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Tularemia is a rare zoonotic disease caused by the two predominant subspecies of Francisella tularensis, namely subspecies tularensis and subspecies holarctica. The latter is less virulent than the former, is endemic in Europe, and usually has a mild disease course, although respiratory involvement and bacteraemia can occur. Tularemia in Belgium is rare, but the incidence seems to be increasing. It therefore seems prudent to raise awareness among clinicians for this potentially severe disease. We report the first case of pneumonic tularemia with bacteraemia from Belgium, and want to recommend including Francisella tularensis in the differential diagnosis of pneumonia when an unfavorable evolution is seen with standard treatment. [ABSTRACT FROM AUTHOR]

• More than a quarter of patients with PMR may have subclinical GCA at diagnosis. • Meta-analysis of a large patients' data set could not identify a marker for subclinical GCA. • Classical inflammatory parameters such as ESR and CRP were not associated with subclinical GCA. • A paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed. To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Background & Aims: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. Methods: A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls). Results: The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6–6.5; P = 2.6 × 10−26; and rs2844559: OR, 4.7; 95% CI, 3.5–6.4; P = 4.2 × 10−26 in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06–1.50; and rs3197999: OR, 1.22; 95% CI, 1.02–1.47, respectively), with circumstantial evidence supporting the G-protein–coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes. Conclusions: Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC. [Copyright &y& Elsevier]

Background/Aims: Primary sclerosing cholangitis (PSC) is a progressive cholestatic disease commonly associated with inflammatory bowel disease (IBD) and characterized by fibrosing inflammatory destruction of bile ducts. The histological features in the liver of PSC patients are similar to those observed in cystic fibrosis (CF). Our aim was to study whether variants in the CFTR gene are associated with the occurrence and/or evolution of PSC. Methods: PSC patients (n =140) were genotyped for F508del, the TGmTn variants, and four additional polymorphic loci (1001+11 C>T, M470V, T854T and Q1463Q), and compared to 136 matched healthy controls. Results: The 1540G-allele, encoding V470, was less frequent in PSC (52%) than in controls (64%, p =0.003), and was associated with protection against PSC in individuals without IBD (OR 0.25, 95% CI 0.12–0.52, p =0.0002). Also TG11-T7 was less frequent in PSC (53%) than in controls (61%, p =0.04), this haplotype was associated with reduced risk for PSC (OR 0.34, 95% CI 0.17–0.70, p =0.003) in individuals without IBD. Conclusions: In this cohort of PSC patients, several CFTR-variants affecting the functional properties of the CFTR protein seem to offer protection against the development of PSC, confirming our hypothesis that CFTR might be implicated in the pathogenesis of PSC. [Copyright &y& Elsevier]

Background & Aims: Three years after the identification of NOD2/CARD15, 2 more genes for inflammatory bowel diseases (IBDs) were reported. The carnitine/organic cation transporter (OCTN) on 5q31 (IBD5) is associated with Crohn’s disease (CD) and DLG5 (10q23), a member of membrane-associated guanylate kinase (MAGUK) family, with IBD. We studied mutation prevalence, assessed phenotypic expression, and performed conditional analysis to examine evidence for gene-gene interactions. Methods: A cohort of 2032 individuals was genotyped for disease-associated OCTN and DLG5 variants, including 981 patients with IBD (CD, n = 769; ulcerative colitis, n = 186; indeterminate colitis, n = 26) followed up at a tertiary IBD center. For 373 patients, DNA from both parents was available (cohort 1) for transmission disequilibrium testing analysis; case-control analysis was performed in 608 patients and 305 controls (cohort 2). Results: There was no distortion of transmission toward affected offspring for any of the variant alleles. Case-control analysis also failed to shown an association. A higher frequency of DLG5 113A was observed in CARD15-positive patients (12.2%) compared with CARD15-negative patients (8.7%; P = .033). The OCTN-TC risk haplotype was associated with penetrating disease (odds ratio, 1.474; 95% confidence interval, 1.028–2.114; P = .035). For DLG5, there were no associations with a particular phenotype. Conclusions: DLG5 and OCTN do not play a role in the susceptibility to IBD, CD, or ulcerative colitis in the Flemish population but play a role in the phenotypic expression of the disease. OCTN variants were associated with perianal and penetrating CD. More studies in independent populations are urgently needed to assess the validity of DLG5 and OCTN in the pathogenesis of IBD. [Copyright &y& Elsevier]

Background & Aims: Clinical presentation at diagnosis and disease course of Crohn''s disease (CD) are heterogeneous and variable over time. Early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. We examined the influence of recently discovered CD-associated susceptibility loci on changes in disease behavior and evaluated whether a genetic risk model for disease progression could be generated. Methods: Complete medical data were available for 875 CD patients (median follow-up time, 14 years; interquartile range, 7–22). Fifty CD-associated polymorphisms were genotyped. Kaplan–Meier survival analyses, multiple logistic regression, and generalized multifactor dimensionality reduction analyses (GMDR) were performed, correcting for follow-up time. Results: Homozygosity for the rs1363670 G-allele in a gene encoding a hypothetical protein near the IL12B gene was independently associated with stricturing disease behavior (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.60–18.83; P = .007) and with shorter time to strictures (P = .01), especially in patients with ileal involvement (P = .0002). Male patients carrying at least one rs12704036 T-allele in a gene desert had the shortest time to non-perianal fistula (P < .0001). The presence of a C-allele at the CDKAL1 single nucleotide polymorphism rs6908425 and the absence of NOD2 variants were independently associated with development of perianal fistula (OR, 8.86; 95% CI, 1.13–69.78; P = .04 and OR, 0.56; 95% CI, 0.38–0.83; P = .004, respectively), particularly when colonic involvement and active smoking were present. Conclusions: CD-associated polymorphisms play a role in disease progression and might be useful in identifying patients who could benefit from an early top-down treatment approach. [Copyright &y& Elsevier]