Long-term follow-up in adults with coeliac disease : predictors and effect on health outcomes

1 Long-term Follow-up in Adults with Coeliac Disease: Predictors and Effect on Health Outcomes Henna Pekki1,2, Katri Kaukinen1-3, Tuire Ilus1,4, Markku Mäki5, Heini Huhtala6, Kaija Laurila5, Kalle Kurppa2,5 1Celiac Disease Research Centre, University of Tampere and Tampere University Hospital, Tampere, Finland 2Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland 3Department of Internal Medicine, Tampere University Hospital, Tampere, Finland 4Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland 5Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland 6Faculty of Social Sciences, University of Tampere, Tampere, Finland Correspondence to Kalle Kurppa, MD, PhD Faculty of Medicine and Life Sciences, University of Tampere, FIN-33014, Tampere, Finland. E-mail: [email protected] The authors report no conflict of interest Word count: 2981 Abbreviations: EmA, Endomysium antibodies, GSRS, Gastrointestinal Symptom Rating Scale; PGWB, Psychological Well-Being Index; SF-36, Short-Form 36; TG2ab, transglutaminase 2 antibodies This is the accepted manuscript of the article, which has been published in Digestive and Liver Disease. 2018, 50(11), 1189-1194. http://dx.doi.org/10.1016/j.dld.2018.05.015 2 Abstract Introduction: Current guidelines recommend regular follow-up in coeliac disease, but effect of this on long-term health outcomes remains unclear. Aims: To evaluate predictors and significance of long-term follow-up Methods: Altogether 677 previously diagnosed coeliac disease patients were recruited for a nationwide health survey. Medical data were gathered through interviews and patient records. Current symptoms and quality of life were assessed by validated questionnaires and blood samples were drawn for serology. All variables were compared between patients with and without long-term (>2 years) follow-up. Results: Only 15% had long-term follow-up, median duration 10 years. Predictors (p<0.05) for the follow-up were immunological (35% vs. 24%) and circulatory (20% vs. 12%) comorbidities, whereas it was less common in subjects with musculoskeletal (23% vs. 34%) comorbidity and those not belonging to any at-risk group (16% vs. 27%). Patients with or without follow-up had comparable age, adherence and ability to manage a gluten-free diet and frequency of seropositivity. Also questionnaire scores paralleled, but those without follow-up reported more overall symptoms (16% vs. 26%). Most patients in both groups wished for follow-up. Conclusion: Only a minority of patients had regular follow-up. However, patients with and without the follow-up were comparable in most long-term outcomes, indicating that it might not be always necessary. The results call for more personalized follow-up policies in coeliac disease. Key words: Gluten-free diet; Treatment, Quality of life; Symptoms; Complications 3 Introduction Coeliac disease is a lifelong gluten-induced autoimmune enteropathy with a prevalence up to 2% in Caucasian populations (1). The only treatment is a strict gluten-free diet, the initiation of which usually elicits a clear clinical and histological response and disappearance of the diseasespecific autoantibodies (2). Unfortunately, the high cost and restrictive nature of the gluten-free diet predisposes to poor adherence and subsequently to persistent enteropathy and an increased risk of serious complications such as osteoporotic fractures and malignancy (3-6). Moreover, there is a subgroup of patients with a condition called refractory coeliac disease, who do not attain adequate clinical and histological recovery despite a strict diet and thus have particularly poor prognosis (7). In order to ensure proper adherence and response to the gluten-free diet and to detect possible complications, most current guidelines recommend regular long-term follow-up in coeliac disease even as often as annually (2, 8). However, there is a paucity of evidence as to how the follow-up is actually implemented in clinical practice, and whether the absence of follow-up really affects the long-term coping and health of the patients (9-15). Interestingly, in a 15-year follow-up we recently found that the lack of a repeat biopsy one year after coeliac disease diagnosis is not associated with an increased risk of adverse outcomes such as reduced well-being or malignancies (16). This would indicate that the association between the presence of follow-up and the prognosis of coeliac disease is more complex than one might expect. To further elucidate the significance of regular follow-up to the treatment success in coeliac disease, we conducted a nationwide survey and compared various patient-related and other relevant factors between large cohorts of coeliac disease patients with or without longterm follow-up after diagnosis. Materials and Methods 4 Patients and study design A nationwide cross-sectional health survey was conducted in Tampere University Hospital and the University of Tampere. The survey was created to investigate variable aspects of coeliac disease, not just factors associated with the long-term follow-up. The participants were recruited through newspaper advertisements and with the aid of coeliac disease societies. Inclusion criteria were age ≥18 years and a biopsy-proven diagnosis at least two years before enrolment. All participants filled validated questionnaires on current symptoms and quality of life and were interviewed systematically by a physician or a study nurse with expertise in coeliac disease. Patients unable to attain the study center were interviewed by phone and questionnaires were sent by mail. Patient records were reviewed in order to confirm the diagnosis and to complement medical data. In addition, blood samples were drawn for serological measurements, in case of phone interviews this was done at the nearest laboratory. Subjects with dermatitis herpetiformis were excluded owing to their different diagnostic and follow-up protocol, as well as patients with an unclear diagnosis or substantially incomplete medical information. Altogether 677 participants, representing approximately 2% of the whole Finnish coeliac population (4), were enrolled for further analyses. After data collection the results were analyzed between subgroups of participants who either had or had not been systematically and regularly assessed for at least two years after the diagnosis by health care for dietary compliance and treatment success. This sorting was based on the patients´ own reporting and medical record data. Also possible coeliac disease controls carried out during health care visits for other conditions were included. Subgroup analyses were carried out in patients with only a short-term follow-up (<2 years) and those without any follow-up. The findings were compared with our national recommendations. In Finland, the follow-up of coeliac disease is decentralized to primary care, with the general practitioners in charge. If needed, the patient can be referred to a specialist in a reasonable time 5 frame. To unify diagnostics and treatment, there are national Current Care Guidelines, which recommend a repeat biopsy one year after diagnosis and regular clinical and serological followup at 2-3-year intervals (Collin 2010). Patient enrolment and collection of study data were conducted with the permission and according to the guidelines of the Ethical Committee of the Pirkanmaa Hospital District. All participants gave written informed consent. Clinical characteristics The clinical information collected included demographic data, the type and the severity of clinical presentation before diagnosis, duration of symptoms and their current self-experienced persistence. Family history of coeliac disease, presence of coeliac disease-associated and other significant chronic comorbidities were also inquired. The latter included particularly immunological (e.g. asthma, allergies), circulatory (e.g. hypertension, coronary artery disease) and musculoskeletal (e.g. arthritis, fibromyalgia) conditions. Current or previous smoking and whether the coeliac disease diagnosis was made in primary, secondary or tertiary public care or in private care were also inquired. The self-perceived severity of clinical presentation was asked to estimate the burden of symptoms. These were further classified into 1) no symptoms; 2) mild symptoms such as occasionally disturbing gastrointestinal or extra-intestinal symptoms or a combination of them and 3) severe symptoms seriously disturbing daily life, such as recurrent awakenings because of pain or symptoms requiring acute inpatient care (17). Small-bowel mucosal biopsies Data on small-bowel mucosal biopsies were collected from the patient records. Our national diagnostic guidelines for coeliac disease recommend at least four duodenal biopsies to be taken routinely from each patient upon coeliac disease suspicion and during the possible repeat 6 endoscopy after one year on a gluten-free diet. The histological specimens are forwarded to the hospitals’ pathology department, where the severity of mucosal damage is evaluated in representative and correctly orientated biopsy cuttings. Demonstration of duodenal villous atrophy is required for celiac disease diagnosis. The degree of mucosal lesion has for decades been graded as partial, subtotal or total villous atrophy, these corresponding approximately grades 3a, 3b and 3c in Marsh-Oberhuber classification. Celiac disease serology Values for serum endomysial antibodies (EmA) at diagnosis were gathered from patient records. Furthermore, EmA and transglutaminase 2 antibodies (TG2ab) were measured in all patients at the time of the current study. Indirect immunofluorescence was used for EmA measurements as previously described (18). Titers 1: ≥5 were considered positive and diluted until negative to 1:50, 1:100, 1:200, 1:500, 1:1000, 1:2000 and 1:4000. These were further classified as low (1:5-1:200) and high positive (1:500-1:4000). TG2ab were tested by commercial ELISA (QUANTA Lite h-tTG IgA, INOVA Diagnostics, San Diego, CA), considering a cut-off >30.0 U/l positive. Corresponding IgG-class antibodies were measured in cases of selective IgA deficiency. Adherence to the gluten-free diet Provision of dietary advice at coeliac disease diagnosis was verified by patient interview and from patient records. Current long-term dietary adherence was also inquired by an experienced study nurse/physician with an expertise in coeliac disease and classified as “strict” (minor inadvertent lapses less than a few times a year), “occasional lapses” (lapses less often than once per month) and “normal diet”.Long-term adherence was further estimated on the basis of 7 coeliac antibody positivity at the time of the present study. Alongside adherence, patient’s overall competency in managing the diet and the possible use of purified oats was asked. Questionnaires Short Form 36 Health Survey (SF-36) and Psychological General Well-Being questionnaires (PGWB) were used to assess patients’ current self-perceived quality of life and gastrointestinal symptoms at time of study. SF-36 comprises 36 separate questions, divided into eight sub-dimensions as follows; physical functioning, role limitations due to physical problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems and mental health (19-23). Items are re-scored from 0 to 100, higher scores indicating better health and quality of life. PGWB is a well-validated and widely used questionnaire both in coeliac disease and in general (18, 20, 22, 23). The 22 separate items can be further divided into six subdimensions measuring anxiety, depression, well-being, self-control, general health and vitality. All items use a 6-grade Likert scale with higher scores representing better well-being and quality of life. Gastrointestinal symptoms were evaluated by the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire (18, 24). It includes 15 separate items which can be added together as a total score and further divided into 5 sub-dimensions measuring abdominal pain, gastroesophageal reflux, indigestion, diarrhea and constipation. The scoring is based on a 7-grade Likert scale, higher scores reflecting more severe gastrointestinal symptom. Statistical analysis 8 Continuous variables are presented as medians with quartiles or ranges. Categorical variables are presented as number of subjects and percentages.Statistical significance in differences between patients with and without long-term follow-up was studied using Mann-Whitney test. Binominal and classified variables were analyzed using Chi-square test. A p-value <0.05 was considered significant in all analyses. All analyses were carried out using SPSS 20.0 (IBM Corp. Armonk, NY). Results The median age of the whole study cohort was 44 (range 22-89) years and 80% were women. The median follow-up time for the whole study group was 10 (range 2-38) years. Out of the 677 participants, 99 (15%) had and 578 (85%) had not received long-term follow-up for coeliac disease. Factors predicting long-term follow-up Existence of follow-up was predicted by the presence of immunological (35% vs 24%, p=0.020) and circulatory (20% vs. 12%, p=0.010) comorbidities, whereas it was less common in subjects with coexisting musculoskeletal disease (23% vs. 34%, p=0.045). Those not belonging to any at-risk group, such as patients with type I diabetes and those with family history for coeliac disease, were more likely to be without follow-up (Table 1). In contrast, follow-up was not predicted by other co-morbidities (data not shown), gender, site of diagnosis, seropositivity for celiac autoantibodies or severity of histological lesion at diagnosis, symptoms in childhood, clinical presentation or duration of symptoms before diagnosis, family risk of coeliac disease or associated condition and smoking (Table 1). Also age at diagnosis (median 42 vs. 44 years, range 18-75 vs. 18-71 years, p = 0.117) or at present (median 54 vs. 54 years, range 22-81 vs 9 21-89 years, p = 0.919) did not significantly differ between patients with and without followup. When looking into the short-term clinical characteristic one year after diagnosis of those patients the data was available, there was no significant association between the presence coeliac autoantibody positivity (6.3% vs. 15.1%, respectively p=0.343; n=95) between groups. Neither did the groups differ in the prevalence of histological recovery (fully normalized 53.0% vs. 60.2%, p=0.378; n=398) in the follow-up and no-follow up groups after one year on a glutenfree diet and existence of long-term follow. Long-term outcomes in patients with and without follow-up Participants in both follow-up and no-follow up groups had similar dietary adherence andability to manage the gluten-free diet, as well as use of purified oats (Table 2). There was also no difference between the groups in current positivity for coeliac autoantibodies (Table 2) or in any of the questionnaire scores measuring health-related quality of life (SF-36, PGWB) and gastrointestinal symptoms (GSRS) (Table 3). However, patients without regular long-term follow-up suffered more from current self-reported overall symptoms (Table 2). Despite this difference in significance, there was a correlation between self-reported symptoms and those evaluated by GSRS. Nevertheless, patients with more indigestion, reflux, constipation and abdominal pain in GSRS are more likely to report more severe self-perceived symptoms. In contrast, the amounts of diarrhea and constipation were not associated with the severity of selfperceived symptoms (Data not shown) Altogether 98 % of patients with regular long-term follow-up wished for it also in the future, and this was also seen in over 80% of the patients of patients not currently under follow-up (Table 2). Most of these patients wished the follow-up to be organized in public 16 18. Kurppa K, Paavola A, Collin P, Sievänen H, Laurila K, Huhtala H, et al. Benefits of a gluten-free diet for asymptomatic patients with serologic markers of celiac disease. Gastroenterology 2014;147:610-617. 19. Haere P, Hoie O, Schulz T, Schonhardt I, Raki M, Lundin KE. Long-term mucosal recovery and healing in celiac disease is the rule - not the exception. Scand J Gastroenterol 2016;18:1-8. 20. 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Spiegel BM, Gralnek IM, Bolus R, Chang L, Dulai GS, Mayer EA, et al. Clinical determinants of health-related quality of life in patients with irritable bowel syndrome. Arch Intern Med 2004;164:1773-1780. 18 35. Lackner JM, Gudleski GD, Ma CX, Dewanwala A, Naliboff B, Representing the IBSOS Outcome Study Research Group. Fear of GI symptoms has an important impact on quality of life in patients with moderate-to-severe IBS. Am J Gastroenterol 2014;109:1815-1823. 36. Ciacci C, Cirillo M, Cavallaro R, Mazzacca G. Long-term follow-up of celiac adults on gluten-free diet: prevalence and correlates of intestinal damage. Digestion 2002;66:178-185. 19 Figure legends Figure 1: Patients’ opinion on where the long-term follow-up of celiac disease should be organized, divided on basis of the lack (No follow-up) or presence (Follow-up) of current regular follow-up. Figure 2. Patients’ opinion on who should be in charge of the long-term follow-up of celiac disease, divided on basis of the lack (No follow-up) or presence (Follow-up) of current regular follow-up.