Disease Penetrance Research Articles

Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease.

Congenital heart disease (CHD) is a rare structural defect that occurs in ∼1% of live births. Studies on CHD genetic architecture have identified pathogenic single-gene mutations in less than 30% of cases. Single-gene mutations often show incomplete penetrance and variable expressivity. Therefore, we hypothesize that genetic background may play a role in modulating disease expression. Polygenic risk scores (PRSs) aggregate effects of common genetic variants to investigate whether, cumulatively, these variants are associated with disease penetrance or severity. However, the major limitations in this field have been in generating sufficient sample sizes for these studies. Here we used CHD-phenotype matched genome-wide association study (GWAS) summary statistics from the UK Biobank (UKBB) as our base study and whole-genome sequencing data from the CHD cohort (n1 = 711 trios, n2 = 362 European trios) of the Gabriella Miller Kids First dataset as our target study to develop PRSs for CHD. PRSs estimated using a GWAS for heart valve problems and heart murmur explain 2.5% of the variance in case-control status of CHD (all SNVs, p = 7.90 × 10−3; fetal cardiac SNVs, p = 8.00 × 10−3) and 1.8% of the variance in severity of CHD (fetal cardiac SNVs, p = 6.20 × 10−3; all SNVs, p = 0.015). These results show that common variants captured in CHD phenotype-matched GWASs have a modest but significant contribution to phenotypic expression of CHD. Further exploration of the cumulative effect of common variants is necessary for understanding the complex genetic etiology of CHD and other rare diseases.

A dominant function of LynB kinase in preventing autoimmunity.

Here, we report that the LynB splice variant of the Src-family kinase Lyn exerts a dominant immunosuppressive function in vivo, whereas the LynA isoform is uniquely required to restrain autoimmunity in female mice. We used CRISPR-Cas9 gene editing to constrain lyn splicing and expression, generating single-isoform LynA knockout (LynAKO) or LynBKO mice. Autoimmune disease in total LynKO mice is characterized by production of antinuclear antibodies, glomerulonephritis, impaired B cell development, and overabundance of activated B cells and proinflammatory myeloid cells. Expression of LynA or LynB alone uncoupled the developmental phenotype from the autoimmune disease: B cell transitional populations were restored, but myeloid cells and differentiated B cells were dysregulated. These changes were isoform-specific, sexually dimorphic, and distinct from the complete LynKO. Despite the apparent differences in disease etiology and penetrance, loss of either LynA or LynB had the potential to induce severe autoimmune disease with parallels to human systemic lupus erythematosus (SLE).

Counseling and prenatal diagnosis in facioscapulohumeral muscular dystrophy: A retrospective study on a 13-year multidisciplinary approach.

Background and AimsThis is the first national population‐based report about prenatal diagnosis for families with a history of facioscapulohumeral muscular dystrophy (FSHD), a complex hereditary disease. The incomplete disease penetrance and the phenotypic heterogeneity observed in carriers of D4Z4 alleles of reduced size, the FSHD molecular hallmark, make the estimate of genetic risk problematic.MethodsWe considered all requests of preconception counseling and prenatal diagnosis received between January 2008 and December 2020 by the genetic counseling service associated with the Italian National Registry for FSHD (INRF). A multidisciplinary team managed the clinical and molecular data of each family.ResultsBetween 2008 and 2020, 60 couples required preconception counseling (PC) for FSHD. In 52 couples was observed at least one partner carried a D4Z4 reduced allele (DRA). Out of these 52 couples, 47 had a follow‐up visit routine yearly. Out of these 47, 26 (55.3%) couples had children: eight asked for prenatal diagnosis (PND), two had assisted reproduction by heterologous in vitro fertilization (IVF), and 16 did not require further assistance. Regarding PND, 50 prenatal analyses were performed for 36 couples. The test resulted positive in 27 pregnancies, 12 (44.4%) were terminated, and 15 (55.6%) were carried to term.ConclusionThe different choices made by the couples show the importance of an integrated approach to support genetic counseling for FSHD. These results remark the relevance of the clinical and molecular investigation of the extended family, preferably before conception.

A Four-Generational Report on Hereditary Head and Neck Paraganglioma.

BackgroundThis article investigates the inheritance, penetrance, clinical presentation, and therapeutic outcomes of hereditary head and neck paragangliomas (HNPGLs) by offering a four-generational report of an 18-member family affected by this rare condition.MethodologyInformation was compiled by examination of patients and a review of medical records and correspondence (retrospective case series).ResultsSix members of the 18-member family were diagnosed with HNPGL between 2002 and 2018. A known pathogenic point mutation in subunit D of the succinyl dehydrogenase complex (SDHD, c.317G>T, p.Gly106Val) was responsible for the tumor phenotype. The mutation could be revealed in seven family members, three diseased adults, one healthy adult, and three healthy children, out of the nine who consented to gene testing. The median age at diagnosis was 33.5 years (range: 22-50 years). Five of the eight primary tumors were glomus caroticum, two were glomus jugulare, and one was a glomus vagale tumor. The therapeutic approaches were multimodal and included embolization therapy, surgery, radiation, and watchful waiting. Follow-up was reported for five of the six patients (mean follow-up of 34.8 months after primary therapy); three showed no disease progression or recurrence.ConclusionsThis study exemplifies the autosomal dominant, parent-of-origin-dependent inheritance and the high disease penetrance in hereditary paraganglioma-pheochromocytoma syndromes. Six out of a total of eight adult descendants (75%) of the original SDHD mutation carrier developed tumors, and the morbidity associated with the disease as well as its therapy was especially high in late-diagnosed, advanced cases. This substantiates the necessity for early radiologic surveillance and genetic testing.

Hypocholesterolemia and Inflammatory Biomarkers Act as Predictors of Severe Vitamin D Deficiency in Patients With Crohn’s Disease: A Clinical Analysis of 862 Patients in China

BackgroundIn this study, we enrolled 862 patients with Crohn’s disease (CD) in China to investigate the correlation between serum vitamin D (SVD) and serum lipids, inflammatory biomarkers, and important clinical parameters.Materials and Methods25(OH)D was measured by LS/MS/MS. Correlation analysis, chi-square tests, and logistic regression analysis were performed to determine the correlations between vitamin D and potential risk factors when vitamin D levels were lower than 10 ng/mL or 20 ng/mL.ResultsThe incidence of severe vitamin D deficiency (SVD < 10 ng/mL) in patients with CD was significantly higher than that in healthy controls (28.9 vs. 9.5%). Multinomial logistic regression analysis showed that penetrating disease [odds ratio (OR) = 2.18], low levels of high-density lipoprotein cholesterol (HDL) (OR = 1.91), high erythrocyte sedimentation rate (OR = 1.73), and platelet count (PLT) (OR = 2.71) were regarded as predictors of severe vitamin D deficiency, while only PLT (OR = 1.90) and HDL (OR = 1.76) were considered as predictors of mild vitamin D deficiency (SVD 10–20 ng/mL).ConclusionOur results confirm a higher incidence of severe vitamin D deficiency in patients with CD in China and show that vitamin D deficiency could result from the combined effects of penetrating disease, inflammation, and low levels of HDL.

Clinical Phenotypes and Outcomes in Monogenic Versus Non-monogenic Very Early Onset Inflammatory Bowel Disease.

Over 80 monogenic causes of very early onset inflammatory bowel disease [VEOIBD] have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-centre cohort of patients with VEOIBD and universal access to whole exome sequencing [WES]. Patients receiving IBD care at a single centre were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise a VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function, or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns. This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients [7.9%] had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn's disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of intensive care unit [ICU] hospitalisation, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, haematopoietic stem cell transplant, and death. A total of 41 patients [19.0%] had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes. Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.

Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis

ObjectiveThis study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives.MethodsA systematic search was performed in PubMed (MEDLINE), Embase,...

Rare and common variants in ROM1 and PRPH2 genes trans-modify Stargardt/ABCA4 disease.

Over 1,500 variants in the ABCA4 locus cause phenotypes ranging from severe, early-onset retinal degeneration to very late-onset maculopathies. The resulting ABCA4/Stargardt disease is the most prevalent Mendelian eye disorder, although its underlying clinical heterogeneity, including penetrance of many alleles, are not well-understood. We hypothesized that a share of this complexity is explained by trans-modifiers, i.e., variants in unlinked loci, which are currently unknown. We sought to identify these by performing exome sequencing in a large cohort for a rare disease of 622 cases and compared variation in seven genes known to clinically phenocopy ABCA4 disease to cohorts of ethnically matched controls. We identified a significant enrichment of variants in 2 out of the 7 genes. Moderately rare, likely functional, variants, at the minor allele frequency (MAF) <0.005 and CADD>25, were enriched in ROM1, where 1.3% of 622 patients harbored a ROM1 variant compared to 0.3% of 10,865 controls (p = 2.41E04; OR 3.81 95% CI [1.77; 8.22]). More importantly, analysis of common variants (MAF>0.1) identified a frequent haplotype in PRPH2, tagged by the p.Asp338 variant with MAF = 0.21 in the matched general population that was significantly increased in the patient cohort, MAF 0.25, p = 0.0014. Significant differences were also observed between ABCA4 disease subgroups. In the late-onset subgroup, defined by the hypomorphic p.Asn1868Ile variant and including c.4253+43G>A, the allele frequency for the PRPH2 p.Asp338 variant was 0.15 vs 0.27 in the remaining cohort, p = 0.00057. Known functional data allowed suggesting a mechanism by which the PRPH2 haplotype influences the ABCA4 disease penetrance. These associations were replicated in an independent cohort of 408 patients. The association was highly statistically significant in the combined cohorts of 1,030 cases, p = 4.00E-05 for all patients and p = 0.00014 for the hypomorph subgroup, suggesting a substantial trans-modifying role in ABCA4 disease for both rare and common variants in two unlinked loci.

Severe Vancomycin-Induced Linear IgA Bullous Dermatosis Case Report

Linear IgA bullous dermatosis is a rare autoimmune blistering disease. Although multiple reports have documented drug exposure as a precipitating factor, formal studies validating the existence of drug-induced LABD are lacking. A 49-year-old man with history of intravenous drug use presented with left hip pain of 3 weeks duration after sustaining a fall. On presentation he was hemodynamically stable and physical examination was notable proximal left thigh tenderness with stiffness and limited range of movement. Laboratory diagnostics were remarkable for elevated inflammatory markers, with no evidence of leukocytosis. CT scan without contrast of the left lower extremity demonstrated severe left hip osteoarthritis without fracture or dislocation. The patient continued to experience severe pain, prompting incision and drainage of the left hip along with acetabuloplasty, removal of the femoral head, and stage I hip replacement with placement of prophylactic prosthetic cement spacer with vancomycin and tobramycin. Within 24 h of surgery, he developed multiple distinct maculopapular/bullous lesions of his torso and medial thigh that rapidly progressed. Punch biopsy was performed and due to involvement of ~ 20% body surface area, he was transferred to a tertiary center. H&E and immunostaining of the histological sample demonstrated linear IgA bullous disease mimicking Stevens-Johnson syndrome. The patient’s bullous lesions improved 2 weeks after discontinuation of vancomycin and initiation of therapy. This case demonstrates the importance of early recognition of the rare adverse effects of commonly used medications. Vancomycin is currently used more frequently given the recent rise in the prevalence of methicillin-resistant Staphylococcus aureus infection. Further studies are needed to understand the pathophysiology, genetic predisposition, and disease penetrance.

Kidney failure in Bardet-Biedl syndrome.

The aim of this study was to explore kidney failure (KF) in Bardet–Biedl syndrome (BBS), focusing on high‐risk gene variants, demographics, and morbidity. We employed the Clinical Registry Investigating BBS (CRIBBS) to identify 44 (7.2%) individuals with KF out of 607 subjects. Molecularly confirmed BBS was identified in 37 KF subjects and 364 CRIBBS registrants. KF was concomitant with recessive causal variants in 12 genes, with BBS10 the most predominant causal gene (26.6%), while disease penetrance was highest in SDCCAG8 (100%). Two truncating variants were present in 67.6% of KF cases. KF incidence was increased in genes not belonging to the BBSome or chaperonin‐like genes (p < 0.001), including TTC21B, a new candidate BBS gene. Median age of KF was 12.5 years, with the vast majority of KF occurring by 30 years (86.3%). Females were disproportionately affected (77.3%). Diverse uropathies were identified, but were not more common in the KF group (p = 0.672). Kidney failure was evident in 11 of 15 (73.3%) deaths outside infancy. We conclude that KF poses a significant risk for premature morbidity in BBS. Risk factors for KF include female sex, truncating variants, and genes other than BBSome/chaperonin‐like genes highlighting the value of comprehensive genetic investigation.

Middle Eastern Genetic Variation Improves Clinical Annotation of the Human Genome.

Genetic variation in populations of Middle Eastern origin remains highly underrepresented in most comprehensive genomic databases. This underrepresentation hampers the functional annotation of the human genome and challenges accurate clinical variant interpretation. To highlight the importance of capturing genetic variation in the Middle East, we aggregated whole exome and genome sequencing data from 2116 individuals in the Middle East and established the Middle East Variation (MEV) database. Of the high-impact coding (missense and loss of function) variants in this database, 53% were absent from the most comprehensive Genome Aggregation Database (gnomAD), thus representing a unique Middle Eastern variation dataset which might directly impact clinical variant interpretation. We highlight 39 variants with minor allele frequency >1% in the MEV database that were previously reported as rare disease variants in ClinVar and the Human Gene Mutation Database (HGMD). Furthermore, the MEV database consisted of 281 putative homozygous loss of function (LoF) variants, or complete knockouts, of which 31.7% (89/281) were absent from gnomAD. This set represents either complete knockouts of 83 unique genes in reportedly healthy individuals, with implications regarding disease penetrance and expressivity, or might affect dispensable exons, thus refining the clinical annotation of those regions. Intriguingly, 24 of those genes have several clinically significant variants reported in ClinVar and/or HGMD. Our study shows that genetic variation in the Middle East improves functional annotation and clinical interpretation of the genome and emphasizes the need for expanding sequencing studies in the Middle East and other underrepresented populations.

OP041: Implementation of 2019 ACMG technical standards for the interpretation and reporting of constitutional CNVs: Experiences from an academic reference laboratory

Classification and reporting of constitutional copy-number variants (CNVs) in the clinical setting can be challenging and may result in discrepancies in interpretation for various reasons. In 2019, the ACMG and ClinGen published technical standards (2019 CNV guidelines) to guide the evaluation of constitutional CNVs. To improve consistency and accuracy in classification and reporting practices at ARUP Laboratories, we began using the 2019 CNV guidelines for genomic microarray testing beginning in 2020, including the adoption of the 5-tier variant classification system, incorporation of the scoring metrics into our CNV investigation workflow, and changing our reporting practices for CNVs involving reduced penetrance or autosomal recessive (AR) disease risk.

Lysosomal ceramides regulate cathepsin B-mediated processing of saposin C and glucocerebrosidase activity.

Variants in multiple lysosomal enzymes increase Parkinson's disease (PD) risk, including the genes encoding glucocerebrosidase (GCase), acid sphingomyelinase (ASMase) and galactosylceramidase. Each of these enzymes generates ceramide by hydrolysis of sphingolipids in lysosomes, but the role of this common pathway in PD pathogenesis has not yet been explored. Variations in GBA1, the gene encoding GCase, are the most common genetic risk factor for PD. The lysosomal enzyme cathepsin B has recently been implicated as an important genetic modifier of disease penetrance in individuals harboring GBA1 variants, suggesting a mechanistic link between these enzymes. Here, we found that ceramide activates cathepsin B, and identified a novel role for cathepsin B in mediating prosaposin cleavage to form saposin C, the lysosomal coactivator of GCase. Interestingly, this pathway was disrupted in Parkin-linked PD models, and upon treatment with inhibitor of ASMase which resulted in decreased ceramide production. Conversely, increasing ceramide production by inhibiting acid ceramidase activity was sufficient to upregulate cathepsin B- and saposin C-mediated activation of GCase. These results highlight a mechanistic link between ceramide and cathepsin B in regulating GCase activity and suggest that targeting lysosomal ceramide or cathepsin B represents an important therapeutic strategy for activating GCase in PD and related disorders.

Gender Related Differences in the Clinical Presentation of Hypertrophic Cardiomyopathy-An Analysis from the SILICOFCM Database.

Background and Objectives: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease that affects approximately 1 in 500 people. Due to an incomplete disease penetrance associated with numerous factors, HCM is not manifested in all carriers of genetic mutation. Although about two-thirds of patients are male, it seems that female gender is associated with more severe disease phenotype and worse prognosis. The objective of this study was to evaluate the gender related differences in HCM presentation. Materials and Methods: This study was conducted as a part of the international multidisciplinary SILICOFCM project. Clinical information, laboratory analyses, electrocardiography, echocardiography, and genetic testing data were collected for 362 HCM patients from four clinical centers (Florence, Newcastle, Novi Sad, and Regensburg). There were 33% female patients, and 67% male patients. Results: Female patients were older than males (64.5 vs. 53.5 years, p < 0.0005). The male predominance was present across all age groups until the age of 70, when gender distribution became comparable. Females had higher number of symptomatic individuals then males (69% vs. 52%, p = 0.003), most frequently complaining of dyspnea (50% vs. 30%), followed by chest pain (30% vs. 17%), fatigue (26% vs. 13%), palpitations (22% vs. 13%), and syncope (13% vs. 8%). The most common rhythm disorder was atrial fibrillation which was present in a similar number of females and males (19% vs. 13%, p = 0.218). Levels of N-terminal pro-brain natriuretic peptide were comparable between the genders (571 vs. 794 ng/L, p = 0.244). Echocardiography showed similar thickness of interventricular septum (18 vs. 16 mm, p = 0.121) and posterolateral wall (13 vs. 12 mm, p = 0.656), however, females had a lower number of systolic anterior motion (8% vs. 16%, p = 0.020) and other mitral valve abnormalities. Conclusions: Female patients are underrepresented but seem to have a more pronounced clinical presentation of HCM. Therefore, establishing gender specific diagnostic criteria for HCM should be considered.

Tryptase in all its states: From allergy to mastocytosis

In normal humans, tryptase, a serine protease with multiple biological activities, is synthesized nearly exclusively by mast cells (MCs). While immature forms of tryptase (α- and β- monomers) are constantly released by MCs and can be measured in the serum of normal individuals as the basal serum tryptase (BST) level, mature tryptases (mostly tetramers of β-tryptase) are retained in the secretory granules of MCs and are released only upon cell activation. Such MC activation occurs during IgE-mediated allergic reactions and increased levels of tryptase, which can be measured immediately after degranulation, are involved in the pathophysiology of immediate hypersensitivity. Interestingly, recent studies have reported that around 5% of the general population present with a genetic trait called hereditary alpha-tryptasemia (HαT). In HαT+ patients, the BST level is increased. Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical MCs in one or several organs/tissues, often accompanied by MC activation. Increased BST level is a hallmark of systemic mastocytosis (SM) and a diagnostic, prognostic and follow-up marker. Interestingly, the incidence of the HαT trait has been found increased in SM patients (up to 18% of the cases) and HαT+ SM patients are more prone to develop anaphylaxis, making HαT a disease penetrance and phenotype modifier.

ILEAL ENTEROCYTE BRUSH BORDER ABNORMALITIES ASSOCIATE WITH PROGRESSIVE DISEASE COURSE IN PEDIATRICS CROHN’S DISEASE

Abstract BACKGROUND Biomarkers are needed to identify the subset of Crohn’s disease (CD) patients at-risk for severe, treatment-refractory disease. Short ileal microvillus length (MVL) is an epithelial biomarker that predicted non-response to treatment in adult CD. Here, we hypothesized that short MVL phenotype would occur in pediatric CD and associate with more severe disease. METHODS H&amp;E-stained ileal tissue sections were obtained from 3 pediatric cohorts: WashU, CCHMC, and RISK (n=58 controls, n=377 CD). MVL was measured in regions not involved in acute inflammation. RISK had baseline “pre-treatment” and follow-up “post-treatment” sampling, clinical phenotyping, and transcriptomic data. Transmission electron microscopy (TEM) and immunofluorescence was performed on paired samples from 6 CD and 6 controls. RESULTS Ileal MVL was shorter in pediatric CD (mean: 1.44 μm) vs. controls (mean: 1.64 μm; P&amp;lt;0.0001). MVL did not associate with body mass index, disease location, endoscopic deep ulcers, or disease activity index scores. Histological inflammation scores were greater in baseline CD vs. controls, but similar between CD with short (defined as &amp;lt;1.46 μm, 10th percentile of controls) or normal MVL. Progression from B1 inflammatory disease behavior to B2 stricturing or B3 internal penetrating disease behavior was more likely to occur in patients with shorter MVL (n=91 follow-up samples collected prior to disease progression event; B2: P=0.0077, B3: P=0.0186). Additionally, progression to B2 occurred sooner in those with short follow-up MVL (P=0.0206). In contrast, associations with disease behavior progression based on baseline MVL were not observed. RNA-seq analysis identified 92 genes differentially expressed between CD and controls and correlated with MVL. Gene function analysis showed enrichment (P&amp;lt;0.001) for actin cytoskeleton, transporter activity, and plasma membrane among the 43 genes positively associated with MVL, and enrichment for myeloid cell, response to bacterium, and extracellular matrix among the 49 genes negatively associated with MVL. TEM showed thinning of the terminal web in CD, with diminished microvillus rootlet length and organelle-free zones, features associated with shortened or disorganized microvilli in mouse models. We next assessed terminal web-associated proteins, PLS1 and MYH14, and found that both were altered in CD samples; PLS1 was abnormally enhanced at the brush border, and MYH14 was aberrantly localized in the cytoplasm. Misexpression of MYH14 was associated with terminal web thinning and shorter MVL. CONCLUSIONS This study supports short ileal MVL phenotype in follow-up CD samples as an epithelial biomarker for more severe disease prognosis, particularly for progression to stricturing disease. Our data suggest that terminal web alterations underlie the short MVL phenotype.

P630 Systematic review and meta-analysis: Diagnostic delay and the subsequent impact on the disease course of adult Inflammatory Bowel Disease

Abstract Background Diagnosis of inflammatory Bowel disease (IBD) can be challenging and time consuming. There is substantial variation in the reported time to diagnosis and the impact of diagnostic delay on disease course. We therefore conducted a systematic review to evaluate the length of time to diagnosis and a meta-analysis of the impact of delay on the disease course of IBD. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and final papers were assessed for risk of bias. We searched MEDLINE and Embase for retrospective and prospective studies, published up to December 2020, that reported diagnostic interval, from the time of symptom onset or first consultation to a confirmed diagnosis of IBD, in adults (age ≥18 years). We extracted data from published studies and calculated the weighted median and interquartile range (IQR) of the reported diagnosis interval. Delay was defined as a time period greater than the 75th centile. From eligible studies, we extracted risk estimates and, using random-effects meta-analysis, calculated the pooled odds ratios (OR) and 95% confidence intervals (CI) of studies that examined the association of diagnostic delay with subsequent clinical outcomes, including disease phenotype and surgical intervention. Statistical heterogeneity was assessed, I2 &amp;gt;50% indicating substantial heterogeneity. Results Of 1,533 studies identified, 28 fulfilled the eligibility criteria, including 25,764 patients diagnosed with IBD: Crohn’s disease (CD) = 13,206 and ulcerative colitis (UC) = 12,558. In CD, the pooled weighted median for the diagnostic interval was 8.8 months (IQR 3.0–61.1 months). In UC, the pooled weighted median was 15.2 months (IQR 2.4–62.8). Considering studies from high income countries alone, the pooled weighted median was 6.4 months (IQR 1.7–46.7) in CD, and 2.5 months (IQR 0.3–23.0) in UC. 11 studies were eligible for inclusion in the meta-analysis, representing 6,403 patients diagnosed with IBD (CD; n = 4,902 and UC; n = 1,501). In CD, pooled analysis showed an association between delayed diagnosis and stricturing disease (OR:1.77, CI 1.28–2.46; I2 =61%), penetrating disease (OR: 1.48, CI 1.21–1.82; I2=0%) and intestinal surgery (OR:1.88, CI 1.45–2.44; I2 =34%; figure 1a). In UC, delayed diagnosis was associated with an increased risk of colectomy (OR:4.13, CI 1.04–16.40; I2 =0%; figure 1b). Conclusion Measures are required to reduce delay in the diagnosis of IBD, which is associated with an increase in stricturing and penetrating disease phenotype in CD and a substantially increased risk of surgery in both CD and UC.

P284 Prophylactic medication for the prevention of endoscopic recurrence after ileocolonic resection in Crohn’s disease: a prospective study based on clinical risk stratification

Abstract Background In patients with Crohn’s disease (CD), postoperative prophylactic medication based on clinical risk stratification is recommended in international guidelines to prevent recurrence after ileocolonic resection (ICR). This study aimed to evaluate the risk of endoscopic recurrence after implementation of a predefined management algorithm after ICR incorporating clinical risk stratification. Methods In this multicenter, prospective clinical cohort study, CD patients (≥16 years) were included who were scheduled for ICR and gave informed consent. Endoscopy-guided treatment (no prophylactic medication directly after ICR) was recommended in patients at low risk (LR) of postoperative recurrence, and prophylactic medication (immunosuppressant/biological) in high risk (HR). HR was defined as ≥1 risk factor: smoking, penetrating disease, re-resection. Clinical and histologic risk factors for endoscopic recurrence (Rutgeerts’ score ≥i2) were assessed using logistic regression models and ROC curves based on predicted probabilities. Results In total 213 CD patients were included (median age 34.5 years, 65.3% women): 93 (43.7%) at LR and 120 (56.3%) at HR (smoking 45 (21.3%); penetrating disease 51 (23.9%); re-resection 51 (23.9%)). Adherence to the proposed management algorithm was 65%; 76/93 (81.7%) in the LR (no prophylaxis) and 61/120 (50.8%) in the HR population (prophylaxis). Endoscopic recurrence in LR patients was 69% without prophylaxis versus 48% with prophylaxis (p=0.070); in HR 78% without prophylaxis versus 55% with prophylaxis (p=0.019). Clinical risk stratification corresponded with an area under the curve (AUC) of 0.64 (95%CI 0.55–0.73) (Figure 1). Clinical factors combined with histology (active inflammation, granulomas, plexitis in resection margins) increased the AUC to 0.69 (95% CI 0.61–0.88) (Figure 1). Conclusion This prophylactic medication algorithm in CD patients based on clinical risk stratification after ICR, results in an absolute risk reduction of endoscopic recurrence of 23% in HR versus 21% increase in LR patients in whom medication is omitted. For this latter population, further refinement of risk stratification is required, and may include histologic assessment.

P146 Initial response to induction treatment more important than type of induction treatment for achieving sustained steroid free remission at 1 year in new-onset paediatric Crohn’s disease

Abstract Background For paediatric patients with high risk of complicated Crohn’s disease (CD) [stricturing or penetrating disease], paediatric guidelines recommend upfront anti-tumor necrosis factor-alpha (ATA). Early ATA therapy has been demonstrated to result in higher steroid- and surgery-free remission rates at 1 year than induction with conventional treatment (CONV) [Exclusive Enteral Nutrition (EEN) or corticosteroids followed by immunomodulatory therapy]. However, it is unknown whether either type of induction treatment or achieving steroid free remission (SFR) at 3 months is a more important predictor of sustained SFR (SSFR) at 1 year. Therefore, we aimed to evaluate the independent effect of early ATA use after achieving induction of remission on sustained SFR (SSFR) rates at 1 year in an international prospective observational study. Methods Since January 2017, children (0–18 years) with newly-diagnosed CD were prospectively enrolled in 28 European and Asian paediatric IBD centers. Extensive demographic and clinical data were collected at baseline, and at 1, 3, 6 and 12 months. The primary outcome was SSFR at 1 year, defined as a weighted Paediatric CD Activity Index (wPCDAI) &amp;lt;12.5 without steroids at 3, 6, and 12 months. Secondary outcomes included SFR at 3 and 12 months, and treatment escalation to ATA. Outcomes were compared between the early ATA induction treatment group (defined as ATA within 3 months after diagnosis) and the CONV induction treatment group (EEN or corticosteroids), using χ 2 tests. Results Up to July 2021, 235 children with new-onset CD were included and completed at least 1 year of follow-up (61.7% male, median age 13.7 [IQR 11.4–15.0]). At 1 year, 62/203 (30.5%) achieved SSFR. Patients that received early ATA were more likely to achieve SSFR compared to patients with CONV (35/79 [44%] vs. 27/110 [25%], p=0.004). After induction treatment, 99/213 [47%] achieved SFR at 3 months. Patients with early ATA had higher rates of SFR at 3 months (48/84 [57%]) than those with CONV (51/129 [40%], p=0.012), and higher rates of low faecal calprotectin (67% vs. 17%, p&amp;lt;0.001) or low CRP (&amp;lt; 5 mg/l) (82% vs. 53%, p&amp;lt;0.001). Of those patients in SFR at 3 months, 71% achieved SSFR, which was not significantly different between those in SFR at 3 months with early ATA vs. with CONV (35/45 [78%] vs. 27/43 [63%], p=0.12). Conclusion While only one-third of paediatric CD patients achieve SSFR at 1 year, 71% of patients achieve SSFR after having achieved SFR at 3 months. Patients with early ATA had higher rates of SFR at 3 months and SSFR at 1 year than those without early ATA. Remission at 3 months was found to be more important for SSFR than type of induction treatment, highlighting the importance of initial response to induction treatment.

P416 Addition of oral antibiotics to mechanical bowel preparation significantly improves anastomotic healing after ileocolic resection for Crohn’s disease

Abstract Background Addition of oral antibiotics (OA) to mechanical bowel preparation (MBP) is thought to reduce postoperative morbidity compared to MBP alone. However, data supporting this concept in Crohn’s disease patients undergoing ileocolic resection do not exist. Methods Starting, 2016, all ileocolic resections were performed after preoperative MBP combined with OA consisting of two separate dosages of Metronidazole/Neomycine or Metronidazol/Paramomycine. These patients were compared to previous controls undergoing ileocolic resection after mere MBP (1992–2005). Between, 2005 and, 2016, surgeries were performed without preoperative MBP. Patients undergoing an ileocolic resection without construction of anastomosis (i.e., two staged resection) and patients not receiving MBP were excluded from the study. „Anastomotic complications“ were defined as anastomotic leakage, presence of abscess or peritonitis in direct proximity to anastomosis. Results 312 patients underwent ileocolic resections with construction of an anastomosis:, 159 after MBP only and, 153 after preoperative MBP+OA. Patients in MBP+OA group were older (39 y. vs., 35 y., p=0.001), had penetrating disease less frequently (50% vs., 69%, p=0.001), were on biologicals more frequently (31% vs., 1%, p&amp;lt;0.001), on steroids less frequently (12% vs., 59%, p&amp;lt;0.001), underwent laparoscopic surgery more often (80% vs., 15%, p&amp;lt;0.001), and received preoperative parenteral nutrition more often (16% vs., 7%, p=0.033). Patients receiving OA were not able to complete MBP more often (19% vs., 9%, p=0.009). By the multivariate analysis, addition of OA to MBP was associated with a significant reduction of anastomotic complication rate (3% vs., 11%, Hazard ratio, 0.24, p=0.036). Weight loss and steroids were associated with an increased anastomotic morbidity. Conclusion Oral antibiotics added to MBP further improve the anastomotic healing in Crohn’s disease patients undergoing ileocolic resection, although the study has demonstrated an apparent time bias. Further research is needed to clarify whether OA without MBP are as protective as MBP+OA.