethical approval

The study was approved by the Ethics Committee of the National Medical Institute of the Ministry of the Interior and Administration in Warsaw (approval no. 71/2024; 15 October 2024). Routine clinical data were deidentified before analysis. Because of the retrospective, non-interventional design, written informed consent was waived. The study complied with the Declaration of Helsinki and national regulations.

Conflict of interest

HZ declares no competing interests. KJ declares no competing interests. ETM declares lecture fees and/or educational and travel grants from Ewopharm, Abbvie, Bayer, Sobi, Sandoz, and PROMED.PL. EB declares educational grants from Recordati and Polpharma. PE declares lecture fees and/or educational and travel grants from Takeda, Abbvie, Celltrion, Eli Lilly, Recordati, Ferring, Sandoz, Pfizer, AlfaSigma, and Janssen Cilag. MC declares lecture fees and/or travel grants from Abbvie, AlfaSigma, Eli Lilly, and Recordati. PD declares no competing interests. RTW declares lecture fees or educational and travel grants from Abbvie, AlfaSigma, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Recordati, Janssen Cilag, and Takeda. EMW declares compensation from Mylan and Ferring Eli Lilly for services as a consultant, payment for lectures from Ferring and Janssen, Bayer, and Aurovitas, and reimbursements for travel/accommodation/meeting expenses from PRO.MED.Pl. and Recordati. GR declares consultancies, and speaking and writing fees from the following: ActivLab, Abbvie, AlfaSigma, Bayer, Biocodex, Bristol Myers Squibb, Celtrion, Ferring, Johnson & Johnson, Eli Lilly, Opella, PRO.MED.Pl, Polpharma, Recordati, Sandoz, Sanprobi, SOBI, Swixx BioPharma, and Takeda. KL declares honoraria for the following: lectures from Recordati, Eli Lilly, Opella, and SOBI; lectures, travel grants, and participation in advisory boards from Ferring; and lectures as well as travel grants from AlfaSigma, Takeda, Abbvie, Johnson & Johnson, and PRO.MED.Pl.