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Background: Variations within the gene locus encoding protein tyrosine phosphatase non-receptor type 22 (PTPN22) are associated with the risk to develop inflammatory bowel disease (IBD). PTPN22 is involved in the regulation of T- and B-cell receptor signaling, but although it is highly expressed in innate immune cells, its function in other signaling pathways is less clear. Here, we study whether loss of PTPN22 controls muramyl-dipeptide (MDP)-induced signaling and effects in immune cells. Material & Methods: Stable knockdown of PTPN22 was induced in THP-1 cells by shRNA transduction prior to stimulation with the NOD2 ligand MDP. Cells were analyzed for signaling protein activation and mRNA expression by Western blot and quantitative PCR; cytokine secretion was assessed by ELISA, autophagosome induction by Western blot and immunofluorescence staining. Bone marrow derived dendritic cells (BMDC) were obtained from PTPN22 knockout mice or wild-type animals. Results: MDP-treatment induced PTPN22 expression and activity in human and mouse cells. Knockdown of PTPN22 enhanced MDP-induced activation of mitogen-activated protein kinase (MAPK)-isoforms p38 and c-Jun N-terminal kinase as well as canonical NF-κB signaling molecules in THP-1 cells and BMDC derived from PTPN22 knockout mice. Loss of PTPN22 enhanced mRNA levels and secretion of interleukin (IL)-6, IL-8 and TNF in THP-1 cells and PTPN22 knockout BMDC. Additionally, loss of PTPN22 resulted in increased, MDP-mediated autophagy in human and mouse cells. Conclusions: Our data demonstrate that PTPN22 controls NOD2 signaling, and loss of PTPN22 renders monocytes more reactive towards bacterial products, what might explain the association of PTPN22 variants with IBD pathogenesis. [ABSTRACT FROM AUTHOR]

Background/Aims: Extraintestinal manifestations (EIM) involving joints, skin, eyes and liver represent an important problem in the treatment of IBD patients. The aim of this study was to identify factors that are associated with the occurrence of joint EIM and therefore allow an early diagnosis and guide medical treatment. Methods: We studied clinical and epidemiological data from 3298 patients included in the Swiss IBD Cohort Study (SIBDCS), 1860 suffered from Crohn’s disease (CD) and 1438 from ulcerative colitis or IBD unclassified (UC/IBDU). Results: We found female gender as well as a longer disease duration and activity (specified as CDAI or MTWAI, respectively) to be related to the appearance of arthritis/arthralgia, but also sacroiliitis/ankylosing spondylitis in IBD patients. IBD patients with arthritis/arthralgia or sacroiliitis/ankylosing spondylitis were more often treated with anti-TNF and patients with arthritis/arthralgia underwent more often IBD-related surgeries. We revealed that eye or skin EIM were more frequent in patients with arthritis/arthralgia or sacroiliitis/ankylosing spondylitis. In multivariate analysis, we confirmed female gender, longer disease duration, IBD-related surgery, presence of other EIM and treatment with anti-TNF to be independent risk factors for the onset of arthritis/arthralgia in CD and UC/IBDU patients. Conclusion: In this study, we demonstrated that markers for a more severe disease course were associated with the onset of joint EIM in IBD patients. Our data suggest that in particular females under anti-TNF treatment and patients suffering from non-joint and/or IBD-related surgery should be close and carefully monitored for presence of arthritis or sacroiliitis/ankylosing spondylitis. [ABSTRACT FROM AUTHOR]

Background/Aims: Extraintestinal cutaneous manifestations of IBD represent a severe disease complication and an early and accurate treatment might positively influence the disease course. Using the patient collective of the Swiss IBD Cohort Study (SIBDCS), we analysed epidemiological as well as clinical factors being associated with the onset of pyoderma gangrenosum, erythema nodosum and aphthous ulcers in IBD patients. Methods: We included 3266 SIBDCs patients, 1840 with Crohn’s disease (CD) and 1426 with ulcerative colitis (UC) or IBD unclassified (IBDU) and analysed the association of cutaneous manifestations with age, age at diagnosis time, type of disease, gender, family history, HLA-allotype, smoking, intestinal disease activity, therapy and other extraintestinal manifestations (EIM). Results: 354 CD patients and 136 UC/IBDU patients presented with skin manifestations at any time during their disease course. In both, CD and UC, female gender and younger age at IBD diagnosis were significantly associated with extraintestinal skin manifestations. For CD, we also detected a positive family history as associated factor. As an indicator of more intensive intestinal disease activity, patients with cutaneous manifestations of IBD needed more frequently therapy with antibiotics, steroids, immunomodulators and anti-TNF. Multivariate analysis revealed female gender, younger age at diagnosis and presence of other extraintestinal manifestations as factors being associated with skin EIM in IBD patients and anti-TNF as well as immunomodulatory treatment in CD patients. Conclusion: Our results suggest that young females with a positive family history of IBD might be at increased risk for the onset of skin manifestations and require a careful screening for such complications. [ABSTRACT FROM AUTHOR]

Background: Gallstones and kidney stones are known complications of inflammatory bowel diseases (IBD). Risk factors have been insufficiently studied and explanatory studies date back up to 30 years. It remains unclear, whether improved treatment options also influenced risk factors for these complications. Objectives: Identifying risk factors for gallstones and kidney stones in IBD patients. Methods: Using data from the Swiss Inflammatory Bowel Disease Cohort Study we assessed associations of diseases characteristics with gallstones and kidney stones in univariate and multivariate logistic regression analyses. Results: Out of 2323 IBD patients, 104 (7.8%) Crohn’s disease (CD) and 38 (3.8%) ulcerative colitis (UC) patients were diagnosed with gallstones. Significant risk factors for gallstones were diagnosis of CD, age at diagnosis, disease activity and duration, NSAID intake, extra-intestinal manifestations and intestinal surgery. Kidney stones were described in 61 (4.6%) CD and 30 (3.0%) UC patients. Male gender, disease activity, intestinal surgery, NSAID usage and reduced physical activity were significant risk factors. Hospitalization was associated with gallstones and kidney stones. The presence of gallstones increased the risk for kidney stones (OR 4.87, p<0.001). Conclusion: The diagnosis of CD, intestinal surgery, prolonged NSAID use, disease activity and duration and bowel stenosis were significantly associated with cholecystonephrolithiasis in IBD. [ABSTRACT FROM AUTHOR]

Background: Protein tyrosine phosphatase non-receptor type 22 (PTPN22) plays an important role in immune cell function and intestinal homeostasis. The single nucleotide polymorphism (SNP) rs2476601 within the PTPN22 gene locus results in aberrant function of PTPN22 protein and protects from Crohn’s disease (CD). Here, we investigated associations of PTPN22 SNP rs2476601 in inflammatory bowel disease (IBD) patients in the Swiss IBD Cohort Study (SIBDCS). Methods: 2’028 SIBDCS patients (1173 CD and 855 ulcerative colitis (UC) patients) were included. The clinical characteristics were analysed for an association with the presence of the PTPN22 SNP rs2476601 genotypes ‘homozygous variant’ (AA), ‘heterozygous’ (GA) and ‘homozygous wild-type’ (GG). Results: 13 patients (0.6%) were homozygous variant (AA) for the PTPN22 polymorphism, 269 (13.3%) heterozygous variant (GA) and 1’746 (86.1%) homozygous wild-type (GG). In CD, AA and GA genotypes were associated with less use of steroids and antibiotics, and reduced prevalence of vitamin D and calcium deficiency. In UC the AA and GA genotype was associated with increased use of azathioprine and anti-TNF antibodies, but significantly less patients with the PTPN22 variant featured malabsorption syndrome (p = 0.026). Conclusion: Our study for the first time addressed how presence of SNP rs2476601 within the PTPN22 gene affects clinical characteristics in IBD-patients. Several factors that correlate with more severe disease were found to be less common in CD patients carrying the A-allele, pointing towards a protective role for this variant in affected CD patients. In UC patients however, we found the opposite trend, suggesting a disease-promoting effect of the A-allele. [ABSTRACT FROM AUTHOR]

Background: Thiopurines are known to cause lymphopenia (<1,500 lymphocytes/μl). As severe lymphopenia (<500C/μl) is associated with opportunistic infections, we investigated severity of thiopurine-related lymphopenia and development of opportunistic infections in our tertiary referral centre. Methods: We retrospectively screened medical records of 1,070 IBD patients and identified 100 individuals that developed a total of 161 episodes of lymphopenia during thiopurine treatment between 2002 and 2014. Occurrence of opportunistic infections was documented. A control group consisted of IBD patients receiving thiopurines but without developing lymphopenia. Results: Of a total of 161 episodes of lymphopenia, 23% were severe (<500C/μl). In this subgroup, thiopurine dosing was modified in 64% (dosage reduction: 32%, medication discontinued: 32%). We identified 9 cases (5.5%) of opportunistic infections, of which only two occurred during severe lymphopenia. One opportunistic infection (4.5%) was identified in the control group. No association was found between opportunistic infections and severity of lymphopenia. All patients who suffered from opportunistic infections were receiving additional immunosuppressive medication. Conclusion: Our patients treated with thiopurines rarely developed severe lymphopenia and opportunistic infections did not occur more often than in the control group. A careful monitoring of lymphocytes and prophylactic adjustment of thiopurine therapy might contribute to this low incidence. [ABSTRACT FROM AUTHOR]

Background: The human intestinal microbiota is a crucial factor in the pathogenesis of various diseases, such as metabolic syndrome or inflammatory bowel disease (IBD). Yet, knowledge about the role of environmental factors such as smoking (which is known to influence theses aforementioned disease states) on the complex microbial composition is sparse. We aimed to investigate the role of smoking cessation on intestinal microbial composition in 10 healthy smoking subjects undergoing controlled smoking cessation. Methods: During the observational period of 9 weeks repetitive stool samples were collected. Based on abundance of 16S rRNA genes bacterial composition was analysed and compared to 10 control subjects (5 continuing smokers and 5 non-smokers) by means of Terminal Restriction Fragment Length Polymorphism analysis and high-throughput sequencing. Results: Profound shifts in the microbial composition after smoking cessation were observed with an increase of Firmicutes and Actinobacteria and a lower proportion of Bacteroidetes and Proteobacteria on the phylum level. In addition, after smoking cessation there was an increase in microbial diversity. Conclusions: These results indicate that smoking is an environmental factor modulating the composition of human gut microbiota. The observed changes after smoking cessation revealed to be similar to the previously reported differences in obese compared to lean humans and mice respectively, suggesting a potential pathogenetic link between weight gain and smoking cessation. In addition they give rise to a potential association of smoking status and the course of IBD. [ABSTRACT FROM AUTHOR]