Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

Features of Autoimmune Pancreatitis Associated With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Few people know of autoimmune pancreatitis (AIP), a rare disorder associated with inflammatory bowel diseases (IBD). We aimed to describe phenotype and outcomes of IBD and AIP when associated. METHODS: We performed a retrospective study of cases of AIP in IBD identified from the multicenter Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif in Belgium and France from July 2012 through July 2015. Patients were diagnosed with AIP based on the International Consensus Diagnostic Criteria for AIP. A definitive AIP diagnosis was based on histological analysis of pancreatic resection specimens or samples collected by fine-needle aspiration during endoscopic ultrasound. Patients with probable type 1 AIP were identified based on imaging findings, clinical and/or radiologic responses to steroids, level of serum immunoglobulin G4, and involvement of other organs. Patients with probable type 2 AIP were identified based on imaging findings, clinical and/or radiologic responses to steroids, and association with IBD. The primary objective was to collect information on the characteristics of AIP in patients with IBD. We also compared features of patients with IBD with and without AIP in a case-control analysis, using multivariate analysis. RESULTS: We analyzed data from 91 individuals with AIP and IBD (47 women) seen at 23 centers (58 had ulcerative colitis [UC] and 33 Crohn's disease [CD]). Eighty-nine patients had type 2 AIP, and 2 patients had type 1 AIP. The mean age at diagnosis of AIP was 35 ± 12 years, and for IBD it was 32 ± 12 years. AIP preceded IBD in 19 patients (21%). Over a mean follow-up period of 5.7 ± 4.9 years, 31 patients (34%) relapsed, 11 patients (12%) developed diabetes, and 17 patients (19%) developed exocrine pancreatic insufficiency. In patients with UC, factors independently associated with AIP included proctitis (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.3-6.3; P = .007) and colectomy (OR, 7.1; 95% CI, 2.5-20; P = .0003). In patients with CD, AIP was significantly associated with fewer perianal lesions (OR, 0.16; 95% CI, 0.03-0.77; P = .023), non-stricturing non-penetrating CD (OR, 6.7; 95% CI, 1.25-33.3; P = .0029), and higher rate of colectomy (OR, 27.8; 95% CI, 3.6-217; P = .0029). CONCLUSIONS: In a multicenter retrospective analysis of patients with AIP and IBD, followed for an average of 5.7 ± 4.9 years, we found most to have type 2 AIP. Two-thirds of patients have UC, often with proctitis. One-third of patients have CD, often with inflammatory features. Patients with IBD and AIP have higher rates of colectomy than patients with just IBD.

Contribution of mycobiota to the pathogenesis of spondyloarthritis.

This review lists current evidences for a contribution of gut mycobiota to the pathogenesis of SpA and related conditions. Gut mycobiota has a small size as compared to bacterial microbiota, but an even greater inter- and intra-individual variability. Although most fungi (brought by food or air) are only transitory present, a core mycobiota of gut resident fungi exists, and interplays with bacteria in a complex manner. A dysbiosis of this gut mycobiota has been observed in Crohn's disease and sclerosing cholangitis, with decreased proportion of Saccharomyces cerevisiae and outgrowth of more pathogenic gut fungi. Fungal-induced lower number of commensal gut bacteria can promote translocation of some bacterial/fungal antigens through mucosae, and live fungi can also cross the epithelial border in Crohn's disease. This dysbiosis also lower the ability of bacteria to metabolize tryptophan into regulatory metabolites, consequently enhancing tryptophan metabolism within human cells, which might contribute to fatigue. Translocation of mycobiotal antigens like curdlan (beta-glucan), which plays a major role in the pathogenesis of SpA in the SGK mice, has been observed in humans. This translocation of fungal antigens in human SpA might account for the anti-Saccharomyces antibodies found in this setting. Contribution of fungal antigens to psoriasis and hidradenitis suppurativa would fit with the preferential homing of fungi in the skin area most involved in those conditions. Fungal antigens also possess autoimmune uveitis-promoting function. As genes associated with SpA (CARD9 and IL23R) strongly regulate the innate immune response against fungi, further studies on fungi contribution to SpA are needed.

Multi-expert annotation of Crohn's disease images of the small bowel for automatic detection using a convolutional recurrent attention neural network.

Background and study aims Computer-aided diagnostic tools using deep neural networks are efficient for detection of lesions in endoscopy but require a huge number of images. The impact of the quality of annotation has not been tested yet. Here we describe a multi-expert annotated dataset of images extracted from capsules from Crohn's disease patients and the impact of the quality of annotations on the accuracy of a recurrent attention neural network. Methods Images of capsule were annotated by a reader first and then reviewed by three experts in inflammatory bowel disease. Concordance analysis between experts was evaluated by Fleiss' kappa and all the discordant images were, again, read by all the endoscopists to obtain a consensus annotation. A recurrent attention neural network developed for the study was tested before and after the consensus annotation. Available neural networks (ResNet and VGGNet) were also tested under the same conditions. Results The final dataset included 3498 images with 2124 non-pathological (60.7 %), 1360 pathological (38.9 %), and 14 (0.4 %) inconclusive. Agreement of the experts was good for distinguishing pathological and non-pathological images with a kappa of 0.79 ( P  < 0.0001). The accuracy of our classifier and the available neural networks increased after the consensus annotation with a precision of 93.7 %, sensitivity of 93 %, and specificity of 95 %. Conclusions The accuracy of the neural network increased with improved annotations, suggesting that the number of images needed for the development of these systems could be diminished using a well-designed dataset.

Anti-TNF therapy for genital fistulas in female patients with Crohn's disease: a nationwide study from the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID).

BACKGROUND: Genital fistulas represent a devastating complication of Crohn's disease. Only studies with small sample sizes have evaluated the efficacy of anti-TNF therapy for this complication. AIMS: To assess the efficacy of anti-TNF therapy for genital fistulas complicating Crohn's disease and to identify predictive factors associated with clinical response at 1 year. METHODS: Consecutive patients treated with anti-TNF therapy for genital fistulas complicating Crohn's disease from 1999 to 2016 in 19 French centres from the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif were included in a retrospective cohort study. Outcome was clinical fistula closure at 1 year. RESULTS: Among the 204 women with genital fistulas who received anti-TNF therapy, 131 were analysed. The first anti-TNF given was infliximab (79%), adalimumab (20%), or certolizumab (1%). At start of anti-TNF therapy, 56% of patients had seton drainage and 53% had concomitant immunosuppressive treatment. A complementary surgery was performed during the first year in 10 patients (8%). At 1 year, 37% of patients had complete clinical fistula closure, 22% had a partial response, and 41% had no response. Among patients without complementary surgery, 34% (41/121) had complete clinical fistula closure. Only complementary surgery was associated with better response on multivariate analysis (adjusted relative risk: 2.02, 95% CI: 1.25-3.26, P = 0.0043). CONCLUSIONS: In the anti-TNF era, approximately one-third of patients with genital fistula in Crohn's disease had complete fistula closure at 1 year. Collaboration between surgeons and gastroenterologists appears to be very important to improve the rate of fistula closure.

Efficacy and safety of adalimumab 80 mg weekly in luminal Crohn's disease.

BACKGROUND: In case of a loss of response to adalimumab, some patients with Crohn's disease may derive benefit from increasing the dosing frequency to 40 mg weekly. Efficacy and safety of adalimumab 80 mg weekly remain unknown. METHODS: From February 2011 to September 2012, all adults who had active Crohn's disease, defined at least by Crohn's disease activity index >150 and 1 objective sign of inflammation, and required an adalimumab dose escalation to 80 mg weekly were enrolled in a prospective multicenter cohort study. Crohn's disease activity index and C-reactive protein levels were recorded during the first 14 weeks following adalimumab optimization and at 6 months. All adverse events were recorded. RESULTS: Forty-two patients were included. The median age was 33 years, and the median disease duration was 8.6 years. Adalimumab was associated with steroids in 28% of cases and with immunomodulators in 10% of patients. Within the 14 weeks after adalimumab optimization, 14 patients (33.3%) achieved clinical remission (Crohn's disease activity index <150), and 23 patients (54.8%) had a clinical response. Clinical improvement was associated with a drop in the C-reactive protein level from 18 to 5 mg/L (P = 0.0008). After a median follow-up of 14.5 months, 5 patients underwent major abdominal surgery. Adverse events were reported in 13 patients (31%). CONCLUSIONS: Adalimumab 80 mg weekly seems to be well-tolerated and may be effective in inducing clinical remission in patients with luminal Crohn's disease who failed to respond to 40 mg weekly or 80 mg every other week.

The prevalence and outcome of jejunal lesions visualized by small bowel capsule endoscopy in Crohn's disease.

BACKGROUND: Small bowel capsule endoscopy is the most sensitive technique for the detection of lesions in the small intestine. The aims of the study were to assess the prevalence and clinical significance of jejunal lesions detected by small bowel capsule endoscopy in patients with an established Crohn's disease. RESULTS: One hundred and eight patients, including 32 patients with ileal disease, 25 patients with colonic disease, and 51 patients with ileocolonic disease, underwent small bowel capsule endoscopy, and findings were analyzed retrospectively. Jejunal lesions were detected in 56% of these patients, of whom 18 (17%) had lesions only in the jejunum. Jejunal lesions were less frequently detected (12% versus 38%, P = 0.001) when location of the disease was limited to the colon at ileocolonoscopy. Conversely, when Crohn's disease affected the ileum, jejunal lesions were more frequently detected (40% versus 17%, P = 0.007). During a median follow-up time of 24.0 months (interquartile, 8.0-46.2), 50 clinical relapses occurred. The presence of jejunal lesions was the only independent factor associated with an increased risk of relapse (P = 0.02). In nonsmokers and in patients treated by immunosuppressors, the presence of jejunal lesions tended to increase the risk of relapse (P = 0.06 and 0.05, respectively). CONCLUSIONS: Jejunal lesions are detected in more than half of the patients with Crohn's disease. The prevalence of jejunal lesions is higher when the terminal ileum is involved and associated with an increased risk of further clinical relapse. It may be regarded as a factor of severity.