Early Initiation of Biologics and Disease Outcomes in Adults and Children With Inflammatory Bowel Diseases: Results From the Epidemiology Group of the Nationwide Israeli Inflammatory Bowel Disease Research Nucleus Cohort.

BACKGROUND & AIMS: In this nationwide study, we explored whether early initiation of biologics is associated with improved outcomes in children and adults with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: All patients diagnosed with CD or UC in Israel (2005-2020) were included in the Epidemiology Group of the Israeli Inflammatory Bowel Disease Research Nucleus cohort, encompassing 98% of the population. We compared disease duration at biologics initiation (ie, 0-3 months, >3-12 months, >1-2 years, and >2-3 years) using the cloning, censoring, and weighting by inverse probabilities method to emulate a target trial, adjusting for time-varying confounders and selection bias. RESULTS: Of the 34,375 included patients (of whom 5240 [15%] were children), 7452 of 19,264 (39%) with CD and 2235 of 15,111 (15%) with UC received biologics. In CD, by 10 years postdiagnosis, the probability of CD-related surgery decreased gradually but modestly with earlier initiation of biologics; a significant difference was noted between >2-3 years (31%) and 0-3 months (18%; P = .02; number needed to treat, 7.7), whereas there was no difference between the 0-3-month and >3-12-month periods. The 10-year probability of steroid dependency for the 0-3-month period (19%) differed both from the >2-3-year (31%; P < .001) and 1-2-year periods (37%; P < .001). In UC, no significant differences in colectomy or steroid dependency rates were observed between the treatment initiation periods. Similar trends were noted in the pediatric population. CONCLUSIONS: Very early initiation of biologics was not associated with some outcomes except for a modest risk reduction of surgery and steroid dependency for CD, which requires confirmation in future studies. In UC, early introduction of biologics was not associated with reduced risk of colectomy or steroid dependency.

Familial Mediterranean fever in patients with inflammatory bowel diseases: A nationwide study from the epi-IIRN.

BACKGROUND AND AIMS: Inflammatory Bowel Diseases (IBD) and Familial Mediterranean Fever (FMF) are auto-inflammatory diseases with common clinical and biological features. We aimed to determine their association and characterize the natural history in patients with both diagnoses. METHODS: Utilizing data from the epi-IIRN cohort, which includes 98% of Israel's population, we calculated the adjusted prevalence of FMF among IBD patients vs non-IBD controls. Case ascertainment of IBD was determined according to validated algorithms and for FMF by ICD-9 codes and colchicine purchase. RESULTS: In total, 34 375 IBD patients (56% Crohn's disease [CD] and 44% ulcerative colitis [UC]) were compared with 93 602 matched controls. Among IBD patients, 157 (0.5%) had FMF compared with 160 (0.2%) of non-IBD controls (OR = 2.68 [95%CI 2.2-3.3]; p< 0.001). Pediatric-onset IBD had a higher prevalence of FMF compared with adult-onset IBD (30/5,243 [0.6%] vs 127/29 132 [0.4%]), without statistical significanse (OR = 1.31 [0.88-1.96]; p= 0.2). FMF was more prevalent in CD (114/19 264 [0.6%]) than UC (43/15 111 [0.3%]; OR = 2.1 [1.5-3.0]), p< 0.001). FMF diagnosis preceded that of IBD in 130/157 cases (83%). FMF was associated with a more severe disease activity in UC patients at diagnosis, but not in CD patients. Outcomes were comparable between patients with CD+FMF vs CD alone; however in patients with UC+FMF, time to biologic treatment was shorter. CONCLUSION: FMF is more prevalent in IBD patients than in the general population, particularly in CD. The diagnosis of FMF precedes the diagnosis of IBD in most cases, and may be associated with a more severe course in UC.

Nationwide Evaluation of Quality of Care Indicators for Individuals with Severe Mental Illness and Diabetes Mellitus, Following Israel's Mental Health Reform.

Diabetes Mellitus (DM) is more common among individuals with severe mental illness (SMI). We aimed to assess quality-of-care-indicators in individuals with SMI following the 2015 Israel's Mental-Health-reform. We analyzed yearly changes in 2015-2019 of quality-of-care-measures and intermediate-DM-outcomes, with adjustment for gender, age-group, and socioeconomic status (SES) and compared individuals with SMI to the general adult population. Adults with SMI had higher prevalences of DM (odds ratio (OR) = 1.64; 95% confidence intervals (CI): 1.61-1.67) and obesity (OR = 2.11; 95% CI: 2.08-2.13), compared to the general population. DM prevalence, DM control, and obesity rates increased over the years in this population. In 2019, HbA1c testing was marginally lower (OR = 0.88; 95% CI: 0.83-0.94) and uncontrolled DM (HbA1c > 9%) slightly more common among patients with SMI (OR = 1.22; 95% CI: 1.14-1.30), control worsened by decreasing SES. After adjustment, uncontrolled DM (adj. OR = 1.02; 95% CI: 0.96-1.09) was not associated with SMI. Cardio-metabolic morbidity among patients with SMI may be related to high prevalences of obesity and DM rather than poor DM control. Effective screening for metabolic diseases in this population and social reforms are required.

Incidence, Management, and Outcomes of Very Early Onset Inflammatory Bowel Diseases and Infantile-Onset Disease: An Epi-IIRN Study.

BACKGROUND & AIMS: In this nationwide study from the Israeli Inflammatory Bowel Disease Research Nucleus, we aimed to describe the incidence of very early onset inflammatory bowel diseases (VEOIBDs) with a focus on infantile-onset disease and to compare management and disease course with older children. METHODS: Data were retrieved from the 4 Israeli Health Maintenance Organizations covering 98% of the population. Pediatric-onset IBD was categorized as follows: adolescent onset (10 to <18 y), early onset (6 to <10 y), VEOIBD (0 to <6 y), toddler onset (2 to <6 y), and infantile onset (<2 y). RESULTS: A total of 5243 children with 35,469 person-years of follow-up evaluation, were diagnosed with IBD during 2005 to 2020: 4444 (85%) with adolescent onset, 548 (10%) with early onset, and 251 (4.8%) with VEOIBD, of whom 81 (1.5%) had infantile onset. The incidence of pediatric-onset IBD increased from 10.8 per 100,000 in 2005 to 15.3 per 100,000 in 2019 (average annual percentage change, 2.8%; 95% CI, 2.2%-3.4%), but that of VEOIBD remained stable (average annual percentage change, 0%; 95% CI, -2.5% to 2.6%). The infantile-onset and toddler-onset groups were treated less often with biologics (36% and 35%, respectively) vs the early onset (57%) and adolescent-onset groups (53%; P < .001). The time to steroid dependency was shorter in infantile-onset (hazard ratio [HR], 2.1; 95% CI, 1.5-2.9) and toddler-onset disease (HR, 1.6; 95% CI, 1.2-2.0) vs early onset and adolescent-onset disease, but time to hospitalizations, time to surgery, and growth delay were worse only in infantile-onset disease. In a multivariable model, infantile-onset patients had a higher risk for surgery (HR, 1.4; 95% CI, 1.1-1.9) and hospitalization (HR, 1.7; 95% CI, 1.2-2.4) than the toddler-onset group. CONCLUSIONS: The incidence of VEOIBD remained stable. Infantile-onset IBD had worse outcomes than older children, while toddler onset had mostly similar outcomes, despite less frequent use of biologics.

COVID-19 Vaccine Is Effective in Inflammatory Bowel Disease Patients and Is Not Associated With Disease Exacerbation.

BACKGROUND & AIMS: Studies have shown decreased response to coronavirus disease 2019 (COVID-19) vaccinations in some populations. In addition, it is possible that vaccine-triggered immune activation could trigger immune dysregulation and thus exacerbate inflammatory bowel diseases (IBD). In this population-based study we used the epi-Israeli IBD Research Nucleus validated cohort to explore the effectiveness of COVID-19 vaccination in IBD and to assess its effect on disease outcomes. METHODS: We included all IBD patients insured in 2 of the 4 Israeli health maintenance organizations, covering 35% of the population. Patients receiving 2 Pfizer-BioNTech BNT162b2 vaccine doses between December 2020 and June 2021 were individually matched to non-IBD controls. To assess IBD outcomes, we matched vaccinated to unvaccinated IBD patients, and response was analyzed per medical treatment. RESULTS: In total, 12,109 IBD patients received 2 vaccine doses, of whom 4946 were matched to non-IBD controls (mean age, 51 ± 16 years; median follow-up, 22 weeks; interquartile range, 4-24). Fifteen patients in each group (0.3%) developed COVID-19 after vaccination (odds ratio, 1; 95% confidence interval, 0.49-2.05; P = 1.0). Patients on tumor necrosis factor (TNF) inhibitors and/or corticosteroids did not have a higher incidence of infection. To explore IBD outcomes, 707 vaccinated IBD patients were compared with unvaccinated IBD patients by stringent matching (median follow-up, 14 weeks; interquartile range, 2.3-20.4). The risk of exacerbation was 29% in the vaccinated patients compared with 26% in unvaccinated patients (P = .3). CONCLUSIONS: COVID-19 vaccine effectiveness in IBD patients is comparable with that in non-IBD controls and is not influenced by treatment with TNF inhibitors or corticosteroids. The IBD exacerbation rate did not differ between vaccinated and unvaccinated patients.

How compassionate use enabled Israel to deliver the Pfizer-BioNTech COVID-19 vaccination to vulnerable children aged 12-15 years before regulatory approval.

AIM: This paper describes the emergency, compassionate use of the COVID-19 vaccination for high-risk adolescents aged 12-15 years prior to approval by the American Food and Drugs Administration in May 2021. The target audience had underlying health conditions associated with severe disease and multisystem inflammatory syndrome in children (MIS-C) or severely immunosuppressed household members. METHODS: An orderly approval system was established in Israel for adolescents aged 12-15 years, based on a professional position paper and compassionate treatment regulations. From 12 February 2021, eligible adolescents were referred to the Israeli Ministry of Health for permission to vaccinate, via four health maintenance organisations. Data were collected about adverse events after vaccinations and the incidence of any cases of COVID-19. RESULTS: By 15 March 2021, the vaccine had been approved for 607 adolescents: 333 had received one dose, and 92 had received two doses. The median age was 14.6 years, and the major indication was obesity. Only one child tested positive for the virus, 4 days after vaccination, and no adverse effects were recorded. CONCLUSION: The emergency use of COVID-19 vaccination for 333 adolescents aged 12-15, 92 of them with 2 doses, based on a position paper and compassionate treatment regulations, did not result in any adverse effects. Since 27 July 2021, the same process was further applied in Israel among younger children, aged 5-11, preceding formal release of the clinical trial.

Israeli COVID lockdowns mildly reduced overall use of preventive health services, but exacerbated some disparities.

BACKGROUND: During 2020, Israel experienced two COVID-19-related lockdowns that impacted the provision of primary and secondary preventive care. METHODS: We examined the month-by-month performance of selected preventive care services using data from Israel's national Quality Indicators in Community Healthcare program. Process of care measures included hemoglobin A1c (HbA1c) testing, cholesterol testing, colon cancer screening and mammography. Intermediate outcome measures included low-density lipoprotein control and HbA1c control. Measures were stratified by sex and by area-level socioeconomic position (SEP). Diabetes and mammography are presented in this abstract due to space limitations. RESULTS: Annual HbA1c testing among persons with diabetes decreased from 90.9% in 2019 to 88.0% in 2020. Performance of HbA1c tests during lockdown months was as low as half the usual amount. There were compensatory increases in testing during post-lockdown months that did not quite make up for the missed tests. In 2019, 9.0% of Israelis with diabetes had poor glycemic control (HbA1c ≥ 9.0); in 2020, it was 8.8%. In total, 4.5% fewer mammograms were performed in 2020 compared with 2019. Women in the lowest SEP level performed 10.4% fewer mammograms in 2020 than in 2019, while women in the highest SEP level performed 3.1% more mammograms. CONCLUSIONS: Prolonged COVID lockdowns in 2020 were associated with marked decreases in the performance of preventive health services during those months. Compensatory spikes following the end of lockdowns partly, but did not completely, make up for the missed care. COVID lockdowns may have exacerbated socioeconomic disparities in some preventive health services.

Pediatric-onset Inflammatory Bowel Disease Has Only a Modest Effect on Final Growth: A Report From the epi-IIRN.

OBJECTIVES: The impact of pediatric-onset inflammatory bowel disease (IBD) on growth is debated. We aimed to investigate the effect of IBD on anthropometric measures at young adulthood. METHODS: Children diagnosed with Crohn disease (CD) or ulcerative colitis (UC) (2005-2019) were identified in a national database along with matched non-IBD controls. RESULTS: Overall, 2229 IBD cases (68% CD) were matched to 4338 controls. Only females with CD differed in final height from controls (z scores: -0.37 ±â€Š1.09 vs -0.25 ±â€Š1.06, respectively; P = 0.01), corresponding to a mean difference of 0.7 ±â€Š0.2 cm (all females) and 1.2 ±â€Š0.3 cm in females diagnosed <14 years (P = 0.02). Final height was reduced in both sexes according to adjusted mean height difference analysis (-0.43 cm, 95% confidence interval -0.85 to -0.02; P = 0.04). This difference increased in patients with CD who underwent abdominal surgery (-0.91 cm, 95% confidence interval -1.39 to -0.42; P = 0.01). The proportion of patients with CD achieving final height z scores of -1 and zero differed significantly from controls for both males (71.1% and 34.8% vs 79.1% and 43.0%, respectively; P < 0.001) and females (67.7% and 30.4% vs 79.6%, and 43.3%, respectively; P < 0.001). Patients treated with anti-tumor necrosis factor agents during growth potential had similar height improvement to other regimens. Predominantly, patients with CD were leaner, with a greater proportion of subjects with underweight, compared with controls. CONCLUSIONS: In pediatric-onset IBD, absolute final height was modestly affected by females with CD. Nevertheless, greater proportions of both sexes with early diagnosis of CD failed to achieve normal final height, compared with controls.

Enteral nutrition compared with corticosteroids in children with Crohn's disease: A long-term nationwide study from the epi-IIRN.

BACKGROUND: Both corticosteroids and exclusive enteral nutrition (EEN) have been used as induction therapy in children with Crohn's disease (CD). AIM: To compare in a nationwide study the long-term outcomes of children with CD receiving either EEN or corticosteroids as induction therapy. METHODS: We retrieved data of all children diagnosed with CD (2005-2020) from the epi-IIRN cohort covering 98% of the Israeli population. The primary outcome was time to complicated disease course (i.e., surgery, steroid-dependency, or at least 2 biologic class). Patients were matched individually utilising propensity score adjustments. RESULTS: We included 410 children treated with EEN and 375 with corticosteroids without other treatments (median follow-up, 4.73 [IQR: 2.2-7.2] years [1433 patient-years]). For 274 matched children, the probability of a complicated course was higher with corticosteroids than EEN at 0.5, 3 and 5 years (14% vs. 4%, 42% vs. 27% and 54% vs. 41%, respectively, p = 0.0066), despite similar use of biologics. Steroid-dependency (10% vs. 2%, 15% vs. 3%, and 20% vs. 5%, respectively, p = 0.00018), and hospitalisations (20% vs. 11%, 37% vs. 26%, and 55% vs. 38%, respectively, p = 0.002) were higher with corticosteroids. During follow-up, children receiving corticosteroids as induction treatment were more often further exposed to corticosteroids, and those on EEN were more often further exposed to nutritional treatment (p < 0.001). Induction with EEN had no advantage over corticosteroids regarding survival probability of surgeries, biologic use and growth. CONCLUSIONS: EEN in paediatric CD is associated with lower long-term risks of corticosteroid dependency and hospitalisation than corticosteroids. These results may lend support to favouring nutritional therapy in paediatric CD.

Durability of the First Biologic in Patients with Crohn's Disease: A Nationwide Study from the epi-IIRN.

BACKGROUND: In this nationwide study we aimed to compare the durability of the first initiated biologic in Crohn's disease [CD], stratified by monotherapy and combotherapy. METHODS: We used data from the epi-IIRN cohort, which includes 98% of the Israeli inflammatory bowel disease population [2005-2020]. Durability was defined as consistent treatment without surgery or added medications [except for combination therapy with thiopurines or methotrexate]. All comparisons were based on stringent propensity-score matching and paired time-to-event analyses. RESULTS: A total of 19 264 patients with CD were included, of whom 7452 [39%] received biologics with a median follow-up of 6.8 years (interquartile range [IQR] 3.6-10.7). Time to biologics decreased gradually from 6.7 years [IQR 2.7-10.4] in 2005 to 0.2 years [0.07-0.23] in 2020. The durability of the first biologic after 1 and 3 years was higher with adalimumab monotherapy [88%/61%] than vedolizumab monotherapy [81%/59%; n = 394 matched patients, p = 0.04] and similar between infliximab monotherapy and vedolizumab monotherapy [65%/43%; n = 182 matched patients, p = 0.1]. Durability was higher in adalimumab monotherapy vs infliximab monotherapy [83%/62% vs 71%/48% at 1/3 years; p <0.001] and it was similar in adalimumab monotherapy vs infliximab combotherapy [87%/63% vs 80%/58%, respectively; p = 0.1]. Durability was higher in combotherapy compared with monotherapy for both infliximab [85%/64% vs 67%/43%, respectively; n = 496 matched pairs, p <0.001], and adalimumab [93%/76% vs 82%/62%, respectively; n = 540 matched pairs, p <0.001]. CONCLUSION: Durability of the first biologic in CD was highest for adalimumab monotherapy. Combotherapy further increased the durability of adalimumab and infliximab. Unless otherwise indicated, our data may support using anti-tumour necrosis factors [TNFs] as first-line biologics in CD, particularly adalimumab if monotherapy is advised.

Residence in Peripheral Regions and Low Socioeconomic Status Are Associated With Worse Outcomes of Inflammatory Bowel Diseases: A Nationwide Study From the epi-IIRN.

BACKGROUND: Timely access to quality medical care impacts patient outcomes in inflammatory bowel disease (IBD). In a nationwide study from the epidemiology group of the Israeli IBD research nucleus we aimed to assess the impact of residence and socioeconomic status (SES) on disease outcomes. METHODS: We utilized data from the 4 health maintenance organizations in Israel, representing 98% of the population. Regions were defined as central, northern and southern; SES was graded from lowest to highest (from 1 to 4) as per Israel Central Bureau of Statistics. The primary outcome was steroid dependency, with secondary outcomes of surgeries and biologic therapy use. RESULTS: A total of 28 216 IBD patients were included: 15 818 (56%) Crohn's disease (CD) and 12 398 (44%) ulcerative colitis; 74%, 12% and 14% resided in central, southern, and northern Israel, respectively (SES 1: 21%, SES 4: 12%). Lower SES was associated with steroid dependency (20% in SES 1 vs 12% in SES 4 in CD; P < .001; and 18% vs 12% in ulcerative colitis; P < .001), and higher surgery rates (12% vs 7%; P < .001, and 1.4% vs 0.7%; P = .115, respectively). There were higher steroid dependency and CD surgery rates in peripheral vs central regions. In multivariable models, both SES and peripheral region were independently associated with poorer outcomes. CONCLUSIONS: We found that lower SES and peripheral residence were associated with deleterious outcomes in IBD. This should be considered by policymakers and should encourage strategies for improving outcomes in populations at risk.

In a novel nationwide population study, we found that patients with inflammatory bowel disease living in peripheral regions and those with lower socioeconomic status had significantly worse inflammatory bowel disease outcomes, notably higher corticosteroid dependency, higher surgery rate, and higher repeat surgery rate.

Prevalence and Outcomes of No Treatment Versus 5-ASA in Ulcerative Colitis: A Nationwide Analysis From the epi-IIRN.

BACKGROUND: Data regarding patients with ulcerative colitis (UC) not receiving maintenance treatment are scarce. In this nationwide study, we aimed to explore the frequency and long-term outcomes of untreated patients with UC vs treated patients. METHODS: We retrieved data from Israel's Health Maintenance Organizations, covering 98% of the population. No maintenance treatment (NMT) was defined as lack of treatment during the period from 3 to 6 months from diagnosis, allowing at most 3 months for induction treatment. RESULTS: A total of 15 111 patients have been diagnosed with UC since 2005, of whom 4410 (29%) have had NMT, with 36 794 person-years of follow-up. NMT was more likely in adults (31%) and in elderly-onset UC (29%) than in pediatric-onset UC (20%; P < .001) and decreased from 38% in 2005 to 18% in 2019 (P < .001). The probability of remaining without treatment was 78%, 49%, and 37% after 1, 3, and 5 years from diagnosis, respectively. In propensity score-matched analysis of 1080 pairs of treated (93% with 5-aminosalicylic acid) and untreated patients, outcomes were comparable for time to biologics (P = .6), surgery (P = .8), steroid dependency (P = .09), and hospitalizations (P = .2). Multivariable modeling indicated that failing NMT was less likely in adults or elderly-onset patients who received at most rectal therapy or antibiotics as induction therapy. CONCLUSIONS: Nowadays, 18% of patients with UC do not receive maintenance therapy, of whom half remain without treatment after 3 years. Matched pairs of patients on NMT and 5-aminosalicylic acid, representing the mildest patients of the latter, had similar outcomes. Prospective studies are needed to further explore the role of NMT in UC.

The rate of no maintenance treatment (NMT) decreased in the last years, but in a propensity score­matched analysis, 5-aminosalicylic acid monotherapy did not demonstrate any therapeutic advantage over NMT. NMT seems to be a viable option in a subset of patients with mild ulcerative colitis.

Durability of the First Biologic in Children and Adults With Ulcerative Colitis: A Nationwide Study from the epi-IIRN.

BACKGROUND: In this nationwide study, our objective was to compare the durability of first-line biologics in ulcerative colitis (UC), categorized into monotherapy and combotherapy with immunomodulators. METHODS: We utilized data from the nationwide epi-IIRN cohort from 2005 to 2020. Durability was defined as consistent treatment without surgery. Comparisons were based on stringent propensity score-matching. RESULTS: We included 15 111 patients with UC, of whom 2322 (15%) received biologics, with a median follow-up of 7.0 years (interquartile range, 3.8-11.0). The durability rate was similar between pediatric-onset and adults after 1 and 5 years from initiation of treatment (72% and 43% vs 71% and 43%, respectively; P = .8). Durability of adalimumab vs infliximab after 1 or 5 years was similar, whether prescribed as monotherapy (65%/46% vs 63%/33%, respectively; n = 182 matched pairs, P = .3) or combotherapy (78%/56% vs 91%/58%, respectively; n = 46 matched pairs, P = .4). Durability of infliximab was higher as combotherapy (85%/50%) vs monotherapy (69%/42%; n = 174 matched pairs, P = .007), while it was similar for adalimumab (80%/52% vs 74%/52%; n = 53 matched pairs, P = .4). The durability rate was similar for vedolizumab monotherapy (77%/56%) compared with adalimumab monotherapy (69%/52%; n = 125 matched patients, P = .1), and infliximab monotherapy (73%/55% vs 62%/44%; n = 78 matched patients, P = .1). However, combotherapy of antitumor necrosis factors (TNFs) had longer durability than vedolizumab (85%/50% vs 75%/43%, respectively; n = 131 matched pairs, P = .02). CONCLUSION: After 5 years of treatment, 43% of the patients with UC sustained their first biologic, with similar durability in pediatric and adult-onset onset disease. Anti-TNFs had similar durability to vedolizumab and superior durability when prescribed as combotherapy.

Predictors of Complicated Disease Course in Adults and Children With Crohn's Disease: A Nationwide Study from the epi-IIRN.

BACKGROUND: Since data on predictors of complicated Crohn's disease (CD) from unselected populations are scarce, we aimed to utilize a large nationwide cohort, the epi-IIRN, to explore predictors of disease course in children and adults with CD. METHODS: Data of patients with CD were retrieved from Israel's 4 health maintenance organizations, whose records cover 98% of the population (2005-2020). Time-to-event modeled a complicated disease course, defined as CD-related surgery, steroid-dependency, or the need for >1 class of biologics. Hierarchical clustering categorized disease severity at diagnosis based on available laboratory results. RESULTS: A total of 16 659 patients (2999 [18%] pediatric-onset) with 121 695 person-years of follow-up were included; 3761 (23%) had a complicated course (750 [4.5%] switched to a second biologic class, 1547 [9.3%] steroid-dependency, 1463 [8.8%] CD-related surgery). Complicated disease was more common in pediatric- than adult-onset disease (26% vs 22%, odds ratio, 1.3; 95% confidence interval [CI], 1.2-1.4). In a Cox multivariate model, complicated disease was predicted by induction therapy with biologics (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6) and severity of laboratory tests at diagnosis (HR, 1.7; 95% CI, 1.2-2.2), while high socioeconomic status was protective (HR, 0.94; 95% CI, 0.91-0.96). In children, laboratory tests predicted disease course (HR, 1.8; 95% CI, 1.2-2.5), as well as malnutrition (median BMI Z score -0.41; 95% CI, -1.42 to 0.43 in complicated disease vs -0.24; 95% CI, -1.23 to 0.63] in favorable disease; P < .001). CONCLUSIONS: In this nationwide cohort, CD course was complicated in one-fourth of patients, predicted by laboratory tests, type of induction therapy, socioeconomic status, in addition to malnutrition in children.

Prognostic factors of complicated disease course are vital for considering early escalation to biologics. In this nationwide cohort, complicated disease course was apparent in approximately one-fourth of patients and was predicted particularly by routinely collected laboratory tests, age, and type of induction therapy at diagnosis.

Durability of Adalimumab and Infliximab in Children With Crohn's Disease: A Nationwide Comparison From the epi-IIRN Cohort.

BACKGROUND: In a nationwide cohort, we aimed to compare the durability of infliximab and adalimumab as first biologic treatment in children with Crohn's disease (CD), stratified as combotherapy or monotherapy. METHODS: We used data from the epi-IIRN cohort that includes all patients with inflammatory bowel diseases in Israel. Durability was defined as consistent treatment without surgery or treatment escalation. All comparisons followed stringent propensity-score matching in Cox proportional hazard models. RESULTS: Of the 3487 children diagnosed with CD since 2005, 2157 (62%) received biologics (1127 [52%] infliximab, 964 [45%] adalimumab and 52 [2%] vedolizumab as first biologic), representing a higher proportion than that among adults diagnosed during the same time period (5295 of 15 776 [34%]; P < .001). Time from diagnosis to initiation of biologic was shorter in pediatric-onset compared with adult-onset disease (median time during the last 3 years was 2.7 months [interquartile range 1.2-5.4] vs 5.2 months [2.6-8.9]; P < .001). The durability of adalimumab monotherapy after 1 and 5 years from initiation of treatment was better than infliximab monotherapy (79%/54% vs 67%/37%, respectively; n = 452 matched children; hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.3-2.3; P < .001), while in those treated with combotherapy, durability was similar (94%/66% with infliximab vs 90%/54% with adalimumab; n = 100; HR, 1.7; 95% CI, 0.9-3.3; P = .1). Durability was higher in children treated with infliximab combotherapy vs infliximab monotherapy (87%/45% vs 75%/39%; n = 440; HR, 1.4; 95% CI, 1.1-1.8; P = .01). The durability of adalimumab monotherapy was similar to infliximab combotherapy (83%/53% vs 89%/56%, respectively; n = 238; HR, 0.9; 95% CI, 0.7-1.2; P = .4). CONCLUSION: Our results support using adalimumab monotherapy as a first-line biologic in children with CD. When infliximab is used, combotherapy may be advantageous over monotherapy.

The epidemiology of inflammatory bowel diseases during the COVID-19 pandemic: comparison of two nationwide cohorts.

BACKGROUND: We aimed to explore the epidemiology of inflammatory bowel diseases (IBD) in association with the COVID-19 pandemic in two countries with different lockdown policies. METHODS: We utilized nationwide IBD cohorts in Israel and Sweden to explore the incidence of IBD during the pandemic compared to three years prior (2017- 2019). We examined temporal trends through the presence of inflection points by Joinpoint regression analysis and reported average monthly percentage changes (AMPC). RESULTS: A total of 155,837 patients with IBD were included (Israel, 58,640; Sweden, 97,197). The annual incidence of IBD was stable until 2019 in both countries and since, it decreased in Israel (AAPC of -16.6% [95%CI -19.9% to -10.0%]) and remained stable in Sweden (AAPC of -3.5% [95%CI -11.6% to 3.7%]). When exploring the monthly incidence during the pandemic, in Israel the rate remained stable until November 2020 (AMPC 2.3% [95%CI -13.4% to 29.9%]) and then decreased sharply (AMPC -6.4% [95%CI-20.8% to 17.0%]) until February 2021 and -20.1% [95%CI -38.9% to -4.7%]) from February 2021), while in Sweden, which had a less stringent lockdown policy, it decreased slightly until July 2020 (AMPC -3.3% [95%CI -21.6% to 20.3%]), but increased thereafter (AMPC 13.6% [95%CI -12.6% to 27.0%]). The change of incidence rate in Sweden occurred mainly in elderly-onset patients, the only population with significant restrictions during the pandemic. CONCLUSION: The incidence of IBD decreased during the pandemic in association with lockdowns, more so in Israel, which had more stringent policies. Future studies are needed to determine the long-term effect of the pandemic on IBD.

Predictors of Complicated Disease Course in Children and Adults With Ulcerative Colitis: A Nationwide Study From the epi-IIRN.

BACKGROUND: Data on predictors of complicated ulcerative colitis (UC) course from unselected populations cohorts are scarce. We aimed to utilize a nationwide cohort to explore predictors at diagnosis of disease course in children and adults with UC. METHODS: Data of patients diagnosed with UC since 2005 were retrieved from the nationwide epi-IIRN cohort. Complicated disease course was defined as colectomy, steroid-dependency, or the need for biologic drugs. Hierarchical clustering categorized disease severity at diagnosis based on complete blood count, albumin, C-reactive protein and erythrocyte sedimentation rate (ESR), analyzed together. RESULTS: A total of 13 471 patients with UC (1427 [11%] pediatric-onset) including 103 212 person-years of follow-up were included. Complicated disease course was recorded in 2829 (21%) patients: 1052 (7.9%) escalated to biologics, 1357 (10%) experienced steroid-dependency, and 420 (3.1%) underwent colectomy. Probabilities of complicated disease course at 1 and 5 years from diagnosis were higher in pediatric-onset (11% and 32%, respectively) than adult-onset disease (4% and 16%; P < .001). In a Cox multivariate model, complicated course was predicted by induction therapy with steroids (hazard ratio [HR], 1.5; 95% CI, 1.2-2.0), extraintestinal manifestations (HR, 1.3; 95% CI, 1.03-1.5) and the disease severity clusters of blood tests (HR, 1.8; 95% CI, 1.01-3.1), while induction therapy with enemas (HR, 0.6; 95% CI, 0.5-0.7) and older age (HR, 0.99; 95% CI, 0.98-0.99) were associated with noncomplicated course. CONCLUSION: In this nationwide cohort, the probability of complicated disease course during the first 5 years from diagnosis was 32% in pediatric-onset and 16% in adults with UC and was associated with more severe clusters of routinely collected laboratory tests, younger age at diagnosis, extraintestinal manifestations, and type of induction therapy.

Prognostic factors of complicated disease course are vital for clinical decision-making of early escalation to intensive treatment. In this nationwide cohort, one-third of children and one-fifth of adults with UC developed complicated disease course. Disease course was predicted particularly by routinely collected laboratory tests, age, extraintestinal manifestations, and type of induction therapy at diagnosis.

Thiopurines Have Longer Treatment Durability than Methotrexate in Adults and Children with Crohn's Disease: A Nationwide Analysis from the epi-IIRN Cohort.

BACKGROUND: Thiopurines and methotrexate have long been used to maintain remission in Crohn's disease [CD]. In this nationwide study, we aimed to compare the effectiveness and safety of these drugs in CD. METHODS: We used data from the epi-IIRN cohort, including all patients with CD diagnosed in Israel. Outcomes were compared by propensity-score matching and included therapeutic failure, hospitalisations, surgeries, steroid dependency, and adverse events. RESULTS: Of the 19264 patients diagnosed with CD since 2005, 3885 [20%] ever received thiopurines as monotherapy and 553 [2.9%] received methotrexate. Whereas the use of thiopurines declined from 22% in 2012-2015 to 12% in 2017-2020, the use of methotrexate remained stable. The probability of sustaining therapy at 1, 3, and 5 years was 64%, 51%, and 44% for thiopurines and 56%, 30%, and 23% for methotrexate, respectively [p <0.001]. Propensity-score matching, including 303 patients [202 with thiopurines, 101 with methotrexate], demonstrated a higher rate of 5-year durability for thiopurines [40%] than methotrexate [18%; p <0.001]. Time to steroid dependency [p = 0.9], hospitalisation [p = 0.8], and surgery [p = 0.1] were comparable between groups. These outcomes reflect also shorter median time to biologics with methotrexate (2.2 [IQR 1.6-3.1 years) versus thiopurines (6.6 [2.4-8.5]; p = 0.02). The overall adverse events rate was higher with thiopurines [20%] than methotrexate [12%; p <0.001], including three lymphoma cases in males, although the difference was not significant [4.8 vs 0 cases/10 000 treatment-years, respectively; p = 0.6]. CONCLUSION: Thiopurines demonstrated higher treatment durability than methotrexate but more frequent adverse events. However, disease outcomes were similar, partly due to more frequent escalation to biologics with methotrexate.

Medical concept embedding of real-valued electronic health records with application to inflammatory bowel disease.

Deep learning approaches are gradually being applied to electronic health record (EHR) data, but they fail to incorporate medical diagnosis codes and real-valued laboratory tests into a single input sequence for temporal modeling. Therefore, the modeling misses the existing medical interrelations among codes and lab test results that should be exploited to promote early disease detection. To find connections between past diagnoses, represented by medical codes, and real-valued laboratory tests, in order to exploit the full potential of the EHR in medical diagnosis, we present a novel method to embed the two sources of data into a recurrent neural network. Experimenting with a database of Crohn's disease (CD), a type of inflammatory bowel disease, patients and their controls (~1:2.2), we show that the introduction of lab test results improves the network's predictive performance more than the introduction of past diagnoses but also, surprisingly, more than when both are combined. In addition, using bootstrapping, we generalize the analysis of the imbalanced database to a medical condition that simulates real-life prevalence of a high-risk CD group of first-degree relatives with results that make our embedding method ready to screen this group in the population.

Pediatric overweight and obesity increased in Israel during the COVID-19 period.

Reports from many settings suggest that pediatric overweight and obesity increased in 2020 and 2021, presumably due to lifestyle changes associated with the COVID-19 pandemic. Many of these previous reports have relied on convenience samples or subsets of the population. Here, we present results of a longitudinal study of the entire population of Israel, a nation of approximately 9 million people, with the proportion with underweight, normal weight, overweight, and obesity at age 7 and at age 14-15, across the years 2017-2021. Our results show that the prevalence of overweight and obesity, which had been steady or improving through 2019, increased relatively quickly in 2020 and 2021. For example, among 7-year-olds, the percentage of children with obesity in 2019 was 6.8% (99% CI: 6.69-7.05), and by 2021, it had increased to 7.7% (99% CI: 7.53-7.93). There were important disparities in overweight and obesity based on SES; for example, the rate ratio for obesity comparing the poorest with the wealthiest 14-15-year-olds in 2019 was 1.63 (99% CI: 1.55-1.72). However, these disparities did not change meaningfully in 2020 and 2021, implying that while obesity did become more prevalent, this increase in prevalence was not differential across socioeconomic status. Like many other nations, Israel too experienced considerable increases in pediatric overweight and obesity in 2020-2021, erasing the improvements of the previous years among younger children.