Real‑world patterns of early 5‑ASA use and time to treatment escalation in Crohn’s disease: a nationwide cohort study using Korean NHIS data

Real‑world patterns of early 5‑ASA use and time to treatment escalation in Crohn’s disease: a nationwide cohort study using Korean NHIS data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real‑world patterns of early 5‑ASA use and time to treatment escalation in Crohn’s disease: a nationwide cohort study using Korean NHIS data OneZoong KIM, Jiae Choi, Hyun-Jung Kim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8183788/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Aminosalicylates (mesalazine, sulfasalazine) are used for mild Crohn’s disease, but real‑world comparative data are limited. Aim To compare the time to initiation of corticosteroids or immunosuppressants in Korean patients with Crohn’s disease treated with mesalazine versus sulfasalazine. Methods We conducted a nationwide retrospective cohort study using the Korean National Health Insurance Service database from 2002 to 2022. Adults with Crohn’s disease who received mesalazine or sulfasalazine for more than 30 days were included. The primary outcome was the interval from aminosalicylate initiation to first corticosteroid or immunosuppressant prescription. Demographic and clinical variables were analysed, and multivariable Cox regression identified predictors of treatment escalation. Results Of 18,288 eligible patients, 17,217 (94.1%) received mesalazine and 1,071 (5.9%) received sulfasalazine. Mesalazine prescribing increased from 79.3% in 2002 to 98.9% in 2022, whereas sulfasalazine decreased from 20.7% to 1.1%. Median time to corticosteroid or immunosuppressant initiation was shorter with mesalazine (72.3 days) than with sulfasalazine (100.7 days; P = 0.0089). Earlier escalation was associated with male sex, younger age, metropolitan residence, and absence of hypertension or cerebrovascular disease. Conclusions In this nationwide cohort, mesalazine was the predominant aminosalicylate and was associated with earlier treatment escalation than sulfasalazine, alongside marked shifts in prescribing patterns over two decades. These findings describe real‑world associations from administrative data and may inform, but cannot determine, comparative effectiveness between aminosalicylate formulations. Crohn’s disease Aminosalicylates Mesalazine Sulfasalazine Immunosuppressive agents Nationwide cohort study Figures Figure 1 Figure 2 Introduction Crohn’s disease is a rare but increasingly prevalent condition in South Korea. Traditionally, aminosalicylates have been used for the induction of remission in patients with mild Crohn’s disease. Various formulations of aminosalicylates have been developed. 5-ASA(5-aminosalicylic acid, mesalazine, or mesalamine) conjugated formulations include sulfasalazine, which consists of 5-ASA linked to sulfapyridine; olsalazine, a dimer of 5-ASA; and balsalazide, in which 5-ASA is bound to 4-aminobenzoyl-β-alanine. 1 The delivery method of oral 5-ASA varies across different formulations. For instance, Pentasa uses an ethyl cellulose coating to continuously release the drug throughout the small and large intestine. 2 Salofalk is coated with an acrylic-based resin (Eudragit-L) that releases the drug at pH 6 in the proximal small intestine, while Asacol uses Eudragit-S to release 5-ASA at pH 7 in the terminal ileum and colon. 3 Mezavant utilizes a multi-matrix system (MMX) for gradual drug release from the terminal ileum to the rectum. 4 According to Korean clinical guidelines, sulfasalazine may be used for inducing remission in patients with mild Crohn’s disease. Although the efficacy of 5-ASA in this context is considered limited, its favorable safety profile and ease of administration make it a treatment option worth considering. 5 In clinical practice, 5-ASA is more commonly prescribed than sulfasalazine due to concerns over adverse effects such as reduced sperm count associated with the latter. However, there are no domestic studies providing precise data on this prescribing pattern. A U.S. study using an insurance claims database reported that 5-ASA agents—including mesalamine, balsalazide, and olsalazine—accounted for approximately 57% of prescriptions, whereas sulfasalazine was prescribed in only 3.02% of cases. 6 Nevertheless, that study merely compared usage frequency and did not evaluate the relative effectiveness of sulfasalazine versus 5-ASA. Therefore, the aim of this study is to investigate the current use of aminosalicylates in Korean patients with Crohn’s disease and to compare the time to initiation of biologic therapy between patients treated with sulfasalazine and those treated with 5-ASA, in order to determine which agent may be more clinically useful. We sought to provide real‑world evidence on early 5‑ASA choice and treatment escalation, bridging gaps between trials and practice in Asian populations. Methods Study design and database This population-based retrospective cohort study used data from the National Health Insurance Service (NHIS) of Korea. The NHIS is a mandatory nationwide insurance system operated by the Korean government that covers about 97% of the Korean population. While the Medical Aid Program covers the remaining 3% of the population, the NHIS also reviews their medical claims. Therefore, the NHIS database essentially covers the entire Korean population. Diagnostic codes are classified according to the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10 CM). The patient's prescription information includes detailed data such as the type of medication, daily dosage, prescription date, and duration of use. The NHIS database is accessible to qualified researchers after approval of the study protocol by the official review committee. This noninterventional, observational design analyzed routinely collected claims data (real‑world data) to generate real‑world evidence in line with contemporary FDA framing and terminology, emphasizing explicit description of data provenance and study architecture to avoid ambiguity We followed the STROBE guideline and EQUATOR recommendations for transparent reporting of observational studies[2][3]. Because present‑on‑admission (POA) flags are unavailable in the Korean claims database, we prespecified sensitivity analyses using extended look‑back windows and early‑event exclusion to mitigate potential misclassification of in‑hospital onset events, consistent with best practice to address claims‑based ascertainment/timing biases and residual confounding in observational research. This study adhered to the principles of the Declaration of Helsinki, and the Institutional Review Board of Uijeongbu Eulji University Hospital (UEMC IRB 2023-02-007-001) approved the study protocol. Study population Figure 1 shows the process for selecting the study population. Patients with Crohn's disease were defined according to the following criteria: (1) the presence of ICD-10-CM codes K50 including subcodes and claims for at least one 5-ASA (mesalamine or sulfasalazine) at baseline. Using this definition, we initially selected 422,146 individuals with Crohn’s disease over the age of 18 by the Korean NHIS between January 2002 and December 2022. We then excluded individuals without a prescription for 5-ASA (n = 347,091) before the time of follow-up screening, prescription duration of 30 days or less (n = 14,805) and individuals without a diagnosis about Crohn's disease (n = 15,547) or died (n = 8) within a year after the follow-up screening. Finally, we included 31,430 and tracked until December 2022. Clinical variables We investigated the demographic and clinical characteristics of patients who were prescribed mesalazine or sulfasalazine. Variables analyzed included sex, age, region of residence, socioeconomic status, and underlying comorbidities such as diabetes mellitus, hypertension, dyslipidemia, cancer, ischemic heart disease, and cerebrovascular disease. Outcomes The primary outcome was the number of days from initiation of sulfasalazine or 5-ASA therapy to the first use of corticosteroids or immunosuppressants. In addition, we conducted a time-to-event analysis to identify factors associated with the initiation of corticosteroids or immunosuppressants among patients treated with 5-ASA or sulfasalazine. Statistical analysis Continuous variables were expressed as the mean and standard deviation, and categorical variables were expressed as numbers and percentages. Between group comparisons were performed using the chi-square test for categorical variables and one-way analysis of variance for continuous variables. The incidence of initiation of immunosuppressants or biologic agents was calculated as the number of events per 1000 people per year. Multivariable Cox proportional hazards regression models were used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) Statistical analyses were performed using STATA version 18.0 (StataCorp, College Station, TX, USA). A two-sided p -value of < 0.05 was considered statistically significant. Results Baseline Clinical Characteristics of Patients A total of 29,244 patients were diagnosed with Crohn’s disease (CD) during the study period (Fig. 1 ). The baseline clinical characteristics of these patients are summarized in Table 1. Among them, 18,288 patients were treated with either mesalazine or sulfasalazine. There was a higher proportion of male patients (12,300; 67.38%). In terms of age distribution, 10,935 patients (59.79%) were between 18 and 39 years old, 4,748 patients (25.96%) were between 40 and 59, and 2,602 patients (14.24%) were aged 60 or older. Regarding residential areas, 4,830 patients (26.41%) lived in rural regions, 4,542 (24.84%) resided in metropolitan cities, and 8,916 (48.75%) lived in the capital region surrounding Seoul. The 5-ASA group had a significantly higher proportion of patients from rural areas. In terms of income levels, 925 patients (5.06%) were in the lowest income quartile ( 75%). The sulfasalazine group included a significantly greater proportion of patients from lower-income groups. Regarding comorbidities, the prevalence of cancer and ischemic heart disease did not differ between the two groups. However, diabetes, hypertension, and prior cerebrovascular disease were significantly more common in the sulfasalazine group, whereas dyslipidemia was more prevalent in the 5-ASA group. Annual Proportion of Patients Prescribed 5-ASA The prescription rate of mesalamine increased by 19.66%, from 79.27% (7,080 out of 8,931) in 2002 to 98.93% in 2022. In contrast, the prescription rate of sulfasalazine decreased by 19.66%, from 20.73% (1,851 out of 8,931) in 2002 to 1.07% in 2022(Fig. 2 ). While the absolute number of mesalazine prescriptions increased over time, the prescription volume of sulfasalazine declined despite an overall increase in the number of patients. Time to Initiation of Corticosteroids or Immunosuppressants Among patients treated with aminosalicylates, 17,217 individuals (94.14%) were prescribed 5-ASA, while 1,071 patients (5.86%) received sulfasalazine. The time from initial treatment to the use of corticosteroids or immunosuppressants was significantly shorter in the 5-ASA group, with a median duration of 72.32 days compared to 100.72 days in the sulfasalazine group (P = 0.0089) (Table 2). Factors Associated with the Use of Corticosteroids or Immunosuppressants When considering the initiation of corticosteroids or immunosuppressants as the event of interest and accounting for time-to-event data, several risk factors were identified. These included male sex, younger age, residence in metropolitan cities, absence of hypertension, and absence of prior cerebrovascular accidents (CVA) (Table 3). Discussion In the United States, a large multicenter study demonstrated that administering sulfasalazine at a dose of 4–6 g/day for one month in 74 patients resulted in a 38% response rate. 7 However, in Europe, treatment with 3 g of sulfasalazine for 18 weeks in 54 patients showed no statistically significant difference compared to placebo. 8 When oral mesalazine (Asacol) at 3.2 g/day was administered to 38 patients with Crohn’s disease over four months, 60% of patients achieved complete or partial remission. 9 In another study, 43% of patients achieved remission after receiving 4 g of mesalazine (Pentasa) for 16 weeks in a cohort of 310 patients. 10 However, a later meta-analysis of three double-blind, placebo-controlled, randomised trials using 4 g of Pentasa showed that although it reduced the CDAI (Crohn’s Disease Activity Index) compared to placebo, the clinical significance was unclear. Specifically, a statistically significant difference was observed in studies shorter than 28 days, but not in those lasting 28 days or longer. 2 In our nationwide study, patients initially treated with sulfasalazine had a longer interval before initiation of corticosteroids or immunosuppressants than those treated with mesalazine. This pattern is consistent with the possibility that sulfasalazine may provide some early symptom control in selected patients; however, it is also likely influenced by treatment selection based on unmeasured disease characteristics and physician preferences. The average duration of approximately 100.7 days before escalation in sulfasalazine users and 72.3 days in mesalazine users should therefore be interpreted primarily as reflecting real‑world treatment trajectories rather than definitive evidence of differential efficacy. These findings may help clinicians contextualize how aminosalicylates are used in practice and how quickly escalation commonly occurs, but they should be integrated with contemporary treatment paradigms in Crohn’s disease, in which biologic and targeted agents are preferred for induction and maintenance in moderate‑to‑severe disease. Regarding adverse effects of sulfasalazine, 12.88% of patients in the U.S. reported side effects such as nausea, vomiting, anorexia, headache, and arthralgia, 11 while in Europe, 6.22% experienced adverse events, including nausea, anorexia, headache, hypertension, and infections. 8 The lower incidence in Europe may be attributable to the lower dose used in those studies. A meta-analysis assessing the maintenance efficacy of sulfasalazine and mesalazine in Crohn’s disease found that both agents significantly reduced the risk of relapse over one year [relative risk (RR) = 0.77; 95% confidence interval (CI), 0.64–0.92]. However, this effect was driven by mesalazine, as sulfasalazine did not show a statistically significant benefit in preventing relapse [mesalazine: RR = 0.63; 95% CI, 0.50–0.79; sulfasalazine: RR = 1.08; 95% CI, 0.81–1.44]. 12 Taken together with our data, these observations suggest that sulfasalazine may retain a limited role in early symptom management or in specific clinical contexts, whereas its role in long‑term maintenance appears modest and is likely overshadowed by mesalazine and advanced therapies. Several methodological considerations must be acknowledged. First, potential channeling bias and unmeasured confounding—such as differences in disease location, severity, behavior, and concomitant therapies—could have influenced both the choice of aminosalicylate and the likelihood and timing of treatment escalation. Our multivariable models adjusted for available demographic and comorbidity variables, but important clinical variables were not captured in claims data. Therefore, observed differences in time to escalation between mesalazine and sulfasalazine should be interpreted as associations within a specific prescribing context rather than as causal comparative effectiveness estimates. Second, reliance on administrative claims introduces risks of misclassification and imprecision in defining both exposure and outcomes, including inability to distinguish induction from maintenance therapy, uncertainty around treatment adherence, and the absence of present‑on‑admission indicators. Although we applied uniform definitions and look‑back periods, residual misclassification remains possible. We also did not stratify patients by dose of sulfasalazine or mesalazine, nor could we separate induction‑only users from those transitioning to or maintained on these agents. Disease activity at the time of treatment initiation was not available, and the substantial disparity in patient numbers between the sulfasalazine and mesalazine groups limited the precision of comparisons. Finally, our analysis was conducted within the Korean National Health Insurance context, and practice patterns may differ in other healthcare systems. Consequently, these findings are best viewed as descriptive of real‑world treatment patterns and escalation timing in a large national cohort, and may be more useful for informing expectations about disease course and patient counseling than for guiding individual drug selection in isolation.. Conclusions In this nationwide cohort of Korean patients with Crohn’s disease, aminosalicylate use patterns shifted markedly over two decades, with mesalazine becoming the predominant formulation and sulfasalazine use declining to a small minority of cases. Patients initiating mesalazine experienced earlier treatment escalation to corticosteroids or immunosuppressants than those initiating sulfasalazine, but this difference is likely influenced by treatment selection, underlying disease characteristics, and other unmeasured factors. Our findings primarily characterize real‑world prescribing patterns and typical timeframes to escalation, rather than establishing comparative efficacy between mesalazine and sulfasalazine. As such, they may aid clinicians in setting expectations about treatment trajectories and in educating patients about the potential need for earlier escalation beyond aminosalicylates. Definitive conclusions about the optimal role of specific aminosalicylate formulations in Crohn’s disease will require studies with more granular clinical data and designs better suited to causal inference. Declarations Author Contribution O.Z.K. conceived and designed the study.J.C. performed data acquisition and data management.H.J.K. contributed to data interpretation and critical revision of the manuscript.H.J.K. drafted the manuscript.All authors reviewed and approved the final version of the manuscript. References Hanauer SB. Review article: aminosalicylates in inflammatory bowel disease. Aliment Pharmacol Ther . Oct 2004;20 Suppl 4:60–5. doi: 10.1111/j.1365-2036.2004.02048.x Hanauer SB, Strömberg U. Oral Pentasa in the treatment of active Crohn's disease: A meta-analysis of double-blind, placebo-controlled trials. Clin Gastroenterol Hepatol . May 2004;2(5):379–88. doi: 10.1016/s1542-3565(04)00122-3 Dew MJ, Hughes PJ, Lee MG, Evans BK, Rhodes J. An oral preparation to release drugs in the human colon. Br J Clin Pharmacol . Sep 1982;14(3):405–8. doi: 10.1111/j.1365-2125.1982.tb01999.x Tenjarla S, Romasanta V, Zeijdner E, Villa R, Moro L. Release of 5-aminosalicylate from an MMX mesalamine tablet during transit through a simulated gastrointestinal tract system. Adv Ther . Jul–Aug 2007;24(4):826–40. doi: 10.1007/bf02849976 Park JJ, Yang SK, Ye BD, et al. Second Korean guidelines for the management of Crohn's disease. Intest Res . Jan 2017;15(1):38–67. doi: 10.5217/ir.2017.15.1.38 Noureldin M, Cohen-Mekelburg S, Mahmood A, et al. Trends of 5-Aminosalicylate Medication Use in Patients With Crohn Disease. Inflamm Bowel Dis . Mar 15 2021;27(4):516–521. doi: 10.1093/ibd/izaa127 Summers RW, Switz DM, Sessions JT, Jr., et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology . Oct 1979;77(4 Pt 2):847–69. Malchow H, Ewe K, Brandes JW, et al. European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment. Gastroenterology . Feb 1984;86(2):249–66. Tremaine WJ, Schroeder KW, Harrison JM, Zinsmeister AR. A randomized, double-blind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation, Asacol, in the treatment of symptomatic Crohn's colitis and ileocolitis. J Clin Gastroenterol . Dec 1994;19(4):278–82. doi: 10.1097/00004836-199412000-00003 Singleton JW, Hanauer SB, Gitnick GL, et al. Mesalamine capsules for the treatment of active Crohn's disease: results of a 16-week trial. Pentasa Crohn's Disease Study Group. Gastroenterology . May 1993;104(5):1293–301. doi: 10.1016/0016-5085(93)90337-c Singleton JW, Law DH, Kelley ML, Jr., Mekhjian HS, Sturdevant RA. National Cooperative Crohn's Disease Study: adverse reactions to study drugs. Gastroenterology . Oct 1979;77(4 Pt 2):870–82. Steinhart AH, Hemphill D, Greenberg GR. Sulfasalazine and mesalazine for the maintenance therapy of Crohn's disease: a meta-analysis. Am J Gastroenterol . Dec 1994;89(12):2116–24. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files floatimage2.jpeg Table 1 floatimage4.jpeg Table 2 floatimage5.jpeg Table 3 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8183788","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":557543737,"identity":"e983c72a-7b8c-417c-9624-d7c9519754f7","order_by":0,"name":"OneZoong KIM","email":"","orcid":"","institution":"CHA Bundang Medical Center","correspondingAuthor":false,"prefix":"","firstName":"OneZoong","middleName":"","lastName":"KIM","suffix":""},{"id":557543738,"identity":"4590a26c-dd99-4107-9d41-e2da5462b22b","order_by":1,"name":"Jiae Choi","email":"","orcid":"","institution":"Cochrane Korea","correspondingAuthor":false,"prefix":"","firstName":"Jiae","middleName":"","lastName":"Choi","suffix":""},{"id":557543739,"identity":"5d9a0678-33ef-4776-a69b-5c339321ae93","order_by":2,"name":"Hyun-Jung Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAs0lEQVRIiWNgGAWjYHACxgMMBjZypOk5wFCRZkyqljOHExuIVq7b3nzgwMc25vTt7GcMH1cw2MnpEtJsduZYwsGZbWy5O3tyjA3PMCQbmx0gpOVGjsFh3jae3A0H0tIkGxgOJG4jSsvfNol0g/PP0n8Sr4XhjEGCwY3kY4zEaQH5paciwXDDjceHJRsMiPHL8eaDD34Y/Jc3OJ/Y+LGhwk6OoBY0YECa8lEwCkbBKBgFOAAAYSFJYobGIjUAAAAASUVORK5CYII=","orcid":"","institution":"Cochrane Korea","correspondingAuthor":true,"prefix":"","firstName":"Hyun-Jung","middleName":"","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2025-11-23 06:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8183788/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8183788/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98421635,"identity":"f712cba2-9e51-4c3b-8140-963b661d16a7","added_by":"auto","created_at":"2025-12-17 16:28:45","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":472798,"visible":true,"origin":"","legend":"","description":"","filename":"Realworldpatternsofearly5ASAuseandtimetotreatmentescalationinCrohnsdiseaseanationwidecohortstudyusingKoreanNHISdata.docx","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/dc6f0f55d627ca04f8d953b4.docx"},{"id":98421898,"identity":"f8f848f4-7af9-43ab-af3d-27a496b32363","added_by":"auto","created_at":"2025-12-17 16:29:54","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5302,"visible":true,"origin":"","legend":"","description":"","filename":"c688900bc31e49ceb701f051249658f2.json","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/a4c03ec4f2397160928dd53a.json"},{"id":97932025,"identity":"e77ee710-5aab-47c1-ab92-999353d8bb4e","added_by":"auto","created_at":"2025-12-11 00:42:37","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":46644,"visible":true,"origin":"","legend":"","description":"","filename":"c688900bc31e49ceb701f051249658f21enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/0eb8bbeba96107593294607e.xml"},{"id":97932030,"identity":"95df1840-90fe-47ab-9408-cd9faaea29b0","added_by":"auto","created_at":"2025-12-11 00:42:37","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37961,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/1bb1f3c17f5d31596a4bcf94.png"},{"id":98422163,"identity":"8518a04f-9c7b-49da-b5ed-e6469e19dacf","added_by":"auto","created_at":"2025-12-17 16:30:35","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18877,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/963d45a5d3e2c634ed2d047b.png"},{"id":97932033,"identity":"8652b065-6313-43f6-8bda-d992b982dcb1","added_by":"auto","created_at":"2025-12-11 00:42:37","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20945,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/551bde260ed4e2298a12a5de.png"},{"id":98422786,"identity":"7fd59af5-5446-4568-9c4c-2cf7bdcc7ef2","added_by":"auto","created_at":"2025-12-17 16:31:30","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":23139,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/879ae73832a02dc5ce93b888.png"},{"id":97932039,"identity":"0fd188bb-71b9-42ca-a764-e3dd74b622c3","added_by":"auto","created_at":"2025-12-11 00:42:37","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":56213,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/9f24b06c8c80769895de351e.png"},{"id":97932038,"identity":"97f93057-8cc0-4149-8a20-cfec1e5289f5","added_by":"auto","created_at":"2025-12-11 00:42:37","extension":"xml","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":44939,"visible":true,"origin":"","legend":"","description":"","filename":"c688900bc31e49ceb701f051249658f21structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/6d39555351f53aeb614f78a7.xml"},{"id":97932037,"identity":"09410cfa-ab52-426d-a5e1-e4ca07d97039","added_by":"auto","created_at":"2025-12-11 00:42:37","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":52105,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/df6728dd8e6b5178f2626e48.html"},{"id":98421557,"identity":"6a2a09d4-29dc-4ec7-aacd-1704c45550d8","added_by":"auto","created_at":"2025-12-17 16:28:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":90145,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of patients.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/606db33f98b75a05e0195847.png"},{"id":97932028,"identity":"970006ce-6d0f-4cee-8579-7d7e7a53b1cd","added_by":"auto","created_at":"2025-12-11 00:42:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":75567,"visible":true,"origin":"","legend":"\u003cp\u003eAnnual rates of 5-ASA prescriptions in patients with Crohn’s disease from 2002 to 2022 in Korea.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/f9f71d7bfc65b339d5a6be69.png"},{"id":99314950,"identity":"6b8b0737-6890-48e9-af8e-be5228e00566","added_by":"auto","created_at":"2025-12-31 16:25:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":613189,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/996e2c9e-bb24-451f-a8f9-619a36eab78d.pdf"},{"id":97932027,"identity":"b6f42623-2b6f-4103-a53d-c210a544c6b5","added_by":"auto","created_at":"2025-12-11 00:42:37","extension":"jpeg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":56648,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/7e1ffc915b1776de76947f80.jpeg"},{"id":98421576,"identity":"24ae2fea-f8bc-4abb-ac12-16c282c904c7","added_by":"auto","created_at":"2025-12-17 16:28:35","extension":"jpeg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":64714,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/a4156b07b7672bc49ec722a2.jpeg"},{"id":97932036,"identity":"943d7c48-6022-46fe-9f18-19cb899ed1a8","added_by":"auto","created_at":"2025-12-11 00:42:37","extension":"jpeg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":130465,"visible":true,"origin":"","legend":"\u003cp\u003eTable 3\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8183788/v1/339cb9f25e5e9dd1f11891f4.jpeg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Real‑world patterns of early 5‑ASA use and time to treatment escalation in Crohn’s disease: a nationwide cohort study using Korean NHIS data","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCrohn\u0026rsquo;s disease is a rare but increasingly prevalent condition in South Korea. Traditionally, aminosalicylates have been used for the induction of remission in patients with mild Crohn\u0026rsquo;s disease. Various formulations of aminosalicylates have been developed. 5-ASA(5-aminosalicylic acid, mesalazine, or mesalamine) conjugated formulations include sulfasalazine, which consists of 5-ASA linked to sulfapyridine; olsalazine, a dimer of 5-ASA; and balsalazide, in which 5-ASA is bound to 4-aminobenzoyl-β-alanine.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e The delivery method of oral 5-ASA varies across different formulations. For instance, Pentasa uses an ethyl cellulose coating to continuously release the drug throughout the small and large intestine.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Salofalk is coated with an acrylic-based resin (Eudragit-L) that releases the drug at pH 6 in the proximal small intestine, while Asacol uses Eudragit-S to release 5-ASA at pH 7 in the terminal ileum and colon.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Mezavant utilizes a multi-matrix system (MMX) for gradual drug release from the terminal ileum to the rectum.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e According to Korean clinical guidelines, sulfasalazine may be used for inducing remission in patients with mild Crohn\u0026rsquo;s disease. Although the efficacy of 5-ASA in this context is considered limited, its favorable safety profile and ease of administration make it a treatment option worth considering.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIn clinical practice, 5-ASA is more commonly prescribed than sulfasalazine due to concerns over adverse effects such as reduced sperm count associated with the latter. However, there are no domestic studies providing precise data on this prescribing pattern. A U.S. study using an insurance claims database reported that 5-ASA agents\u0026mdash;including mesalamine, balsalazide, and olsalazine\u0026mdash;accounted for approximately 57% of prescriptions, whereas sulfasalazine was prescribed in only 3.02% of cases.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Nevertheless, that study merely compared usage frequency and did not evaluate the relative effectiveness of sulfasalazine versus 5-ASA.\u003c/p\u003e\u003cp\u003eTherefore, the aim of this study is to investigate the current use of aminosalicylates in Korean patients with Crohn\u0026rsquo;s disease and to compare the time to initiation of biologic therapy between patients treated with sulfasalazine and those treated with 5-ASA, in order to determine which agent may be more clinically useful. We sought to provide real‑world evidence on early 5‑ASA choice and treatment escalation, bridging gaps between trials and practice in Asian populations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and database\u003c/h2\u003e\u003cp\u003eThis population-based retrospective cohort study used data from the National Health Insurance Service (NHIS) of Korea. The NHIS is a mandatory nationwide insurance system operated by the Korean government that covers about 97% of the Korean population. While the Medical Aid Program covers the remaining 3% of the population, the NHIS also reviews their medical claims. Therefore, the NHIS database essentially covers the entire Korean population. Diagnostic codes are classified according to the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10 CM).\u003c/p\u003e\u003cp\u003eThe patient's prescription information includes detailed data such as the type of medication, daily dosage, prescription date, and duration of use. The NHIS database is accessible to qualified researchers after approval of the study protocol by the official review committee. This noninterventional, observational design analyzed routinely collected claims data (real‑world data) to generate real‑world evidence in line with contemporary FDA framing and terminology, emphasizing explicit description of data provenance and study architecture to avoid ambiguity\u003c/p\u003e\u003cp\u003e We followed the STROBE guideline and EQUATOR recommendations for transparent reporting of observational studies[2][3]. Because present‑on‑admission (POA) flags are unavailable in the Korean claims database, we prespecified sensitivity analyses using extended look‑back windows and early‑event exclusion to mitigate potential misclassification of in‑hospital onset events, consistent with best practice to address claims‑based ascertainment/timing biases and residual confounding in observational research.\u003c/p\u003e\u003cp\u003e This study adhered to the principles of the Declaration of Helsinki, and the Institutional Review Board of Uijeongbu Eulji University Hospital (UEMC IRB 2023-02-007-001) approved the study protocol.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the process for selecting the study population. Patients with Crohn's disease were defined according to the following criteria: (1) the presence of ICD-10-CM codes K50 including subcodes and claims for at least one 5-ASA (mesalamine or sulfasalazine) at baseline. Using this definition, we initially selected 422,146 individuals with Crohn\u0026rsquo;s disease over the age of 18 by the Korean NHIS between January 2002 and December 2022. We then excluded individuals without a prescription for 5-ASA (n\u0026thinsp;=\u0026thinsp;347,091) before the time of follow-up screening, prescription duration of 30 days or less (n\u0026thinsp;=\u0026thinsp;14,805) and individuals without a diagnosis about Crohn's disease (n\u0026thinsp;=\u0026thinsp;15,547) or died (n\u0026thinsp;=\u0026thinsp;8) within a year after the follow-up screening. Finally, we included 31,430 and tracked until December 2022.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eClinical variables\u003c/h3\u003e\n\u003cp\u003eWe investigated the demographic and clinical characteristics of patients who were prescribed mesalazine or sulfasalazine. Variables analyzed included sex, age, region of residence, socioeconomic status, and underlying comorbidities such as diabetes mellitus, hypertension, dyslipidemia, cancer, ischemic heart disease, and cerebrovascular disease.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was the number of days from initiation of sulfasalazine or 5-ASA therapy to the first use of corticosteroids or immunosuppressants. In addition, we conducted a time-to-event analysis to identify factors associated with the initiation of corticosteroids or immunosuppressants among patients treated with 5-ASA or sulfasalazine.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eContinuous variables were expressed as the mean and standard deviation, and categorical variables were expressed as numbers and percentages. Between group comparisons were performed using the chi-square test for categorical variables and one-way analysis of variance for continuous variables. The incidence of initiation of immunosuppressants or biologic agents was calculated as the number of events per 1000 people per year. Multivariable Cox proportional hazards regression models were used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) Statistical analyses were performed using STATA version 18.0 (StataCorp, College Station, TX, USA). A two-sided \u003cem\u003ep\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eBaseline Clinical Characteristics of Patients\u003c/h2\u003e\u003cp\u003eA total of 29,244 patients were diagnosed with Crohn\u0026rsquo;s disease (CD) during the study period (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The baseline clinical characteristics of these patients are summarized in Table\u0026nbsp;1. Among them, 18,288 patients were treated with either mesalazine or sulfasalazine.\u003c/p\u003e\u003cp\u003eThere was a higher proportion of male patients (12,300; 67.38%). In terms of age distribution, 10,935 patients (59.79%) were between 18 and 39 years old, 4,748 patients (25.96%) were between 40 and 59, and 2,602 patients (14.24%) were aged 60 or older.\u003c/p\u003e\u003cp\u003eRegarding residential areas, 4,830 patients (26.41%) lived in rural regions, 4,542 (24.84%) resided in metropolitan cities, and 8,916 (48.75%) lived in the capital region surrounding Seoul. The 5-ASA group had a significantly higher proportion of patients from rural areas.\u003c/p\u003e\u003cp\u003eIn terms of income levels, 925 patients (5.06%) were in the lowest income quartile (\u0026lt;\u0026thinsp;25%), 3,525 (19.27%) were in the lower-middle quartile (25\u0026ndash;50%), 5,616 (30.7%) were in the upper-middle quartile (50\u0026ndash;75%), and 8,223 (44.96%) were in the highest income quartile (\u0026gt;\u0026thinsp;75%). The sulfasalazine group included a significantly greater proportion of patients from lower-income groups.\u003c/p\u003e\u003cp\u003eRegarding comorbidities, the prevalence of cancer and ischemic heart disease did not differ between the two groups. However, diabetes, hypertension, and prior cerebrovascular disease were significantly more common in the sulfasalazine group, whereas dyslipidemia was more prevalent in the 5-ASA group.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eAnnual Proportion of Patients Prescribed 5-ASA\u003c/h3\u003e\n\u003cp\u003eThe prescription rate of mesalamine increased by 19.66%, from 79.27% (7,080 out of 8,931) in 2002 to 98.93% in 2022. In contrast, the prescription rate of sulfasalazine decreased by 19.66%, from 20.73% (1,851 out of 8,931) in 2002 to 1.07% in 2022(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWhile the absolute number of mesalazine prescriptions increased over time, the prescription volume of sulfasalazine declined despite an overall increase in the number of patients.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eTime to Initiation of Corticosteroids or Immunosuppressants\u003c/h2\u003e\u003cp\u003eAmong patients treated with aminosalicylates, 17,217 individuals (94.14%) were prescribed 5-ASA, while 1,071 patients (5.86%) received sulfasalazine. The time from initial treatment to the use of corticosteroids or immunosuppressants was significantly shorter in the 5-ASA group, with a median duration of 72.32 days compared to 100.72 days in the sulfasalazine group (P\u0026thinsp;=\u0026thinsp;0.0089) (Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eFactors Associated with the Use of Corticosteroids or Immunosuppressants\u003c/h2\u003e\u003cp\u003eWhen considering the initiation of corticosteroids or immunosuppressants as the event of interest and accounting for time-to-event data, several risk factors were identified. These included male sex, younger age, residence in metropolitan cities, absence of hypertension, and absence of prior cerebrovascular accidents (CVA) (Table\u0026nbsp;3).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the United States, a large multicenter study demonstrated that administering sulfasalazine at a dose of 4\u0026ndash;6 g/day for one month in 74 patients resulted in a 38% response rate.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e However, in Europe, treatment with 3 g of sulfasalazine for 18 weeks in 54 patients showed no statistically significant difference compared to placebo.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e When oral mesalazine (Asacol) at 3.2 g/day was administered to 38 patients with Crohn\u0026rsquo;s disease over four months, 60% of patients achieved complete or partial remission.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e In another study, 43% of patients achieved remission after receiving 4 g of mesalazine (Pentasa) for 16 weeks in a cohort of 310 patients.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e However, a later meta-analysis of three double-blind, placebo-controlled, randomised trials using 4 g of Pentasa showed that although it reduced the CDAI (Crohn\u0026rsquo;s Disease Activity Index) compared to placebo, the clinical significance was unclear. Specifically, a statistically significant difference was observed in studies shorter than 28 days, but not in those lasting 28 days or longer.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIn our nationwide study, patients initially treated with sulfasalazine had a longer interval before initiation of corticosteroids or immunosuppressants than those treated with mesalazine. This pattern is consistent with the possibility that sulfasalazine may provide some early symptom control in selected patients; however, it is also likely influenced by treatment selection based on unmeasured disease characteristics and physician preferences. The average duration of approximately 100.7 days before escalation in sulfasalazine users and 72.3 days in mesalazine users should therefore be interpreted primarily as reflecting real‑world treatment trajectories rather than definitive evidence of differential efficacy. These findings may help clinicians contextualize how aminosalicylates are used in practice and how quickly escalation commonly occurs, but they should be integrated with contemporary treatment paradigms in Crohn\u0026rsquo;s disease, in which biologic and targeted agents are preferred for induction and maintenance in moderate‑to‑severe disease.\u003c/p\u003e\u003cp\u003eRegarding adverse effects of sulfasalazine, 12.88% of patients in the U.S. reported side effects such as nausea, vomiting, anorexia, headache, and arthralgia,\u003csup\u003e11\u003c/sup\u003e while in Europe, 6.22% experienced adverse events, including nausea, anorexia, headache, hypertension, and infections. \u003csup\u003e8\u003c/sup\u003e The lower incidence in Europe may be attributable to the lower dose used in those studies.\u003c/p\u003e\u003cp\u003eA meta-analysis assessing the maintenance efficacy of sulfasalazine and mesalazine in Crohn\u0026rsquo;s disease found that both agents significantly reduced the risk of relapse over one year [relative risk (RR)\u0026thinsp;=\u0026thinsp;0.77; 95% confidence interval (CI), 0.64\u0026ndash;0.92]. However, this effect was driven by mesalazine, as sulfasalazine did not show a statistically significant benefit in preventing relapse [mesalazine: RR\u0026thinsp;=\u0026thinsp;0.63; 95% CI, 0.50\u0026ndash;0.79; sulfasalazine: RR\u0026thinsp;=\u0026thinsp;1.08; 95% CI, 0.81\u0026ndash;1.44].\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Taken together with our data, these observations suggest that sulfasalazine may retain a limited role in early symptom management or in specific clinical contexts, whereas its role in long‑term maintenance appears modest and is likely overshadowed by mesalazine and advanced therapies.\u003c/p\u003e\u003cp\u003eSeveral methodological considerations must be acknowledged. First, potential channeling bias and unmeasured confounding\u0026mdash;such as differences in disease location, severity, behavior, and concomitant therapies\u0026mdash;could have influenced both the choice of aminosalicylate and the likelihood and timing of treatment escalation. Our multivariable models adjusted for available demographic and comorbidity variables, but important clinical variables were not captured in claims data. Therefore, observed differences in time to escalation between mesalazine and sulfasalazine should be interpreted as associations within a specific prescribing context rather than as causal comparative effectiveness estimates. Second, reliance on administrative claims introduces risks of misclassification and imprecision in defining both exposure and outcomes, including inability to distinguish induction from maintenance therapy, uncertainty around treatment adherence, and the absence of present‑on‑admission indicators. Although we applied uniform definitions and look‑back periods, residual misclassification remains possible.\u003c/p\u003e\u003cp\u003eWe also did not stratify patients by dose of sulfasalazine or mesalazine, nor could we separate induction‑only users from those transitioning to or maintained on these agents. Disease activity at the time of treatment initiation was not available, and the substantial disparity in patient numbers between the sulfasalazine and mesalazine groups limited the precision of comparisons. Finally, our analysis was conducted within the Korean National Health Insurance context, and practice patterns may differ in other healthcare systems. Consequently, these findings are best viewed as descriptive of real‑world treatment patterns and escalation timing in a large national cohort, and may be more useful for informing expectations about disease course and patient counseling than for guiding individual drug selection in isolation..\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this nationwide cohort of Korean patients with Crohn\u0026rsquo;s disease, aminosalicylate use patterns shifted markedly over two decades, with mesalazine becoming the predominant formulation and sulfasalazine use declining to a small minority of cases. Patients initiating mesalazine experienced earlier treatment escalation to corticosteroids or immunosuppressants than those initiating sulfasalazine, but this difference is likely influenced by treatment selection, underlying disease characteristics, and other unmeasured factors.\u003c/p\u003e\u003cp\u003eOur findings primarily characterize real‑world prescribing patterns and typical timeframes to escalation, rather than establishing comparative efficacy between mesalazine and sulfasalazine. As such, they may aid clinicians in setting expectations about treatment trajectories and in educating patients about the potential need for earlier escalation beyond aminosalicylates. Definitive conclusions about the optimal role of specific aminosalicylate formulations in Crohn\u0026rsquo;s disease will require studies with more granular clinical data and designs better suited to causal inference.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eO.Z.K. conceived and designed the study.J.C. performed data acquisition and data management.H.J.K. contributed to data interpretation and critical revision of the manuscript.H.J.K. drafted the manuscript.All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHanauer SB. Review article: aminosalicylates in inflammatory bowel disease. \u003cem\u003eAliment Pharmacol Ther\u003c/em\u003e. Oct 2004;20 Suppl 4:60\u0026ndash;5. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1365-2036.2004.02048.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1365-2036.2004.02048.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHanauer SB, Str\u0026ouml;mberg U. Oral Pentasa in the treatment of active Crohn's disease: A meta-analysis of double-blind, placebo-controlled trials. \u003cem\u003eClin Gastroenterol Hepatol\u003c/em\u003e. May 2004;2(5):379\u0026ndash;88. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s1542-3565(04)00122-3\u003c/span\u003e\u003cspan address=\"10.1016/s1542-3565(04)00122-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDew MJ, Hughes PJ, Lee MG, Evans BK, Rhodes J. An oral preparation to release drugs in the human colon. \u003cem\u003eBr J Clin Pharmacol\u003c/em\u003e. Sep 1982;14(3):405\u0026ndash;8. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1365-2125.1982.tb01999.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1365-2125.1982.tb01999.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTenjarla S, Romasanta V, Zeijdner E, Villa R, Moro L. Release of 5-aminosalicylate from an MMX mesalamine tablet during transit through a simulated gastrointestinal tract system. \u003cem\u003eAdv Ther\u003c/em\u003e. Jul\u0026ndash;Aug 2007;24(4):826\u0026ndash;40. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/bf02849976\u003c/span\u003e\u003cspan address=\"10.1007/bf02849976\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePark JJ, Yang SK, Ye BD, et al. Second Korean guidelines for the management of Crohn's disease. \u003cem\u003eIntest Res\u003c/em\u003e. Jan 2017;15(1):38\u0026ndash;67. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5217/ir.2017.15.1.38\u003c/span\u003e\u003cspan address=\"10.5217/ir.2017.15.1.38\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNoureldin M, Cohen-Mekelburg S, Mahmood A, et al. Trends of 5-Aminosalicylate Medication Use in Patients With Crohn Disease. \u003cem\u003eInflamm Bowel Dis\u003c/em\u003e. Mar 15 2021;27(4):516\u0026ndash;521. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ibd/izaa127\u003c/span\u003e\u003cspan address=\"10.1093/ibd/izaa127\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSummers RW, Switz DM, Sessions JT, Jr., et al. National Cooperative Crohn's Disease Study: results of drug treatment. \u003cem\u003eGastroenterology\u003c/em\u003e. Oct 1979;77(4 Pt 2):847\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMalchow H, Ewe K, Brandes JW, et al. European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment. \u003cem\u003eGastroenterology\u003c/em\u003e. Feb 1984;86(2):249\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTremaine WJ, Schroeder KW, Harrison JM, Zinsmeister AR. A randomized, double-blind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation, Asacol, in the treatment of symptomatic Crohn's colitis and ileocolitis. \u003cem\u003eJ Clin Gastroenterol\u003c/em\u003e. Dec 1994;19(4):278\u0026ndash;82. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00004836-199412000-00003\u003c/span\u003e\u003cspan address=\"10.1097/00004836-199412000-00003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingleton JW, Hanauer SB, Gitnick GL, et al. Mesalamine capsules for the treatment of active Crohn's disease: results of a 16-week trial. Pentasa Crohn's Disease Study Group. \u003cem\u003eGastroenterology\u003c/em\u003e. May 1993;104(5):1293\u0026ndash;301. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/0016-5085(93)90337-c\u003c/span\u003e\u003cspan address=\"10.1016/0016-5085(93)90337-c\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingleton JW, Law DH, Kelley ML, Jr., Mekhjian HS, Sturdevant RA. National Cooperative Crohn's Disease Study: adverse reactions to study drugs. \u003cem\u003eGastroenterology\u003c/em\u003e. Oct 1979;77(4 Pt 2):870\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSteinhart AH, Hemphill D, Greenberg GR. Sulfasalazine and mesalazine for the maintenance therapy of Crohn's disease: a meta-analysis. \u003cem\u003eAm J Gastroenterol\u003c/em\u003e. Dec 1994;89(12):2116\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Crohn’s disease, Aminosalicylates, Mesalazine, Sulfasalazine, Immunosuppressive agents, Nationwide cohort study","lastPublishedDoi":"10.21203/rs.3.rs-8183788/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8183788/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAminosalicylates (mesalazine, sulfasalazine) are used for mild Crohn\u0026rsquo;s disease, but real‑world comparative data are limited.\u003c/p\u003e\u003ch2\u003eAim\u003c/h2\u003e\u003cp\u003eTo compare the time to initiation of corticosteroids or immunosuppressants in Korean patients with Crohn\u0026rsquo;s disease treated with mesalazine versus sulfasalazine.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a nationwide retrospective cohort study using the Korean National Health Insurance Service database from 2002 to 2022. Adults with Crohn\u0026rsquo;s disease who received mesalazine or sulfasalazine for more than 30 days were included. The primary outcome was the interval from aminosalicylate initiation to first corticosteroid or immunosuppressant prescription. Demographic and clinical variables were analysed, and multivariable Cox regression identified predictors of treatment escalation.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOf 18,288 eligible patients, 17,217 (94.1%) received mesalazine and 1,071 (5.9%) received sulfasalazine. Mesalazine prescribing increased from 79.3% in 2002 to 98.9% in 2022, whereas sulfasalazine decreased from 20.7% to 1.1%. Median time to corticosteroid or immunosuppressant initiation was shorter with mesalazine (72.3 days) than with sulfasalazine (100.7 days; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0089). Earlier escalation was associated with male sex, younger age, metropolitan residence, and absence of hypertension or cerebrovascular disease.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eIn this nationwide cohort, mesalazine was the predominant aminosalicylate and was associated with earlier treatment escalation than sulfasalazine, alongside marked shifts in prescribing patterns over two decades. These findings describe real‑world associations from administrative data and may inform, but cannot determine, comparative effectiveness between aminosalicylate formulations.\u003c/p\u003e","manuscriptTitle":"Real‑world patterns of early 5‑ASA use and time to treatment escalation in Crohn’s disease: a nationwide cohort study using Korean NHIS data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-11 00:42:30","doi":"10.21203/rs.3.rs-8183788/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"04c5ae7f-f2cf-40ae-b15d-0ba08c10c362","owner":[],"postedDate":"December 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-25T22:53:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-11 00:42:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8183788","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8183788","identity":"rs-8183788","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}