Overall and Cause-Specific Mortality in Adult Celiac Disease and Dermatitis Herpetiformis Diagnosed in the 21st Century

1 Overall and cause-specific mortality in adult celiac disease and dermatitis herpetiformis diagnosed in the 21st century Inka Koskinen, MD1,2, Lauri J Virta, MD, PhD3, Heini Huhtala, MSc4, Tuire Ilus, MD, PhD1,5, Katri Kaukinen, MD, PhD1,6 and Pekka Collin, MD, PhD1,5 1Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Finland 2Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä, Finland 3Research Department, Social Insurance Institution of Finland, Turku, Finland 4Faculty of Social Sciences, Tampere University, Finland 5Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland 6Department of Internal Medicine, Tampere University Hospital, Tampere, Finland Corresponding author: Katri Kaukinen, MD, PhD. E-mail: [email protected] Word count: 2965 Conflicts of interest Guarantor of the article: Katri Kaukinen, MD, PhD This is the accepted manuscript of the article, which has been published in American journal of gastroenterology, 2020, 115:7, 1117-1124. http://dx.doi.org/10.14309/ajg.0000000000000665 2 Specific author contributions: Inka Koskinen: study design, project coordination, data collection, data interpretation and writing the article; Lauri J. Virta: study design, data collection, data interpretation and manuscript revision; Heini Huhtala: data analysis and manuscript revision ; Tuire Ilus: study design and manuscript revision; Katri Kaukinen: study design, data interpretation and manuscript revision; Pekka Collin: study design, data interpretation and manuscript revision . All authors have read and approved the final manuscript. Financial support: This work was supported by grants to the Celiac Disease Study Group from the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (Grant 9P060) Potential competing interest: None Running head: Mortality in celiac disease Keywords: celiac disease, adult, 21st century, recent diagnostic advances, mortality 3 Study Highlights 1. WHAT IS KNOWN •Celiac disease has been associated with increased mortality, but the data are contradictory. •Celiac disease patients have an increased risk of dying from lymphoproliferative diseases and gastrointestinal malignancies. 2. WHAT IS NEW HERE •Overall mortality was not increased in a contemporary, large, and nationwide Finnish cohort of celiac patients diagnosed in adulthood. •Mortality from lymphoproliferative diseases was elevated, but lower than previously reported. •Mortality from gastrointestinal malignancies was not increased. •Hazard ratios for death from non-malignant digestive diseases and lymphoproliferative diseases peaked within two years of the celiac disease diagnosis. 4 Abstract Objectives: We assessed whether celiac disease-associated mortality is increased among patients diagnosed in the 21st century given recent improvements in diagnostic and treatment facilities. Methods: Biopsy-proven celiac disease (Marsh III) and dermatitis herpetiformis patients aged 20– 79 years (median 50 years) diagnosed 2005 – 2014 (n=12,803) were identified from the national dietary grant registry. Dates and causes of death were obtained from Statistics Finland. Overall mortality and causes of death were compared to reference individuals (n=38,384) matched for age, sex, and area of residence (at the time of celiac disease diagnosis) selected from the Population Information System. Results: During a mean follow-up of 7.7 years (SD ± 3.0 years), 884 (6.9%) and 2,613 (6.8%) deaths occurred among the celiac cohort and reference group respectively. Overall mortality (hazard ratio (HR) 1.01, 95% confidence intervals (CI) 0.94–1.09), mortality from all malignancies (HR 1.11, 95% CI 0.96-1.27), gastrointestinal tract malignancies (HR 1.21, 95% CI 0.56-1.71) or cardiovascular diseases (HR 0.91, 95% CI 0.77-1.07) were not increased among celiac patients. Overall, mortality from lymphoproliferative diseases (HR 2.36, 95% CI 1.65–3.39) and nonmalignant digestive diseases (HR 2.19, 95% CI 1.40–3.43) was increased, but HRs decreased after exclusion of the first two years of follow-up (HR 1.71, 95% CI 1.10–2.66 and HR 1.75, 95% CI 1.01–3.05 respectively). Conclusions: The overall mortality in adult celiac disease diagnosed 2005-2014 was not increased. Mortality from lymphoproliferative diseases was increased but lower than previously reported. 5 Introduction Recent studies indicate that the prevalence of celiac disease, a dietary gluten-triggered autoimmunemediated enteropathy, is increasing, affecting 1–2% of the population globally (1-5). Nevertheless, the disease remains markedly under-diagnosed (1,6-8). Along with the classical symptoms of diarrhea and malabsorption, celiac disease may manifest with mild abdominal or extraintestinal symptoms, or there may be no symptoms whatsoever. With a strict gluten-free diet, it is possible to heal the damaged small bowel mucosa (9) and to alleviate the symptoms. Celiac disease has been associated with increased mortality mainly caused by lymphoproliferative diseases and diseases of the gastrointestinal organs (10-13). Most publications have concerned tertiary center or hospital-based cohorts of celiac patients diagnosed mainly before the advent of serological testing in the 1980s (10,14-16); at that time celiac disease was commonly diagnosed in childhood with malabsorption, diagnostic delay was prolonged, and facilities for successful treatment were limited. As malabsorption and long diagnostic delay have been associated with complicated celiac disease, these factors may have caused overestimation of mortality. (17,18). A recent study from Nottingham in the UK utilizing general practice data from the 2000s suggested an improved prognosis for celiac patients; the relative mortality risk paralleled that of the general population (19). In Finland, health personnel have been educated about celiac disease and active case-finding has been advocated by screening individuals presenting with mild symptoms or belonging to known celiac disease risk groups since the 1990s (20). This approach has yielded a globally high prevalence (0.7%) of biopsy-proven celiac disease (7,20,21) and a shortened delay from presenting symptoms to diagnosis (15,22-24). Simultaneously, awareness of celiac disease has increased and 6 legislation is in place to ensure the quality of currently widely available gluten-free products. Newly diagnosed patients are referred to dieticians and, according to dietary interview studies, Finnish celiac patients are highly adherent to strict gluten-free diet (25,26) also achieving villous recovery (9). Refractory celiac disease unresponsive to strict gluten-free diet carries a high risk of complications, affects only 0.3% of all adult celiac patients in Finland and is thus expected to have little impact on mortality (7). Overall, earlier research shows contradictory and decidedly scarce results for celiac diseaseassociated mortality in contemporary cohorts of patients. Using an unselected nationwide population-based cohort of adult celiac patients diagnosed in the 21st century and assembled from the Finnish dietary reimbursement registry, we explored whether improved diagnostics and treatment have jointly reduced excess mortality risk. Materials and methods Study population From October 2002 to the end of 2015, all Finnish non-institutionalized celiac disease or dermatitis herpetiformis patients were entitled to a monthly dietary reimbursement of 21 euros to cover the additional costs of maintaining a gluten-free diet. Eligibility for reimbursement was based on histological verification of the diagnosis demonstrated by duodenal villous atrophy with crypt hyperplasia (compatible with Marsh III (27)) in celiac disease or typical granular IgA deposits in the dermal papillae of the skin in dermatitis herpetiformis (28). 7 All applicants for the dietary grant for celiac disease were recorded in a nationwide registry maintained by the Social Insurance Institution of Finland (SII). Before granting the reimbursement, the attainment of the diagnostic criteria was verified by a SII reviewer checking the medical certificate delivered by the treating physician at the time of diagnosis. Reimbursement payments began in the month immediately following the diagnosis (maximum 12 months retrospectively after receiving the application).The validity of the registry has been shown to be excellent (20,21,29). However, only one diagnostic code per patient (K90 for celiac disease or L13 for dermatitis herpetiformis) was accepted thus patients presenting with both manifestations may have been registered under either code. From 2002 to 2004 altogether 21,405 patients joined the registry including those with a prior diagnosis (20). By the end of 2014 the registry included 34,252 patients. Of the reimbursement decisions, 97% were based on code K90 and 3% on code L13 (8). Retrieval of the patient cohort has been described in detail elsewhere (8). For this study, incident celiac disease and dermatitis herpetiformis – patients aged 20 – 79 years with known time of diagnosis were selected from the dietary grant registry. To ensure that incident cases only were included, only patients entered in the registry between 2005 and 2014 were enrolled. Additionally, registry data prior to 2005 was checked and patients previously granted reimbursement excluded (8). Of the 12,847 celiac patients identified, 36 had set a disclosure prohibition preventing the retrieval of vital details and eight were resident abroad at the time of diagnosis and therefore excluded. Thus, the study population comprised 12,803 celiac patients. The preceding month and year when the dietary grant payments began were used as proxies for the date of diagnosis. Reference group 8 For each incident celiac patient, up to three eligible reference individuals matched for age, sex, and place of residence at diagnosis of the corresponding celiac disease cases were selected from the Finnish Population Information System comprising 38,384 individuals. The Population Information System maintained by the Population Register Centre contains basic information on all Finnish and foreign citizens permanently resident in Finland; each individual registered in the system has a unique personal identification code. Mortality data Statistics Finland maintains the registry of causes of death covering more than 99% of all deceased residents of Finland since 1936 (30). Immediate, underlying, and contributary causes of death are derived from the death certificates (30). The personal identification codes of both cohorts were linked with the registry. Dates of death were acquired until the end of 2017 and causes of death until the end of 2016. The registry classifies the causes of death by underlying cause into 54 groups (31). These were used in the analyses of cause-specific mortality. Main categories in analyses (according to the codes of the Tenth Revision of the International Classification of Diseases (ICD10)) included: All malignancies (C00–C97), gastrointestinal tract malignancies covering cancers from esophagus to anus (C15–C21), lymphoproliferative diseases (C81-C96) including all disease locations, cardiovascular diseases (I00–I425, I427–I99), respiratory diseases (J00–J64, J66–J99), and non-malignant digestive diseases (K00–K291, K293–K67, K71–K851, K853–859, K861–K93) covering diseases of liver, pancreas, and gastrointestinal tract (excluding all alcohol-related diseases). Non-Hodgkins lymphomas (C82–C85) and T-cell non-Hodgkins lymphomas (C84) were specifically collected from the mortality data. Concomitant conditions 9 Information on concomitant chronic conditions based on granted drug reimbursements was collected from the Special Reimbursement Registry for medicine expences maintained by the SII. Specific conditions taken into consideration (Supplementary Table 1) included insulin dependent diabetes mellitus, hypertension, cardiovascular diseases (including cardiac insufficiency, ischemic heart disease, chronic arrhythmias, and hyperlipidemic diseases), respiratory diseases (including bronchial asthma and chronic obstructive pulmonary disease), and inflammatory rheumatic diseases. Statistical analyses The follow-up commenced from the month the diagnosis was set for celiac patients and a corresponding date for reference individuals and continued until death, emigration or December 31st, 2017, whichever occurred first. Crude mortality rates per 10,000 person-years were calculated for overall mortality and for the main categories of causes of death and causes of special interest according to the literature. Cox proportional hazards model was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). Analyses were further adjusted for concomitant conditions. Overall mortality and deaths caused by non-malignant digestive diseases, all malignancies, lymphoproliferative diseases, and gastrointestinal tract malignancies were analyzed separately for two different periods of follow-up; the peri-diagnostic period (<2 years after diagnosis) and the post-diagnostic period (≥2 years after diagnosis). A stratified analysis according to sex and age at diagnosis (20–29, 30–39, 40–49, 50–59, 60–69, 70–79 years) was conducted for overall mortality and lymphoproliferative diseases. Celiac disease-associated mortality in lower and higher incidence areas (32.4 and 48.5/100,000 persons/year respectively) within Finland (20) was also assessed. To determine how mortality from diseases other than malignancies, lymphoproliferative diseases, gastrointestinal malignancies, cardiovascular diseases, ischemic heart diseases, cerebrovascular diseases, respiratory diseases, and digestive diseases individually affected the main results, a 16 References 1. 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Characteristics Celiac patients n=12,803 Reference individuals n=38,384 n % n % Gender Male 4,860 38.0 14,573 38.0 Female 7,943 62.0 23,811 62.0 Age at diagnosis, years 20–29 1,629 12.7 4,895 12.7 30–39 2,072 16.2 6,199 16.2 40–49 2,589 20.2 7,761 20.2 50–59 2,868 22.4 8,592 22.4 60–69 2,288 17.9 6,867 17.9 70–79 1,357 10.6 4,070 10.6 Concomitant diseases a Diabetes mellitus 1,303 10.2 3,744 9.8 Hypertension 1,524 11.9 5,208 13.6 Cardiovascular diseases 1,119 8.7 3,052 8.0 Respiratory diseases 1,209 9.4 3,154 8.2 Inflammatory rheumatic diseases 528 4.1 1,354 3.5 a Proportion of patients on long term medication according to drug reimbursement decisions 23 Table 2. Mortality rates per 10,000 person-years and hazard ratios (HR) for overall and cause-specific mortality among celiac patients and their reference individuals. Celiac group (n=12,803) Reference group (n=38,384) Cause of death (end of year 2016) ICD-10 codes n (% of deaths) Mortality rate a n (% of deaths) Mortality rate a HR (95% CI) Overall mortality b 884 89.2 2,613 88.3 1.01 (0.94–1.09) Malignancies C00–C97 261 (33.6) 29.0 705 (30.8) 26.2 1.11 (0.96–1.27) Gastrointestinal tract c C15–C21 49 (5.4) 5.0 114 (4.2) 4.1 1.28 (0.92–1.79) Esophagus C15 4 (0.5) 0.4 12 (0.5) 0.5 1.00 (0.32–3.10) Stomach C16 8 (1.0) 0.9 20 (0.9) 0.7 1.20 (0.53–2.71) Small bowel C17 4 (0.5) 0.4 3 (0.1) 0.1 3.99 (0.89–17.81) Colorectum d C18–C20 31 (4.0) 3.4 78 (3.4) 2.9 1.19 (0.78–1.80) Liver C22 12 (1.5) 1.3 30 (1.3) 1.1 1.19 (0.61–2.33) Pancreas C25 26 (3.4) 2.8 64 (2.8) 2.4 1.21 (0.77–1.91) Lymphoproliferative C81–C96 53 (6.8) 5.9 67 (2.9) 2.5 2.36 (1.65–3.39) NHL C82–C85 44 (5.6) 4.9 29 (1.2) 1.1 4.53 (2.84–7.24) T-cell NHL C84 24 (3.1) 2.7 1 (0.0) 0.0 71.67 (9.70–529.77) Breast e C50 15 (1.9) 1.7 75 (3.3) 2.8 0.60 (0.34–1.04) Gynecological e C51–C58 12 (1.5) 2.1 42 (1.8) 2.5 0.85 (0.45–1.62) Prostate f C61 9 (1.2) 2.7 38 (1.7) 3.8 0.71 (0.34–1.46) Urinary tract C64–C68 11 (1.4) 1.2 34 (1.5) 1.3 0.97 (049–1.91) Digestive diseases K00–K291, K293–K67, K71– K851, K853–859, K861–K93 33 (4.3) 3.7 45 (2.0) 1.7 2.19 (1.40–3.43) Liver cirrhosis K74 7 (0.9) 0.8 5 (0.0) 0.2 4.18 (1.33–13.17) Celiac disease K90 5 (0.6) 0.6 0 (0.0) 0.0 - Volvulus K562 7 (0.9) 0.8 2 (0.1) 0.1 10.48 (2.18-50.44) Cardiovascular diseases I00–I425, I427–I99 183 (23.6) 20.3 603 (26.4) 22.4 0.91 (0.77–1.07) Ischemic heart disease I20–I25 134 (17.3) 14.9 437 (19.1) 16.2 0.92 (0.76–1.11) Cerebrovascular disease I60–I69 46 (5.9) 5.1 176 (7.7) 6.5 0.78 (0.56–1.08) Respiratory diseases J00–J64, J66–J99 36 (4.6) 4.0 104 (4.5) 3.9 1.03 (0.71–1.51) Infectious diseases A00-B99, J65 10 (1.3) 0.1 6 (0.3) 0.2 5.00 (1.81-13.69) Sepsis A40-A41 5 (0.6) 0.6 2 (0.1) 0.1 7.44 (1.44-38.34) HR, hazard ratio; CI, confidence interval; ICD-10, International Classification of Diseases, tenth revision; NHL, non-Hodgkins lymphoma a mortality rate / 10,000 person-years, b analyzed until the end of 2017, c HR for combined gastrointestinal cancers (cancers of the liver, pancreas and gastrointestinal tract) 1.21 (95% CI 0.94-1.56), d anal cancer not included, e analyzed only for females, f analyzed only for males 24 Table 3. Specific relative mortality risks in celiac patients compared to reference individuals in the periand post-diagnostic period. Cause of death Peri-diagnostic period (<2 years after diagnosis), n (deaths) = 708 Post-diagnostic period (≥2 years after diagnosis) a, n (deaths) = 2,355 HR 95% CI HR 95% CI All causes 1.07 0.90–1.26 1.00 0.91–1.10 All malignancies 1.41 1.07–1.86* 1.02 0.86–1.20 Gastrointestinal tract malignancies 2.18 1.14–4.15* 1.07 0.72–1.59 Lymphoproliferative diseases 5.07 2.55–10.06** 1.71 1.10–2.66* Digestive diseases 3.54 1.59–7.90* 1.75 1.01–3.05* HR, hazard ratio; CI, confidence interval a The results were not significantly different when the follow-up was analyzed in time periods < 1, 1-5, and over 5 years. * P < 0.05, ** P < 0.001 25 Table 4. Studies on overall risk of mortality and mortality for lymphoproliferative diseases (non-Hodgkins lymphoma) in diagnosed coeliac disease patients. Study, Year Country Age group Number of CD patients Years of diagnosis or enrollment Personyears for CD patients Overall mortality Risk estimate (95% CI) Mortality for lymphoproliferative diseases Risk estimate (95% CI) Cottone et al. 1999 (50) Italy Adults 216 1980–1997 ND SMR 3.8 (2.0–7.0) - Corrao et al. 2001 (17) Italy Adults 1,072 1962–1994 6,444 SMR 2.0 (1.5–2.7) SMR 69.3 (40.7–112.6) for NHL Peters et al. 2003 (10) Sweden Mixed ᵃ 10,032 1964–1993 81,182 SMR 2.0 (1.8–2.1) SMR 11.4 (7.8–16.0) for NHL West et al. 2004 (13) UK Mixed ᵇ 4,732 1987–2002 18,923 HR 1.3 (1.1–1.5) - Viljamaa et al. 2006 (38) Finland Mixed ᶜ 781 1960–2000 10,956 SMR 1.3 (1.0–1.6) SMR 4.1 (1.7–8.5) Solaymani-Dodaran et al. 2007 (40) UK Adults 340 1961–1981 6,240 SMR 1.6 (1.3–1.8) SMR 14.4 (7.4–25.0) Ludvigsson et al. 2009 (12) Sweden Mixed ᵈ 29,096 1969–2008 ND HR 1.4 (1.3–1.5) - Grainge et al. 2011 (41) UK Mixed ᵉ 1,092 1958–2006 10,152 SMR 1.4 (1.2–1.6) SMR 7.1 (2.6–15.4) for NHL Abdul Sultan et al. 2015 (19) UK Mixed ᶠ 10,825 1998–2012 60,226 HR 0.9 (0.8–1.0) - Holmes & Muirhead 2018 (11) UK Adults 2,174 1978–2014 23,955 SMR 1.6 (1.4–1.8) SMR 6.3 (2.9–12.0) Present study ᶢ Finland Adults 12,803 2005–2014 99,094 HR 1.0 (0.9–1.1) HR 2.4 (1.7–3.4) CD, celiac disease; NHL, non-Hodgkin lymphoma; ND, not defined; SMR, standardized mortality ratio; HR, hazard ratio Proportion of patients diagnosed as children or adolescents: ᵃ 70%, ᵇ 12%, ᶜ ND, ᵈ 41%, ᵉ 10%, ᶠ 13% ᶢ dermatitis herpetiformis patients included