Marko Brinar

Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease†

Background: The autophagy pathway has been linked with Crohns disease (CD) through association of the ATG16L1 and IRGM genes with susceptibility for CD, and also to the Nod2 pathway, involved in CD. Our aim was to investigate polymorphisms in selected autophagy genes for their association with susceptibility to CD. Methods: We prioritized all known human homologs of yeast autophagy (Atg) genes according to their location in a known inflammatory bowel disease (IBD) locus or in a genomic region detected in a genome‐wide association study (GWAS) or GWAS‐meta‐analysis. A total of 70 haplotype tagging single nucleotide polymorphisms (tSNPs) in 12 genes were genotyped in a cohort of CD patients (n = 947) and controls (n = 548). Transmission disequilibrium testing (TDT) was performed in an independent cohort of 335 parent‐child CD‐trios. Results: The frequency of the T‐allele of tSNP rs12303764 in ULK1 was significantly higher in CD (64%) versus controls (57%, corrected P‐value 0.002). TDT demonstrated overtransmission of this allele to affected offspring (P = 0.02). Model‐based multifactor dimensionality reduction (MB‐MDR) interaction analysis confirmed a strong main effect for rs12303764. No interaction was found between ULK1 and CARD15, or between ULK1 genotypes and CD phenotypes. Conclusions: We report a genetic association with a tSNP in ULK1, an interesting candidate gene for IBD, given the role of ULK1 in autophagy initiation, and the interaction between Nod2 and autophagy pathways. To further clarify the role of ULK1 in CD, an in‐depth investigation of the variation in the region and possible role for copy number variation in this region should be evaluated. (Inflamm Bowel Dis 2011)

Costs and resource utilization for diagnosis and treatment during the initial year in a European inflammatory bowel disease inception cohort : an ECCO-EpiCom Study

Background:No direct comparison of health care cost in patients with inflammatory bowel disease across the European continent exists. The aim of this study was to assess the costs of investigations and treatment for diagnostics and during the first year after diagnosis in Europe. Methods:The EpiCom cohort is a prospective population-based inception cohort of unselected inflammatory bowel disease patients from 31 Western and Eastern European centers. Patients were followed every third month from diagnosis, and clinical data regarding treatment and investigations were collected. Costs were calculated in euros (&OV0556;) using the Danish Health Costs Register. Results:One thousand three hundred sixty-seven patients were followed, 710 with ulcerative colitis, 509 with Crohns disease, and 148 with inflammatory bowel disease unclassified. Total expenditure for the cohort was &OV0556;5,408,174 (investigations: &OV0556;2,042,990 [38%], surgery: &OV0556;1,427,648 [26%], biologicals: &OV0556;781,089 [14%], and standard treatment: &OV0556;1,156,520 [22%)]). Mean crude expenditure per patient in Western Europe (Eastern Europe) with Crohns disease: investigations &OV0556;1803 (&OV0556;2160) (P = 0.44), surgery &OV0556;11,489 (&OV0556;13,973) (P = 0.14), standard treatment &OV0556;1027 (&OV0556;824) (P = 0.51), and biologicals &OV0556;7376 (&OV0556;8307) (P = 0.31). Mean crude expenditure per patient in Western Europe (Eastern Europe) with ulcerative colitis: investigations &OV0556;1189 (&OV0556;1518) (P < 0.01), surgery &OV0556;18,414 (&OV0556;12,395) (P = 0.18), standard treatment &OV0556;896 (&OV0556;798) (P < 0.05), and biologicals &OV0556;5681 (&OV0556;72) (P = 0.51). Conclusions:In this population-based unselected cohort, costs during the first year of disease were mainly incurred by investigative procedures and surgeries. However, biologicals accounted for >15% of costs. Long-term follow-up of the cohort is needed to assess the cost-effectiveness of biological agents.

Enlargement of the spinal cord : Inflammation or neoplasm?

Intramedullary spinal tumours are uncommon lesions that can cause significant difficulties in the differential diagnosis between inflammatory diseases such as multiple sclerosis and acute disseminated encephalomyelitis, and vascular malformations or neoplasms. We report five cases in which the history and the clinical symptoms suggested an inflammatory process of the spinal cord but the MRI characteristics were those of neoplastic lesions. Both non-neoplastic and neoplastic intramedullary lesion may have very similar symptoms, and even CSF abnormalities, but in every one of our cases, a more detailed history and longer observation of the clinical course would have led to the correct diagnosis; in such problem cases, empirical treatment and a follow-up MRI after a months observation would be a more prudent approach providing that the patient is not rapidly deteriorating.

Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn's disease patients

BACKGROUND AND AIMS Granulomas are a characteristic microscopic finding in Crohns disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohns disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation. METHODS Surgical specimens from 464 clinically well-documented Crohns patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes. RESULTS Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163). CONCLUSION These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A, ATG2A, FNBP1L and ATG4D, may contribute to granuloma formation.

The differential diagnosis of acute transverse myelitis

The clinical and paraclinical characteristics of acute transverse myelitis (ATM) were analyzed in 31 patients. In some patients there was clinical evidence of complete transection, in others of only partial lesions. Magnetic resonance imaging (MRI) in the acute phase in the first group was normal, but showed cord atrophy subsequently. It is probable that the clinical picture was due to parenchymatous neuronal lesions, analogous to those of axonal polyneuropathy. In the patients with incomplete transverse lesions, the most common finding was demyelination. In the patients with circumscribed demyelinating lesions, the symptoms and MRI were suggestive of clinically isolated syndromes (CIS) predictive of multiple sclerosis (MS). Extensive demyelination was indicative of acute disseminated encephalomyelitis (ADEM) due to hyperergic vasculopathy or various forms of chronic vasculitis. In two patients with variable clinical symptoms, a vascular malformation was the cause of the clinical presentation, and in one patient demyelination was due to the disc compression.

Psychiatric manifestations of multiple sclerosis and acute disseminated encephalomyelitis.

It is unusual for acute disseminated encephalomyelitis and multiple sclerosis to present as purely psychiatric disorders. We report five patients with such demyelinating diseases and symptoms of psychosis, depression or anxiety. The importance of excluding demyelination as the basis for these psychiatric disturbances is emphasized, especially in the presence of unexplained neurologic findings. The possible relationship between psychiatric symptoms and demyelinating disorders is explored.

Serum S100A12 as a new marker for inflammatory bowel disease and its relationship with disease activity

We read with interest the work by Foell et al in which the authors report increased serum levels of the protein S100A12, a marker of neutrophil activation, in patients with Crohns disease and ulcerative colitis in comparison with healthy controls.1 They also demonstrated a correlation between S100A12 in the serum and disease activity as well as a prompt decrease of S100A12 levels in response to infliximab therapy. More recently, the same group showed that faecal S100A12 had even superior sensitivity and specificity than faecal calprotectin in distinguishing active inflammatory bowel disease (IBD) from healthy controls.2 All together, these findings make S100A12 a promising biomarker in IBD. As both studies included only few patients, we wanted to further investigate the accuracy of serum S100A12 in a larger cohort of patients and controls. In brief, S100A12 was determined in …

CNS demyelination in autoimmune diseases

Autoimmune diseases represent a diverse group of disorders that have generally of unknown etiology and poorly understood pathogenesis. They may be organ-specific or systemic, giving rise to overlapping syndromes; more than one autoimmune disease may occur in the same patient. Numerous case reports have documented that multiple sclerosis (MS) may be present concurrently with other autoimmune diseases, most commonly rheumatoid arthritis, autoimmune thyroid disease, type I diabetes mellitus and pernicious anemia. Case reports of disseminated encephalomyelitis (DEM) coincidental with other autoimmune diseases are rare. Many of systemic autoimmune diseases cause central nervous system (CNS) demyelination and are frequently then diagnosed as MS, whereas they often are instances of DEM, the result of vascular, granulomatous or postinfectious manifestations. We have reviewed 15 patients with autoimmune diseases and CNS demyelination in order to determine the nature of the demyelinating process.

Clinical relevance of antibodies against myelin oligodendrocyte glycoprotein in different clinical types of multiple sclerosis

OBJECTIVE Myelin oligodendrocyte glycoprotein (MOG) is a highly immunogenic minor component on the outside surface of CNS myelin which is believed to be one of the autoantigens in multiple sclerosis. The aim of this study was to evaluate the diagnostic potential of anti-MOG IgG antibody levels in cerebrospinal fluid (CSF) and serum of patients with relapsing-remitting multiple sclerosis (RRMS), primary progressive multiple sclerosis (PPMS) and non-inflammatory neurological diseases (NIND) as markers for the different clinical types of multiple sclerosis. PATIENTS AND METHODS Consecutive serum and cerebrospinal fluid samples were taken from 21 patients with RRMS, 7 patients with PPMS and 19 patients with NIND. The antibody responses to MOG were determined in paired samples of these different clinical groups by enzyme-linked immunoassay using a recombinant human MOG protein. RESULTS The performed analysis indicated that the differences in levels of anti-MOG IgG antibody in serum and cerebrospinal fluid from the patients with RRMS, PPMS or NIND were not statistically significant. CONCLUSION The assay is not sensitive or specific enough to be used as a differential diagnostic tool for the clinical types of MS, nor for MS itself.

Natural disease course of Crohn's disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study

Objective The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn’s disease (CD). Design Patients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis. Results In total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5). Conclusion Despite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.