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OPEN
Increased Cumulative Incidence of Dermatomyositis in Ulcerative Colitis: a Nationwide Cohort Study
received: 22 January 2016
Chia-Chun Tseng1,2, Shun-Jen Chang3, Wei-Ting Liao4, Ya-Ting Chan3, Wen-Chan Tsai5, Tsan-Teng Ou5, Cheng-Chin Wu5, Wan-Yu Sung5,6, Ming-Chia Hsieh7,8 & Jeng-Hsien Yen5,6,9
accepted: 31 May 2016 Published: 21 June 2016
On a molecular level, two autoimmune diseases: ulcerative colitis (UC) and dermatomyositis share common genetic determinants. On a clinical level, case reports evidenced the co-occurrence of these two diseases. We therefore hypothesize that UC is potentially associated with increased cumulative incidence of dermatomyositis. The goals of this retrospective cohort study were to evaluate whether UC is associated with increased cumulative incidence of dermatomyositis independent of sex and age. For comparison, we also assessed the cumulative incidence of polymyositis in UC and control subjects. The study enrolled 3,133 UC subjects and 14,726 control subjects. The cumulative incidence of dermatomyositis was significantly higher in UC than that of control subjects (p = 0.026), but the cumulative incidence of polymyositis was comparable between UC and control subjects (p = 0.596). UC was independently associated with the increased incident dermatomyositis (hazard ratio: 6.19, 95% confidence interval = 1.77–21.59, p = 0.004) after adjusting for sex, age, and concomitant rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Similar trends of increased dermatomyositis in UC were observed when patients were stratified based on sex and age. In conclusion, our findings suggest that UC is probably associated with increased cumulative incidence of dermatomyositis, independent of sex, age, and concomitant autoimmune diseases. Both the incidence and prevalence of ulcerative colitis (UC) is increasing worldwide, affecting approximately 0.5% of the general population in the Western world1. Epidemiological data, genetic evidence and clinical features suggest that UC is a polygenic disease. Despite advances in medical management, morbidity remains high, with 30% of affected individuals undergoing colectomy2 due to failure of medical therapy, among other reasons. Though the precise etiology is not completely understood, the current hypothesis is a dysregulated mucosal immune response to commensal gut flora or microbiota in genetically susceptible individuals. Recent meta-analyses have identified several susceptibility loci associated with UC, including vitamin D receptor (VDR)3 and interferon regulatory factor 5 (IRF5)4. These two susceptibility genes are also associated with dermatomyositis (DM)5,6, another rarer autoimmune disease compared to UC that affects the musculoskeletal system and respiratory tract. Interestingly, there are several case reports describing the overlapping of these two autoimmune diseases7,8. The low occurrence of either UC or DM has made accumulating sufficient cases to analyze cumulative incidence and characteristics of each challenging. A high cumulative incidence of cases with both UC and DM co-occurring would suggest genetic overlapping of the two diseases. Studies have shown that, the association of UC with other autoimmune diseases is an important factor in the prognosis of patients diagnosed with UC9. Additionally, early recognition of patients with concurrent DM is associated with higher remission rates, shorter treatment period, and better outcomes for patients diagnosed with DM10. We thus performed a nationwide cohort study to evaluate the cumulative 1
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan. 3Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Kaohsiung, Taiwan. 4Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan. 5Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 6 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 7Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan. 8 Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan. 9Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. Correspondence and requests for materials should be addressed to S.-J.C. (email:
[email protected]) or J.-H.Y. (email:
[email protected]) 2
Scientific Reports | 6:28175 | DOI: 10.1038/srep28175
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www.nature.com/scientificreports/ incidence of DM in UC patients and examined the association between these two diseases. Because there are data indicating that DM and polymyositis (PM) share common pathological and immunological characteristics11,12, we also utilized this nationwide cohort study to estimate the cumulative incidence of PM in UC patients.
Methods
This nationwide cohort study was established using data from the National Health Insurance Research Database (NHIRD) and data from the Registry of Catastrophic Illness. Because these two databases were released with identification numbers encrypted, the researchers were blinded to the identity of individuals. Thus the analysis of the databases was exempt from the ethical approval by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-EXEMPT(I)-20150051).
Source of Sample Subjects. Taiwan initiated its National Health Insurance (NHI) program in 1995 to pro-
vide affordable health care for all citizens, with coverage rate more than 99.6%13. The NHI medical claims database, managed by Taiwan’s National Health Research Institutes (NHRI), has collected the data of all ambulatory care and in-patient claims from NHI program enrollees. The NHI database diagnosis coding mirrors the International Classification of Diseases, Ninth Revision (ICD-9), Clinical Modification diagnostic criteria. The NHRI offered NHIRD 1,000,000 random subjects for this study, which comprised registration data on 1,000,000 beneficiaries randomly sampled from the original NHIRD. This was a representative national sample, with comparable distribution in sex, age, or average insured payroll-related amount between the claimants in the sampled data and the original NHIRD14. Every record in the NHIRD contains information about the date of doctor visit, age, sex, and diagnosis of patients. We used a longitudinal cohort of 1,000,000 subjects from January 1, 1998, to December 31, 2011. Another database offered by NHRI is the Registry of Catastrophic Illness. Every record in the Registry of Catastrophic Illness contains information about the date on which the patient received their first diagnosis of catastrophic illness, the ICD-9 of catastrophic illness, the sex and age of the patient. To avoid financial hardship for families coping with major illnesses, the NHI specifies 31 categories of catastrophic illness (including UC, DM, and PM) for which patients are waived from any copayment. To be registered in the Registry of Catastrophic Illness for UC, the attending physician of these patients, usually a gastroenterologist, must submit related information, including the clinical history, endoscopic, and/or histological findings. Every case must be validated by another expert gastroenterologist to be formally approved and registered. Application of catastrophic illness certificate for DM or PM requires a thorough clinical and laboratory survey that fulfills the criteria proposed by Bohan and Peter15,16. After chart review, particularly reviewing clinical symptoms of muscle weakness, dermatological manifestations, electromyography results, muscular biopsy results, and levels of muscle enzymes (e.g. creatine kinase), lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase, only those with the diagnosis of DM or PM are issued a catastrophic illness certificate for the diseases. To ensure coding accuracy, the NHI Bureau routinely implements cross-checks of each hospital claim with medical charts. Punitive measures were taken against coding infractions to avoid diagnosis up-coding. However, NHI’s reimbursement system ties a hospital’s reimbursement to its patient severity level. As a result, it is in the best interest of a hospital to accurately code diagnoses and care items. These databases have also been utilized for epidemiologic studies of various autoimmune diseases in numerous articles, including UC, DM, and PM17–20. Therefore, the high standard set by the databases allows researchers to analyze the epidemiological profile using the data.
Cohort Selection. Patients with newly diagnosed UC (ICD-9 code: 556)17 from the Registry of Catastrophic Illness for January 1, 1998, to December 31, 2011 were identified as the UC cohort. We only included patients older than 20 years with no diagnosis of DM (ICD-9: 7103) or PM (ICD-9: 7104) before or within 1 year after their diagnosis of UC. Previous studies17–19 also utilized ICD-9 to identify patients with UC, DM, and PM in these databases. We further assigned the date on which they received a diagnosis of UC in the Registry of Catastrophic Illness as the entry date for UC patients. For every UC patient, we randomly selected at most five control subjects without UC, matched in terms of sex, age, and entry date. Control subjects could have other diseases except UC, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and so on. We recruited control subjects from NHIRD. The entry date for UC patients was the date on which the patients received their diagnosis of UC in the Registry of Catastrophic Illness. Similarly for control subjects, the entry date was a matched date on which control subjects used any medical services. Moreover, we ensured that none of our control subjects had ever received a diagnosis of DM or PM prior to or within one year of their entry date. We used this process to ensure that both cohorts shared the same baseline follow-up time. Patients who were followed less than 1 year were excluded from the analysis due to inadequate duration to assess long-term exposure status21. Outcome Definition. Any participant with a DM (ICD-9: 7103) or PM (ICD-9: 7104) diagnosis was identified from the Registry of Catastrophic Illness18,19. The endpoint of follow-up was: the date of last visit before December 31, 2011, or the diagnosis date of DM or PM in the Registry of Catastrophic Illness, whichever came first. Assessment of Covariates. Because other autoimmune diseases including: RA, SLE, and systemic sclerosis
(SSc)22, might be associated with DM or PM, we also ascertained the presence of RA (ICD-9: 7140), SLE (ICD-9: 7100), and SSc (ICD-9: 7101) from the Registry of Catastrophic Illness. Previous studies18,19 also utilized ICD-9 to identify patients with RA, SLE, and SSc in this database.
Statistical Analysis. Since patients with DM or PM diagnosed before or within 1 year after the diagnosis of
UC were excluded from the study, the first year after an UC diagnosis was not included in the follow-up time. The
Scientific Reports | 6:28175 | DOI: 10.1038/srep28175
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www.nature.com/scientificreports/ Males
Females
Gender
UC
Control subjects
UC
Control subjects
Number
(n = 1704)
(n = 7955)
(n = 1429)
(n = 6771)
50.42 ± 16.52
49.70 ± 16.00
53.76 ± 15.38
53.02 ± 14.82
Age(years; mean ± SD) Age group > = 20, = 30, = 40, = 50, = 60, = 70, = 80, = 90
3 (0.18)
6 (0.08)
3 (0.21)
p
6 (0.09)
0.298
0.244
Table 1. The age distribution of patients with ulcerative colitis and control subjects in baseline. SD: standard deviation. UC (n = 3133) Age at baseline (years)
No.a
follow-upb
Control subjects (n = 14726)
Incidence ratec
95% CI
No.
follow-up
Incidence rate
95% CI
DM 20–69
4
12101.58
0.33
0.09–0.85
6
58502.42
0.10
0.04–0.22
> = 70
1
1699.92
0.59
0.01–3.28
1
7006.42
0.14
0.00–0.79
Total
5
13801.50
0.36
0.12–0.85
7
65508.83
0.11
0.04–0.22
3
13822.83
0.22
0.04–0.63
10
65481.17
0.15
0.07–0.28
PM Total
Table 2. Incidence rate of dermatomyositis and polymyositis in ulcerative colitis patients and control subjects stratified by age. aNumbers of new diagnosed DM/PM. bThe total follow-up period (person-years). c Incidence rate per 1000 person-years. follow-up time was therefore defined as starting one year after UC diagnosis for all subjects. The follow-up period was calculated from a year after the cohort entry date to the end of follow-up. We first evaluated the incidence rate of DM/PM and the corresponding 95% confidence interval (95% CI) in patients with UC and control subjects with person-years as the denominator under the Poisson assumption using Exact method23. We then used the Kaplan-Meier analysis to estimate the cumulative incidence of DM or PM after enrollment and differences in the full time-to-event distributions between different groups were compared by a log-rank test. After confirming the assumption of proportional hazards by Schoenfeld residuals trend tests, which examined the interactions between predictors and event time, we constructed Cox proportional hazard regression models with age, sex, RA, SLE, SSc, and UC adjusted simultaneously in the model. Statistical significance was inferred at a two-sided p
