The Economic Iceberg of Celiac Disease: More Than the Cost of Gluten-Free Food.

Celiac disease (CeD) is a chronic autoimmune disorder of global relevance, with the potential for acute and long-term complications. However, the economic burden of CeD is rarely considered and largely thought of as limited to the cost of gluten-free food. Fortunately, recent research has shed light on the various societal costs of CeD across the health care continuum. This article summarizes the current evidence on the economic impacts of CeD, which suggest that the societal economic burden of CeD stretches beyond the cost of gluten-free food. This review provides ample evidence of larger but hidden costs related to excess health care use for complications and comorbidities, as well as reduced productivity. Although significant advances are expected in the management of CeD, their effect on the economic burden of CeD remain uncertain. The aim of this review was to inform stakeholders across society and contribute to improved policies to support patients with CeD.

Histologic Remission in Inflammatory Bowel Disease and Female Fertility: A Nationwide Study.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is linked to reduced female fertility, but it is unclear how fertility rates vary by histologic disease activity. METHODS: Nationwide IBD cohort of Swedish women aged 15 to 44 years. We examined fertility rates during periods with vs without histologic inflammation (n = 21,046; follow-up, 1990-2016) and during periods with vs without clinical activity (IBD-related hospitalization, surgery, or treatment escalation) (n = 24,995; follow-up, 2006-2020). Accounting for sociodemographics and comorbidities, we used Poisson regression to estimate adjusted fertility rate ratios (aFRRs) for live births conceived during 12-month periods of histologic inflammation (vs histologic remission) and 3-month periods of clinically active IBD (vs quiescent IBD). RESULTS: During periods with vs without histologic inflammation, there were 6.35 (95% confidence interval [CI], 5.98-6.73) and 7.09 (95% CI, 6.48-7.70) live births conceived per 100 person-years of follow-up, respectively, or 1 fewer child per 14 women with 10 years of histologic inflammation (aFRR, 0.90; 95% CI, 0.81-1.00). In women with histologic inflammation, fertility was similarly reduced in ulcerative colitis (UC) (aFRR, 0.89 [95% CI, 0.78-1.02]) and Crohn's disease (CD) (aFRR, 0.86 [95% CI, 0.72-1.04]). Clinical IBD activity was associated with an aFRR of 0.76 (95% CI, 0.72-0.79) or 1 fewer child per 6 women with 10 years of clinical activity. Fertility was reduced in clinically active UC (aFRR, 0.75 [95% CI, 0.70-0.81]) and CD (aFRR, 0.76 [95% CI, 0.70-0.82]). Finally, among women with clinically quiescent IBD, histologic inflammation (vs histologic remission) was associated with reduced fertility (aFRR, 0.85 [95% CI, 0.73-0.98]). CONCLUSIONS: An association between histologic and clinical activity and reduced female fertility in CD and UC was found. Notably, histologic inflammation was also linked to reduced fertility in women with clinically quiescent IBD.

Early-life diet and risk of inflammatory bowel disease: a pooled study in two Scandinavian birth cohorts.

OBJECTIVE: We assessed whether early-life diet quality and food intake frequencies were associated with subsequent IBD. DESIGN: Prospectively recorded 1-year and 3-year questionnaires in children from the All Babies in Southeast Sweden and The Norwegian Mother, Father and Child Cohort Study were used to assess diet quality using a Healthy Eating Index and intake frequency of food groups. IBD was defined as >2 diagnoses in national patient registers. Cox regression yielded HRs adjusted (aHRs) for child's sex, parental IBD, origin, education level and maternal comorbidities. Cohort-specific results were pooled using a random-effects model. RESULTS: During 1 304 433 person-years of follow-up, we followed 81 280 participants from birth through childhood and adolescence, whereof 307 were diagnosed with IBD. Compared with low diet quality, medium and high diet quality at 1 year of age were associated with a reduced risk of IBD (pooled aHR 0.75 (95% CI=0.58 to 0.98) and 0.75 (95% CI=0.56 to 1.00)). The pooled aHR per increase of category was 0.86 (0.74 to 0.99). Pooled aHR for children 1 year old with high versus low fish intake was 0.70 (95% CI=0.49 to 1.00) for IBD, and showed association with reduced risk of UC (pooled aHR=0.46; 95% CI=0.21, 0.99). Higher vegetable intake at 1 year was associated with a risk reduction in IBD. Intake of sugar-sweetened beverages was associated with an increased risk of IBD. Diet quality at 3 years was not associated with IBD. CONCLUSION: In this Scandinavian birth cohort, high diet quality and fish intake in early life were associated with a reduced risk of IBD.

Histologic Activity in Inflammatory Bowel Disease and Risk of Serious Infections: A Nationwide Study.

BACKGROUND & AIMS: Individuals with inflammatory bowel disease (IBD) are at increased risk of serious infections, but whether this risk varies by histologic disease activity is unclear. METHODS: This was a national population-based study of 55,626 individuals diagnosed with IBD in 1990 to 2016 with longitudinal data on ileocolorectal biopsy specimens followed up through 2016. Serious infections were defined as having an inpatient infectious disease diagnosis in the Swedish National Patient Register. We used Cox regression to estimate hazard ratios (HRs) for serious infections in the 12 months after documentation of histologic inflammation (vs histologic remission), adjusting for social and demographic factors, chronic comorbidities, prior IBD-related surgery, and hospitalization. We also adjusted for IBD-related medications in sensitivity analyses. RESULTS: With histologic inflammation vs remission, there was 4.62 (95% CI, 4.46-4.78) and 2.53 (95% CI, 2.36-2.70) serious infections per 100 person-years of follow-up, respectively (adjusted HR [aHR], 1.59; 95% CI, 1.48-1.72). Histologic inflammation (vs remission) was associated with an increased risk of serious infections in ulcerative colitis (aHR, 1.68; 95% CI, 1.51-1.87) and Crohn's disease (aHR, 1.59; 95% CI, 1.40-1.80). The aHRs of sepsis and opportunistic infections were 1.66 (95% CI, 1.28-2.15) and 1.71 (95% CI, 1.22-2.41), respectively. Overall, results were consistent across age groups, sex, and education level, and remained largely unchanged after adjustment for IBD-related medications (aHR, 1.47; 95% CI, 1.34-1.61). CONCLUSIONS: Histologic inflammation of IBD was an independent risk factor of serious infections, including sepsis, suggesting that achieving histologic remission may reduce infections in IBD. The study was approved by the Stockholm Ethics Review Board (approval numbers 2014/1287-31/4, 2018/972-32, and 2021-06209-01).

Breastfeeding Duration Is Not Associated With Offspring Inflammatory Bowel Disease Risk in Three Population-Based Birth Cohorts.

BACKGROUND & AIMS: Breastfeeding is critical for offspring health and development. Although many observational studies report a protective effect between breastfeeding and inflammatory bowel disease (IBD), the relationship is not well-understood. METHODS: We used prospectively collected data from 3 population-based birth cohorts (Danish National Birth Cohort, Norwegian Mother, Father, and Child Cohort, and All Babies in Southeast Sweden) and cross-linked national registers to ascertain the impact of breastfeeding duration on offspring IBD risk in each country, using adjusted Cox proportional regression analyses. We performed meta-analyses to determine pooled estimates. RESULTS: We included 148,737 offspring and 169,510 offspring in analyses of exclusive and any breastfeeding duration, respectively. During median follow-up of 16.3-22.3 years, between 1996 and 2021, 543 offspring were diagnosed with IBD. In each country, there was no association between exclusive breastfeeding duration and offspring IBD risk after adjusting for birth year (Denmark), offspring sex, parental IBD status, maternal education, smoking during pregnancy, age at delivery, mode of delivery, preterm birth, and small for gestational age. The pooled adjusted hazard ratio for IBD was 1.24 (95% confidence interval, 0.94-1.62; Q = 0.16, I2 = 0.0%) and 1.02 (95% confidence interval, 0.85-1.21; Q = 1.45, I 2= 0.0%) among offspring breastfed exclusively for ≥6 months and <4 months, respectively, compared with 4-5 months. Similarly, we found null associations in pooled analyses of any breastfeeding duration and IBD, subtypes Crohn's disease and ulcerative colitis, as well as in cohort-specific analyses. CONCLUSIONS: In prospectively collected data from 3 population-based birth cohorts, the duration of exclusive or any breastfeeding was not associated with offspring IBD risk.

Association Between Celiac Disease and Irritable Bowel Syndrome: A Nationwide Cohort Study.

BACKGROUND & AIMS: The aim of this study was to determine the risk of irritable bowel syndrome (IBS) diagnosis in patients with celiac disease (CD) compared with general population comparators. METHODS: Using Swedish histopathology and register-based data, we identified 27,262 patients with CD diagnosed in 2002-2017 and 132,922 age- and sex-matched general population comparators. Diagnoses of IBS were obtained from nationwide inpatient and non-primary outpatient records. Cox regression estimated hazard ratios (aHRs) for IBS adjusted for education level and Charlson Comorbidity Index. To reduce potential surveillance bias our analyses considered incident IBS diagnosis ≥1 year after CD diagnosis. Using conditional logistic regression, secondary analyses were calculated to estimate odds ratios (ORs) for IBS diagnosis ≥1 year before CD diagnosis. RESULTS: During an average of 11.1 years of follow-up, 732 celiac patients (2.7%) were diagnosed with IBS vs 1131 matched general population comparators (0.9%). Overall (≥1-year of follow-up), the aHR for IBS was 3.11 (95% confidence interval [CI], 2.83-3.42), with aHR of 2.00 (95% CI, 1.63-2.45) after ≥10 years of follow-up. Compared with siblings (n = 32,010), celiac patients (n = 19,211) had ≥2-fold risk of later IBS (aHR, 2.42; 95% CI, 2.08-2.82). Compared with celiac patients with mucosal healing, those with persistent villus atrophy on follow-up biopsy were less likely to be diagnosed with IBS (aHR, 0.66; 95% CI, 0.46-0.95). CD was also associated with having an earlier IBS diagnosis (OR, 3.62; 95% CI, 3.03-4.34). CONCLUSIONS: In patients with CD, the risk of IBS is increased long before and after diagnosis. Clinicians should be aware of these long-term associations and their implications on patient management.

Economic Burden of Eosinophilic Esophagitis: A Nationwide Cost-of-Illness Study.

INTRODUCTION: Despite its increasing prevalence, the economic impact of eosinophilic esophagitis (EoE) is understudied. METHODS: We estimated the societal economic burden of EoE by using real-world data from Swedish health registers. RESULTS: Patients with EoE had 45% higher societal cost ($6,290 vs $4,349) compared with the general population, primarily driven by increased healthcare costs ($2,414 vs $1,022), which accounted for 72% of the excess societal cost in EoE. DISCUSSION: EoE is associated with a considerable economic burden to society. With the prevalence of EoE still rising, the economic burden of EoE is expected to continue to grow.

Atopic Dermatitis in Early Childhood and Risk of Inflammatory Bowel Disease: A Scandinavian Birth Cohort Study.

OBJECTIVE: To examine the association between early-life atopic manifestations and later risk of inflammatory bowel disease (IBD), for which prospective data are scarce. STUDY DESIGN: The population-based All Babies in Southeast Sweden (ABIS) and Norwegian Mother, Father, and Child (MoBa) cohorts follow children from birth (ABIS 1997-1999; MoBa 2000-2009) to the end of 2021. Based on validated questionnaires, parents prospectively reported information on asthma, food-related allergic symptoms, atopic dermatitis, and allergic rhinitis by age 3. IBD was defined by ≥ 2 diagnostic records in the national health registries. Cox regression estimated hazard ratios adjusted (aHRs) for parental IBD, atopy, education level, smoking habits, and national origin. Cohort-specific estimates were pooled using a random-effects model. RESULTS: We compiled data on 83 311 children (ABIS, n = 9041; MoBa, n = 74 270). In over 1 174 756 person-years of follow-up, 301 participants were diagnosed with IBD. Children with atopic dermatitis at age 3 had an increased risk of IBD (pooled aHR = 1.46 [95% CI = 1.13-1.88]), Crohn's disease (pooled aHR = 1.53 [95%CI = 1.04-2.26]), and ulcerative colitis (pooled aHR = 1.78 [95%CI = 1.15-2.75]). Conversely, any atopic manifestation by age 3 was not associated with IBD (pooled aHR = 1.20 [95%CI = 0.95-1.52]), nor were analyses specifically focused on early-life food-related allergic symptoms, asthma, and allergic rhinitis. CONCLUSION: While atopic manifestations in early childhood were overall not associated with IBD, children with atopic dermatitis specifically were at increased risk of developing IBD, suggesting shared etiologic traits; these findings might be useful in identifying at-risk individuals for IBD.

Associations of pregnancy dietary quality and diversity with childhood celiac disease.

BACKGROUND AND OBJECTIVE: High gluten and low dietary fiber in pregnancy intake is associated with an increased risk of celiac disease in the child. Early life higher dietary quality is suggested to reduce the subsequent risk of celiac disease. The aim was to investigate associations of pregnancy dietary quality and diversity with child risk of celiac disease (CeD). METHODS: In The Norwegian Mother, Father and Child Cohort Study, 85,122 mother-child pairs had available data from a validated pregnancy food frequency questionnaire. Pregnancy dietary quality and diversity were estimated by a Pregnancy Healthy Eating Index, (mean 99.3, SD 9.9, range 48.8-128.3), and a Diet Diversity Score (mean 7.0, SD 1.0, range 1.6-9.8), respectively. Child CeD was captured by >2 diagnostic codes in the Norwegian Patient Registry. Logistic regression was used to estimate associations between pregnancy dietary quality, diversity and child CeD, adjusted for socio-economic factors and parents CeD (adjusted odds ratio [aOR], 95% confidence intervals [CI]). CeD-susceptible HLA haplotypes (DQ2/DQ8) were present in 30,718 (45.5%). RESULTS: Up to mean age 16.0 (SD 1.8, 12.4-19.8) years, 1,363 (1.6%) children were diagnosed with CeD. Lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD in the child (<5th percentile aOR=0.67, 95%CI 0.48-0.93, >95th percentile aOR=0.71, 95%CI 0.52-0.98, respectively, non-linear squared term p= 0.011). Analyses on genetically susceptible children, adjustments for pregnancy iron supplementation, gluten, and dietary fiber intake, and child early life dietary quality, gluten intake and iron supplementation, supported the finding. Pregnancy dietary diversity was not associated with child CeD (aOR=1.00, 95%CI 0.94-1.07/score) CONCLUSIONS: In this population-based study, lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD diagnosis in the child. In contrast, no such association was observed with maternal dietary diversity.

Higher incidence of paediatric inflammatory bowel disease by increasing latitude in Norway, but stable incidence by age.

AIM: To examine possible geographical and temporal differences in the incidence of childhood-onset inflammatory bowel disease (IBD) in Norway, motivated by previous research indicating relevant environmental factors explaining changing epidemiology. METHODS: We analysed data from children born in Norway from 2004 to 2012 (n = 541 036) in a registry-based nationwide study. After validating registry diagnoses against medical records, we defined IBD as ≥2 entries of International Classification of Diseases, 10th revision (ICD-10) codes K50, K51 and K52.3 in the Norwegian Patient registry. We estimated hazard ratios (HR) for IBD across four geographical regions with a south-to-north gradient and the incidence by period of birth. RESULTS: By the end of follow-up on 31 December 2020, 799 IBD diagnoses were identified (Crohn's disease: n = 465; ulcerative colitis, n = 293, IBD: unclassified, n = 41). Compared to children in the southernmost region, there was almost a two-fold HR for IBD in children in the most Northern region (HR = 1.94, 95% Cl = 1.47-2.57; Mid region: HR = 1.68, 95% CI = 1.29-2.19, ptrend <0.001). These estimates remained largely unchanged after adjustment for potential confounding factors. The cohorts born in 2004-2006 and 2010-2012 had comparable cumulative incidences, with a slightly higher incidence for those born in 2007-2009. CONCLUSION: We observed an increase in the risk of IBD by increasing latitude which may suggest that environmental factors influence the development of IBD, although non-causal explanations cannot be ruled out.

Epidemiology, validation, and clinical characteristics of inflammatory bowel disease: the ABIS birth cohort study.

BACKGROUND: Birth cohort studies with linked register-based data on inflammatory bowel disease (IBD) provide opportunities to prospectively study early-life determinants of the disease. However, register-based data often lack information on clinical characteristics and rely on diagnostic algorithms. Within the All Babies in Southeast Sweden (ABIS) cohort, we examined the validity of a register-based definition of IBD, its incidence, and clinical and therapeutic characteristics at diagnosis. METHODS: We followed 16,223 children from birth (1997-1999) until the end of 2020 for the diagnosis of IBD as defined by a minimum of two diagnostic codes for IBD in the Swedish National Patient Register (NPR). We described the incidence and cumulative incidence of IBD. Through a medical record review of cases diagnosed by the end of 2017, we examined the positive predictive value (PPV) for IBD and described its clinical characteristics and treatment. RESULTS: By 2020, at an average age of 22.2 years, 113 participants (0.74%, 95% confidence interval [CI] = 0.61-0.89) had a register-based diagnosis of IBD, corresponding to an incidence of 31.3 per 100,000 person-years of follow-up; the incidence for Crohn's disease (CD) was 11.1 per 100,000 person-years and 15.8 for ulcerative colitis (UC). Of 77 participants with a register-based definition of IBD by the end of 2017, medical records were identified for 61 participants, of whom 57 had true IBD (PPV = 93%; 95%CI = 0.87-1.00). While oral 5-aminosalicylic acid treatment was equally common in newly diagnosed CD and UC patients, biologics were more often used for newly diagnosed CD. The median faecal calprotectin levels were 1206 mg/kg at diagnosis and 93 mg/kg at the last follow-up (P < 0.001). CONCLUSIONS: In this population-based sample of Swedish children and young adults the cumulative IBD incidence was 0.74. The validity of register-based definition of IBD was high and supports using such data to identify IBD patients in cohort studies.

Lack of Follow-Up for Celiac Disease During Childhood Not Associated With Poor Health Outcomes: A Regional Swedish Cohort Study.

OBJECTIVES: The objective of the study is to examine the association between the lack of follow-up for celiac disease (CD) during childhood and dietary adherence, disease remission, and health-related quality of life (HRQoL). METHODS: We invited 243 randomly selected children diagnosed with CD in 2013-2018 in Gothenburg, Sweden, and 162 consented to participate (67%). We retrieved information on clinical follow-up and current wellbeing using medical and laboratory records data, as well as validated questionnaires on symptoms of CD, dietary adherence, and HRQoL. We analyzed tissue-transglutaminase antibodies (tTGA) as a measure of disease remission. We defined lack of follow-up as no CD-related physician/dietician-led visit or measurement of tTGA over the past 24 months of study enrollment. RESULTS: The mean age at study enrolment was 12.7 (range 7.8-18.2) years. Out of 162 children with an average disease duration of 5.3 (range 2.3-8.8) years, 23 (14%) lacked follow-up. tTGA had normalized in 94% [95% confidence interval (CI) = 71%-100%] of children without follow-up versus 91% (95% CI: 85%-95%) of children with continued follow-up. Of children without follow-up, 65% (95% CI: 38%-86%) reported a dietary adherence score indicating very good adherence, versus 72% (95% CI: 63%-80%) of those with continued follow-up. Also, lack of follow-up was not significantly associated with growth, symptom scores, or HRQoL. CONCLUSIONS: In this regional cohort study of mostly older children and adolescents, lack of follow-up for CD was not significantly linked to dietary adherence, disease remission, or HRQoL. How these results hold in larger, unselected samples with longer follow-up, including transition to adult care, warrants further study.

Regional Swedish study found that one in seven coeliac patients experienced loss of follow up during childhood.

AIM: To examine the clinical follow up of paediatric coeliac disease and the rate of loss of follow up during childhood, for which data are scarce. METHODS: In a cohort of coeliac children diagnosed in 2013-2018 in Gothenburg, Sweden, we retrospectively explored the follow-up practice of paediatric coeliac disease until June 2021. We used medical records from hospital-based paediatric gastroenterology and general paediatric outpatient clinics, laboratory records, and questionnaires. Loss of follow up was defined no coeliac disease-related follow up or tissue transglutaminase test over the past 2 years of study enrolment. RESULTS: We included 162 children (58% girls) aged 7.8-18.2 years (average 12.7). Most participants (76%) were followed at general paediatric outpatient clinics rather than hospital-based clinics. After 2.3-8.8 (average 5.3) years since diagnosis, 23 patients (14%; 95% confidence interval, 9%-21%) had been lost to follow up. Patients with loss of follow up were more often boys (61% versus 39%, p = 0.08), with a somewhat longer average disease duration of 5.8 versus 5.2 years (p = 0.11). There were no between-group differences in socio-economic characteristics and patient-reported experience measures of coeliac disease care. CONCLUSION: One in seven coeliac patients may experience loss of follow up during childhood.

Cancer Risk in 47,241 Individuals With Celiac Disease: A Nationwide Cohort Study.

BACKGROUND & AIMS: Celiac disease (CD) is associated with increased mortality, in part due to cancer. Most studies investigating this cancer risk involved patients diagnosed before widespread increases in CD diagnosis rates and access to gluten-free food. We performed a population-based study of the risk of cancer in CD. METHODS: We identified all patients in Sweden with CD as defined as duodenal/jejunal villus atrophy, using the Epidemiology Strengthened by histoPathology Reports in Sweden cohort. Each patient was matched to ≤5 controls by age, sex, and county. We used stratified Cox proportional hazards model, following patients from diagnosis until first cancer, or by December 31, 2016. RESULTS: Among 47,241 patients with CD, 30,080 (64%) were diagnosed since 2000. After a median follow-up of 11.5 years, the incidence of cancer was 6.5 and 5.7 per 1000 person-years in CD patients and controls, respectively. The overall risk of cancer was increased (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.07-1.15), but it was only significantly elevated in the first year after CD diagnosis (HR, 2.47; 95% CI, 2.22-2.74) and not subsequently (HR, 1.01; 95% CI, 0.97-1.05), although the risks of hematologic, lymphoproliferative, hepatobiliary, and pancreatic cancers persisted. The overall risk was highest in those diagnosed with CD after age 60 years (HR, 1.22; 95% CI, 1.16-1.29) and was not increased in those diagnosed before age 40. The cancer risk was similar among those diagnosed with CD before or after the year 2000. CONCLUSIONS: There is an increased risk of cancer in CD even in recent years, but this risk increase is confined to those diagnosed with CD after age 40 and is primarily present within the first year of diagnosis.

Work Loss in Patients With Celiac Disease: A Population-based Longitudinal Study.

BACKGROUND & AIMS: Celiac disease (CD) affects around 1% of the population worldwide. Data on work disability in patients with CD remain scarce. We estimated work loss in patients with CD, including its temporal relationship to diagnosis. METHODS: Through biopsy reports from Sweden's 28 pathology departments, we identified 16,005 working-aged patients with prevalent CD (villus atrophy) as of January 1, 2015, and 4936 incident patients diagnosed with CD in 2008 to 2015. Each patient was matched to up to 5 general-population comparators. Using nationwide social insurance registers, we retrieved prospectively recorded data on compensation for sick leave and disability leave to assess work loss in patients and comparators. RESULTS: In 2015, patients with prevalent CD had a mean of 42.5 lost work days as compared with 28.6 in comparators (mean difference, 14.7; 95% confidence interval [CI], 13.2-16.2), corresponding to a relative increase of 49%. More than one-half of the work loss (60.1%) in patients with CD was derived from a small subgroup (7%), whereas 75.4% had no work loss. Among incident patients, the annual mean difference between patients and comparators was 8.0 days (range, 5.4-10.6 days) of lost work 5 years before CD diagnosis, which grew to 13.7 days (range, 9.1-18.3 days) 5 years after diagnosis. No difference in work loss was observed between patients with or without mucosal healing at follow-up. CONCLUSIONS: Patients with CD lost more work days than comparators before their diagnosis, and this loss increased after diagnosis. Identifying patients with an increased risk of work loss may serve as a target to mitigate work disability, and thereby reduce work loss, in patients with CD.

Celiac Disease and Serious Infections: A Nationwide Cohort Study From 2002 to 2017.

INTRODUCTION: Patients with celiac disease (CD) have an increased risk of encapsulated bacterial infections. Less is known about other serious infections in CD, especially in patients diagnosed in the 21st century. METHODS: We contacted all 28 pathology departments in Sweden through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) cohort study and identified 20,088 individuals with CD (defined as villous atrophy) diagnosed in 2002-2017. Patients were matched for sex, age, and calendar year to 80,152 general population comparators and followed up until December 31, 2019. Serious infections were defined as having a hospital-based (inpatient and outpatient) diagnosis in the National Patient Register. Cox regression yielded adjusted hazard ratios (aHR) controlling for education, country of birth, and comorbidities. RESULTS: During 173,695 person-years of follow-up, 6,167 individuals with CD (35.5/1,000 person-years) had a serious infection. This was compared with 19,131 infections during 743,260 person-years (25.7/1,000 person-years) in matched comparators, corresponding to an aHR of 1.29 (95% confidence interval [CI] = 1.25-1.33). aHR were similar when restricted to infection requiring hospital admission (1.23; 95% CI = 1.17-1.29). The excess risk of serious infections also persisted beyond the first year after CD diagnosis (aHR = 1.24; 95% CI = 1.20-1.29). Patients with CD were at risk of sepsis (aHR = 1.26; 95% CI = 1.09-1.45) and gastrointestinal infections (1.60; 95% CI = 1.47-1.74). Mucosal healing during CD follow-up did not influence the risk of subsequent serious infections. DISCUSSION: This nationwide study of patients with celiac disease diagnosed in the 21st century revealed a significantly increased risk of serious infections. While absolute risks were modest, vaccinations should be considered during CD follow-up care.

Association of Celiac Disease and Inflammatory Bowel Disease: A Nationwide Register-Based Cohort Study.

INTRODUCTION: To determine the risk of inflammatory bowel disease (IBD) in patients with celiac disease (CeD) (and vice versa ) compared with general-population comparators. METHODS: Using Swedish histopathology and healthcare register data, we identified 48,551 patients with CeD and 83,529 with IBD diagnosed in 1969-2016. Each patient was compared with age- and sex-matched general-population comparators (CeD: n = 240,136; IBD: n = 408,195). Cox regression estimated hazard ratios (HRs) for IBD in patients with CeD and vice versa . Our main analyses were limited to events beyond the first year of follow-up to reduce potential surveillance bias. RESULTS: During follow-up, 784 (1.6%) patients with CeD were diagnosed with IBD compared with 1,015 (0.4%) matched comparators. In patients with CeD, the HR for IBD was 3.91 (95% confidence interval [CI] 3.56-4.31), with largely similar HRs for Crohn's disease (4.36; 3.72-5.11) and ulcerative colitis (3.40; 3.00-3.85). During follow-up, 644 (0.8%) patients with IBD and 597 (0.1%) comparators were diagnosed with CeD. The HR for CeD in patients with IBD was 5.49 (95% CI 4.90-6.16), with the highest risk estimates seen in ulcerative colitis (HR = 6.99; 6.07-8.05), and the HR for Crohn's disease was 3.31 (2.69-4.06). In patients with CeD and IBD, the diagnostic interval was usually <1 year; however, HRs of 3-4 were seen even after 10 years of follow-up. During 20 years of follow-up, 2.5% of patients with CeD developed incident IBD, and 1.3% of patients with IBD developed CeD. DISCUSSION: The bidirectional association between CeD diagnosis and IBD warrants attention in the initial assessment and follow-up of these conditions. Their co-occurrence, independent of temporal sequence, suggests shared etiology.

Celiac disease screening at a pediatric outpatient clinic: a feasibility study.

OBJECTIVES: Celiac disease (CD) is a common yet largely underdiagnosed disease. This study aimed to test the feasibility of incorporating a non-targeted CD screening in a pediatric outpatient setting and evaluate its short-term impact on children with serological evidence of disease. METHODS: Over five months, 500 children (aged 2-17 years) attending a general pediatric outpatient clinic in Gothenburg, Sweden, were enrolled and surveyed for current symptoms, quality of life, and background characteristics; 481 children were screened for tissue-transglutaminase antibodies (tTGA); repeated tTGA-positivity was defined as CD autoimmunity (CDA). Children with CDA were investigated for CD and for one year monitored for changes in symptoms, and quality of life. RESULTS: Eleven of 481 (2.3%) screened children had CDA. Children with CDA were younger (median 3.8 years) than those without CDA (8.8 years). No other major between-group differences were reported in background characteristics, symptoms, or quality of life. The screening was well-accepted by the families/participants. During 1-year follow-up, 8 of 11 children with CDA were diagnosed with CD. Children with screening-detected CD reported no significant changes in symptoms and quality of life and the dietary adherence rate was good. CONCLUSIONS: Non-targeted screening for CD was feasible in a general pediatric outpatient setting. While hampered by small sample size, our results are in line with previous screening studies indicating that symptoms do not differentiate CDA from non-CDA children. Also, among an overall minimal-symptomatic group of children, diagnosing CD and installation of treatment did not significantly change their well-being during 1-year follow-up.

Utilization and Effectiveness of eHealth Technology in the Follow-up of Celiac Disease: A Systematic Review.

OBJECTIVES: To systematically review the literature on the utilization and effectiveness of electronic-health technologies (eHealth), such as smartphone applications, in managing patients with celiac disease (CD). METHODS: PubMed, Scopus, and the Cochrane Library were all searched (until February 2021). Inclusion criteria were full-text English articles reporting original data on the use of eHealth technologies in the follow-up of CD patients, with no age restriction. Exclusion criteria were studies only using non-interactive websites and phone consultation as the primary eHealth method. The results were summarized narratively. RESULTS: Using identified keywords, 926 unique studies were identified. After title and abstract screening by two independent reviewers, 26 studies were reviewed in full text. Finally, eight studies were included in this systematic review, and their quality appraised using standardized forms. Of the eight studies, six were randomized-controlled trials, one mixed-methods study, and one cross-sectional, observational study. Studies were assessed to be of "low" to "moderate" methodological quality. Studied eHealth technologies included web-based interventions, smartphone applications, text messaging, and online consultations. The most consistently reported effects related to improved quality of life (number of studies = 4), knowledge on CD (n = 3), and dietary adherence (n = 2); notably, only one study reported reduced costs of eHealth vs. standard (in-office) care. CONCLUSIONS: Although eHealth has the potential to improve the management of CD, so far, the research in the field is scarce and generally of low-moderate methodological quality. Hence, the effectiveness of eHealth in CD management remains uncertain, and more high-quality evidence is required before its utility is known.

ESPGHAN Position Paper on Management and Follow-up of Children and Adolescents With Celiac Disease.

OBJECTIVES: To gather the current evidence and to offer recommendations for follow-up and management. METHODS: The Special Interest Group on Celiac Diseases of the European Society of Paediatric Gastroenterology Hepatology and Nutrition formulated ten questions considered to be essential for follow-up care. A literature search (January 2010-March 2020) was performed in PubMed or Medline. Relevant publications were identified and potentially eligible studies were assessed. Statements and recommendations were developed and discussed by all coauthors. Recommendations were voted upon: joint agreement was set as at least 85%. RESULTS: Publications (n = 2775) were identified and 164 were included. Using evidence or expert opinion, 37 recommendations were formulated on: The need to perform follow-up, its frequency and what should be assessed, how to assess adherence to the gluten-free diet, when to expect catch-up growth, how to treat anemia, how to approach persistent high serum levels of antibodies against tissue-transglutaminase, the indication to perform biopsies, assessment of quality of life, management of children with unclear diagnosis for which a gluten-challenge is indicated, children with associated type 1 diabetes or IgA deficiency, cases of potential celiac disease, which professionals should perform follow-up, how to improve the communication to patients and their parents/caregivers and transition from pediatric to adult health care. CONCLUSIONS: We offer recommendations to improve follow-up of children and adolescents with celiac disease and highlight gaps that should be investigated to further improve management.