Zsolt Barta

Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn's disease

Aliment Pharmacol Ther 2011; 34: 911–922

Pancreatic autoantibodies are associated with reactivity to microbial antibodies, penetrating disease behavior, perianal disease, and extraintestinal manifestations, but not with NOD2/CARD15 or TLR4 genotype in a hungarian IBD cohort†

Background: Pancreatic autoantibodies (PAB) and goblet cell autoantibodies (GAB) are specific for Crohns disease (CD) and ulcerative colitis (UC), but the sensitivity alone is low. Conventional antibodies and carbohydrates (glycans) are associated with disease phenotype and may be of diagnostic importance in inflammatory bowel disease (IBD). Our aim was to determine the accuracy of PAB and GAB autoantibodies as well as to study relevant phenotype–serotype associations. Methods: A Hungarian study cohort of 1092 subjects, including 689 well‐characterized, unrelated IBD patients (CD: 579, m/f ratio: 274/305, duration: 7.9 ± 11.2 years; UC: 110, m/f ratio: 53/57, duration: 8.9 ± 9.8 years), 139 celiac patients, 100 healthy, and 64 non‐IBD gastrointestinal controls were investigated. Sera were assayed for PAB‐GAB IgA/IgG, anti‐Omp, anti‐Saccharomyces cerevisiae antibodies (ASCA), and anti‐glycans. TLR4 and NOD2/CARD15 was tested by polymerase chain reaction / restriction fragment length polymorphism (PCR‐RFLP). Detailed clinical phenotypes were determined. Results: The prevalence of PAB was significantly more frequent in CD (41.1%) versus UC (22.7%), celiac (22.3%), and controls (8% and 4.6%, P < 0.01 for each), while GAB detection was poor in all groups except UC (15.4%). In CD the combination of PAB and/or anti‐glycans/ASCA increased the sensitivity to 72% and 59%, respectively, for isolated colonic disease. PAB was associated to gylcans (odds ratio [OR] 1.74,P = 0.002), ASCA IgG/IgA (OR 1.75, P = 0.002), Omp (OR 1.86, P = 0.001) as well as perforating, perianal disease, arthritis, ocular, and cutaneous manifestations (P = 0.002–0.032). In contrast, PAB and GAB antibodies were not associated with NOD2/CARD15 or TLR4, response to medical therapy, or need for surgery. No associations were found in UC. Conclusions: PAB autoantibodies in combination with ASCA or anti‐glycan antibodies increase the sensitivity for detecting CD, especially isolated colonic CD. Antibody response to PAB was associated with complicated disease phenotype and extraintestinal manifestations in this Eastern European IBD cohort.

Coeliac disease in Sjögren's syndrome—a study of 111 Hungarian patients

Recent studies report that in patients with Sjögrens syndrome (SS), concomitant coeliac disease (CD) is more frequent than in the average healthy population, with dominance of the latent/silent form. We further investigated this to characterise the clinical and immunolaboratory features of SS patients with CD. One hundred and eleven patients with SS were involved in the study. After detailed history, blood samples were taken for antibodies to gliadin, endomysium, and tissue transglutaminase. Of them, six had positive serology for CD and underwent jejunoscopy and small bowel biopsy to confirm the diagnosis of CD. In five patients, the diagnosis was established histologically. The frequency of CD in the SS population was significantly higher than in the non-SS European population (4.5:100 vs 4.5–5.5:1,000). Laboratory findings in these patients showed significantly higher erythrocyte sedimentation rates and IgG, IgA, and IgM levels. On the basis of these findings, we recommend screening, follow-up, and regular gastrointestinal care of SS patients to identify CD cases and help them to avoid severe malnutrition and intestinal malignancies.

Alfacalcidol treatment restores derailed immune-regulation in patients with undifferentiated connective tissue disease

Vitamin D deficiency may contribute to pathological changes in the number and function of CD4+ T helper cell subsets (CD4+Th1, CD4+Th17, CD4+CD25(bright)Foxp3-natural regulatory T cells-nTreg) in patients with undifferentiated connective tissue disease (UCTD). The aim of the present study was to evaluate, whether alfacalcidol could restore immune-regulatory changes in patients with UCTD. We assessed the optimal dose of alfacalcidol that could normalize the elevated levels of IFN-γ expressed by the CD4+Th1 cells and the IL-17 expressed by Th17 cells. Furthermore alfacalcidol decreased the Th1 and Th17 related cytokine levels, repaired the nTreg/Th7 balance, and restored the functional activity of nTreg cells. Twenty one UCTD patients with Vitamin D deficiency (<30 ng/ml) were administered with three different daily doses of alfacalcidol. Seven patients were supplemented with 0.5 μg/day, 7 patients with 1.0 μg/day, and 7 patients with 1.5 μg/day alfacalcidol treatment during 5 weeks. Our results indicated that 1.0 μg/day alfacalcidol during 5 weeks was the optimal therapeutic regime to increase the vitamin D levels, repair the nTreg/Th17 balance and raise the capacity of nTreg cells to suppress the proliferation of autologous CD4+CD25- cells. 1.5 μg daily dose alfacalcidol was not more effective than the 1.0 μg/day treatment. In this study we described that vitamin D deficiency can contribute to the complex immune-regulatory abnormalities in patients with UCTD and vitamin D substitution therapy can improve the fine balance of pro- and anti-inflammatory processes in the disease.

Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - A Hungarian nationwide observational study

BackgroundInfliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohns disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary.MethodsDuring a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy.ResultsThree hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 ± 11.2 years and the mean duration of disease was 6.7 ± 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Overall response rate was 86.2% (313/363). A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99) and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596). Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%).ConclusionIFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy.

Restriction Enzyme Analysis of Ribosomal DNA Shows that Candida inconspicua Clinical Isolates Can Be Misidentified as Candida norvegensis with Traditional Diagnostic Procedures

ABSTRACT We identified 29 yeast isolates from 22 patients using the API ID32C panel. Twenty-eight of these isolates were Candida norvegensis and one was C. inconspicua. Although C. norvegensis is considered a pseudohypha-producing species, only one isolate produced pseudohyphae. Restriction enzyme analysis of PCR-amplified ribosomal DNA with four different enzymes proved that all isolates were C. inconspicua.

Vitamin D Deficiency and Connective Tissue Disease

Recently, the evidence linking vitamin D status as a potential environmental factor affecting autoimmune disease prevalence continues to accumulate. Beyond that the traditional known metabolic activities, vitamin D has been shown to modulate the immune system and has anti-inflammatory properties. The immune-regulatory role of vitamin D affects both the innate and adaptive immune responses contributing to the immune-tolerance of self-structures. Vitamin D deficiency skews the immunologic response towards loss of tolerance. Serum levels of vitamin D have been found to be significantly lower in several autoimmune or immune-mediated diseases than in the healthy population. Experimental animal models and clinical studies show that 1,25-dihydroxyvitamin D3 or vitamin D receptor (VDR) agonists can either prevent or suppress symptoms of type 1 diabetes, experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erthyematosus and inflammatory bowel disease. The heading aims at reviewing the complex immune-regulatory role of vitamin D from the cellular and humoral level through animal models of autoimmune rheumatic diseases and representing the known contribution of vitamin D in the pathogenesis of connective tissue diseases. Increased vitamin D intakes might reduce the incidence and severity of autoimmune disorders besides reducing the rate of osteoporotic bone fracture.

Celiac disease and microscopic colitis: A report of 4 cases

Celiac disease (CD) is an autoimmune disorder of the small intestine that occurs in genetically predisposed people at all ages. However, it can be associated also to other immunopathological disorders, and may be associated with abnormal histology in segments of the gut other than the small bowel including colonic inflammation. While guidelines for endoscopic investigation of the jejunum are well defined, no indication is defined for colonic investigation. We describe four cases of concurrent CD and microscopic colitis (MC) diagnosed at our department over a 10-year period and analyzed the main features and outcomes of CD in this setting. The symptoms of these patients were improved initially by a gluten-free diet before the onset of MC symptoms. Two of the patients were siblings and had an atypical form of CD. The other two patients with CD and MC also presented with fibrosing alveolitis and were anti-Saccharomyces cerevisiae antibody positive. The co-existence of immune-mediated small bowel and colonic inflammatory and pulmonary diseases are not well-known, and no systematic approach has been used to identify the lifelong patterns of these immune-based diseases. Patients can develop, or present with CD at any stage in life, which can co-exist with other gastrointestinal diseases of (auto-) immune origin. In addition, the familial co-existence and prevalence of MC in patients with a prior diagnosis of CD are unclear. Clinicians managing celiac disease should be aware of these associations and understand when to consider colon investigation.

Seroprevalence of Mycobacterium paratuberculosis in Patients with Crohn's Disease

Although the etiology of Crohns disease remains unclear, in addition to genetic and other environmental factors, microorganisms have been discussed as possibly playing an important role. With increasing concern about the transmission of infectious diseases from animals to humans, attention has refocused on Mycobacterium paratuberculosis as a candidate organism in the etiology of Crohns disease. In a recent population-based case control study of seroprevalence of M. paratuberculosis in patients with Crohns disease and ulcerative colitis, the authors could not prove the difference between inflammatory bowel disease patients and healthy volunteers (1). The rate of positive enzyme-linked immunosorbent assay results was significantly higher for all study groups. In conclusion, in this study, the M. paratuberculosis seropositivity rate was approximately 35% for all groups, and there was no difference in rates among Crohns disease patients, ulcerative colitis patients, healthy controls, and unaffected siblings (1). We also examined the seroprevalence of M. paratuberculosis in 42 Crohns disease patients and 34 healthy, randomly selected volunteers in Debrecen, Hungary. The relatively small number of cases limited our consideration of the possibilities. Adult patients of both sexes were included. All patients had previously received routine Mycobacterium bovis bacillus Calmette-Guerin vaccinations in childhood but had no evidence of tuberculosis in their case histories. The diagnosis of Crohns disease was made using the formally accepted criteria. We used the same adapted enzyme-linked immunosorbent assay (IDEXX Laboratories) as Dr. Bernstein did for serum antibodies to M. paratuberculosis, as Dr. Collins advised (he suggested that we test human sera from healthy blood donors to establish, by analysis of frequency distributions, what a reasonable approximate cutoff level might be for Hungarian patients). We used sera from the healthy controls to set the upper limit of normal with 95% confidence. A positive test for a human serum sample was defined, based on the results with these sera, by a test result equivalent to the mean S/P ratio (0.079) plus 2 standard deviations (2 × 0.123), i.e., 0.325. We proved that only approximately 9% of the controls were seropositive for M. paratuberculosis, in contrast to 33.3% of Crohns disease patients. Even given the small number of subjects in our study, these observations invite further surveys to elucidate the results, as we think they are definitely more than accidental. Our findings may enrich other findings and suggest that M. paratuberculosis has certain importance in Crohns disease after all, but further multicenter research is required for a comparison of results.

Total nasolacrimal duct obstruction in 2 patients with inflammatory bowel disease

To the Editor: Inflammatory bowel diseases (IBDs) are characterized by pathological processes of the systemic, as well as the mucosal immune system, primarily involving the gastrointestinal tract, also potentially affecting several organs, including the eyes and the adjacent structures. Extraintestinal processes of IBD are characterized by immune complex-type hypersensitivity reaction to a colonic antigen. Among extraintestinal manifestations, ocular symptoms of IBD have been reported in 4%–10% of cases and are categorized based on their occurrence frequency, e.g., common, uncommon, and rare. Common manifestations are scleritis, episcleritis, conjunctivitis, and blepharitis, while uncommon is uveitis. Among rare manifestations keratitis, retinitis, pars planitis, marginal corneal disease, scleromalacia perforans, orbital inflammatory disease, central and branch retinal artery occlusions, central retinal vein occlusion, optic neuritis, and retinal vasculitis have been described previously. The development of inflammatory cell infiltrates in extraintestinal sites among other factors are orchestrated by cytokines and chemokines, and also adhesive molecular maintaining the interactions between mucosal immune cells and endothelial cells. Since numerous ocular signs may present together with ulcerative colitis (UC) or Crohn’s disease (CD) and nasolacrimal ductobstruction (NLDO), as an extraintestinal manifestation of active IBD is poorly described, the aim of this study was to assess the clinical, serological, and immunological characteristic features of NLDO in IBDs. Herein we present 2 cases with complete NLDO due to the mucosal involvement of the tear drainage system as the consecutive presenting sign of IBDs.