Contrasting Autoimmune Comorbidities in Microscopic Colitis and Inflammatory Bowel Diseases.

BACKGROUND: Inflammatory bowel diseases (Crohn's disease and ulcerative colitis) and microscopic colitis (lymphocytic and collagenous colitis) are immune-mediated diseases of the gastrointestinal tract, with distinct pathophysiology. OBJECTIVE: We sought to compare the prevalence of autoimmune diseases between microscopic colitis (MC) and inflammatory bowel diseases (IBDs) in our patient cohorts in their medical history. METHODS: We collected data from 611 patients (508 with IBD, 103 with MC). We recorded cases of other autoimmune diseases. The screened documentation was written in the period between 2008 and 2022. We sought to determine whether colonic involvement had an impact on the prevalence of autoimmune diseases. RESULTS: Ulcerative colitis patients and patients with colonic-predominant Crohn's disease had a greater propensity for autoimmune conditions across the disease course than patients with ileal-predominant Crohn's disease. Gluten-related disorders were more common in Crohn's disease than in ulcerative colitis, and slightly more common than in microscopic colitis. In ulcerative colitis, 10 patients had non-differentiated collagenosis registered, which can later develop into a definite autoimmune disease. CONCLUSIONS: Predominantly colonic involvement can be a predisposing factor for developing additional autoimmune disorders in IBD. Ulcerative colitis patients may have laboratory markers of autoimmunity, without fulfilling the diagnostic criteria for definitive autoimmune disorders (non-differentiated collagenosis).

The Effects of Artificial Sweeteners on Intestinal Nutrient-Sensing Receptors: Dr. Jekyll or Mr. Hyde?

The consumption of artificial and low-calorie sweeteners (ASs, LCSs) is an important component of the Western diet. ASs play a role in the pathogenesis of metabolic syndrome, dysbiosis, inflammatory bowel diseases (IBDs), and various inflammatory conditions. Intestinal nutrient-sensing receptors act as a crosstalk between dietary components, the gut microbiota, and the regulation of immune, endocrinological, and neurological responses. This narrative review aimed to summarize the possible effects of ASs and LCSs on intestinal nutrient-sensing receptors and their related functions. Based on the findings of various studies, long-term AS consumption has effects on the gut microbiota and intestinal nutrient-sensing receptors in modulating incretin hormones, antimicrobial peptides, and cytokine secretion. These effects contribute to the regulation of glucose metabolism, ion transport, gut permeability, and inflammation and modulate the gut-brain, and gut-kidney axes. Based on the conflicting findings of several in vitro, in vivo, and randomized and controlled studies, artificial sweeteners may have a role in the pathogenesis of IBDs, functional bowel diseases, metabolic syndrome, and cancers via the modulation of nutrient-sensing receptors. Further studies are needed to explore the exact mechanisms underlying their effects to decide the risk/benefit ratio of sugar intake reduction via AS and LCS consumption.

Liver Abnormalities in Turner Syndrome: The Importance of Estrogen Replacement.

Turner syndrome is one of the most frequently reported sex chromosomal abnormalities, affecting approximately 40 in every 100 000 live female births. The underlying chromosomal alteration is the complete or partial loss of X chromosome or mosaicism. Because of primary ovarian insufficiency, the synthesis of estrogen hormones is compromised, and patients require hormone substitution. Apart from the phenotypical presentation (short stature, primary amenorrhea), the effects of ovarian insufficiency can affect diverse organ systems (such as cardiovascular, endocrine, and lymphatic systems). Hepatobiliary pathology can present on a broad spectrum: from mild asymptomatic hypertransaminasemia to marked architectural changes. Estrogen hormone replacement therapy in these patients can improve the perturbations of laboratory values and can attenuate the progression of hepatic structural changes. Moreover, providing sufficient estrogen replacement has numerous benefits for other conditions of the patients as well. Both the all-cause mortality and deaths from cardiovascular complications are greatly increased in Turner syndrome, and hormone replacement might contribute to the decreased incidence of these events. The diagnostics of Turner syndrome are outside the scope of our paper, and we briefly discuss the cardiovascular complications because many the liver involvement partially involves alterations of vascular origin. Though we sought to highlight the importance of proper hormone replacement therapy, we did not attempt to write a comprehensive recommendation for exact treatment protocols. We provided an overview of preferred therapeutic approaches, as the treatment should be tailored according to the individual patient's needs.

Microscopic colitis in older adults: impact, diagnosis, and management.

Microscopic colitis (comprising lymphocytic and collagenous colitis, albeit an incomplete variant is gaining recognition as well) is a chronic, immune-mediated inflammatory state of the lower gastrointestinal tract (colon). The diagnosis requires diagnostic colonoscopy with characteristic histopathological findings. They have a propensity to present in senior populations (above 60 years of age), particularly women - who are approximately 2.5-3 times more likely to develop microscopic colitis. Preexisting other immune-inflammatory diseases are also shown to predispose patients for the development of microscopic colitis. The classic presentation is profuse watery diarrhea, often during the night or early morning hours. Fecal incontinence and abdominal pain are frequent as well. Thus, the disease impacts patients' quality of life and well-being. The first described cases date back to the seventies and eighties of the twentieth century, thereby they can be considered fairly recently discovered disease states. Our understanding of the disease and its pathophysiology is still incomplete. Although there is a lack of unified recommendation for treatment, most clinicians prefer the use of budesonide, and most published guidelines regard this locally acting glucocorticoid as the therapy of choice. In our article, we aimed for a brief, noncomprehensive overview of the clinical significance, diagnosis, and management of microscopic colitis.

Temporal Relationship of Extraintestinal Manifestations in Inflammatory Bowel Disease.

OBJECTIVES: Thus far, few attempted to characterize the temporal onset of extraintestinal manifestations (EIM) in inflammatory bowel diseases (IBD). We sought to determine the time of onset of these findings in a patient cohort with IBD. METHODS: We reviewed the electronic health records of 508 IBD patients (303 CD, 205 UC) and summarized general patient characteristics and the temporal relationship and order of presentation of extraintestinal manifestations. RESULTS: CD patients were younger at diagnosis. CD patients with ileocolonic involvement (L3) were younger, and UC patients with pancolitis (E3) were slightly younger at diagnosis. A total of 127 out of 303 (41.91%) CD and 81 out of 205 (39.51%) UC patients had EIMs (p = 0.5898). Some patients presented with EIMs before the diagnosis of IBD (9.45% of Crohn's disease and 17.28% of ulcerative colitis patients with EIMs, respectively). Of these, seven cases (four in CD and three in UC) were visible by inspection of the patients (either dermatologic or ocular findings). The diagnosis of IBD and extraintestinal symptoms often occurred within a year (22.83% of CD and 16.04% of UC patients). Typically, the diagnosis of the first extraintestinal symptoms happened after the onset of bowel disease (+4.3 (±6.3) years, range: 10 years before to 30 years after in Crohn's disease and +3.8 (±10) years, range: 24 years before to 30 years after) in ulcerative colitis. UC patients with pancolitis (E3) usually had EIMs earlier in the disease course and displayed EIMs more frequently before IBD diagnosis. Furthermore, patients with pancolitis developed EIMs more frequently than other sub-groups. CONCLUSION: Extraintestinal manifestations in inflammatory bowel diseases can present at any time, relative to the bowel symptoms. In cases, the presence of a characteristic EIM might be a harbinger of the development of IBD.

Microscopic colitis: controversies in clinical symptoms and autoimmune comorbidities.

BACKGROUND: Microscopic colitides are chronic immune-inflammatory bowel diseases. The typical presentation is chronic, watery diarrhoea. Inflammation mostly cannot be visualized via macroscopic inspection. The diagnosis thus requires histologic sampling. The clinical picture can vary. New investigations can prove valuable in setting up recommendations. PATIENTS: A total of 103 patients with microscopic colitis (MC) [28 lymphocytic colitis (LC) 27.2%, 75 collagenous colitis (CC) 72.8%] in the Clinical Centre of the University of Debrecen (tertiary care centre) were included, diagnosed between 1993 and 2020. We aimed for a retrospective analysis characterizing Hungarian MC patients. We sought to compare two subgroups of patients (with either LC or CC). Our investigation focussed on dominant alteration of stool habits, autoimmune and allergic comorbidities. Autoimmune diseases were diagnosed in 39% (40) of the patients, allergic diseases in 26.2% (27) of patients and 22.2% of tested patients had alimentary hypersensitivity to certain foods (18 cases out of 81 tested). RESULTS: Age of diagnosis was younger in LC (44.5 years, SD: 5.3 vs. 51.9 years, SD: 12.8, difference= 7.4 years p = .0151). Autoimmune diseases were equally frequent in the two groups (LC: 10 patients 36%, CC: 30 patients, 40%, difference: 4%, p = .7124). Food-linked hypersensitivities were more common in CC (LC: 1 patient, CC: 17 patients). Difference in allergic diseases (asthma, rhinitis, urticaria) did not differ between groups (LC: 6 patients, 21%; CC: 21 patients, 28%, difference: 7% p = .4739). One-third of the patients did not complain about chronic diarrhoea. These patients had chronic constipation as the main symptom (34 patients, 33%). CONCLUSION: Pre-existing autoimmune and allergic diseases were common in patients with MC. Chronic watery diarrhoea is not experienced in many cases. The absence of certain symptoms should not be used to rule out the condition.

Corneal Manifestations of Inflammatory Bowel Disease.

Purpose: To evaluate detailed corneal parameters of inflammatory bowel disease (IBD) patients, including Crohn's disease (CD) and ulcerative colitis (UC) patients, and to assess associations between anterior segment values and other clinical variables.Methods: This prospective cross-sectional case-control study at a tertiary referral center included 30 CD patients, 36 UC patients and 80 age- and gender-matched controls with no ocular symptoms or ocular surface disorders. All study participants underwent a comprehensive ophthalmological evaluation with special interest in dry eye disease (DED). Corneal parameters were evaluated by Pentacam.Results: The mean age of CD patients, UC patients, and controls was 45.80 ± 11.55 years, 52.00 ± 16.05, and 50.68 ± 14.62, respectively. The average disease duration was 12.72 ± 5.83 years for CD patients and 15.94 ± 10.09 years for UC patients. All pachymetric (center, apex and thinnest) and corneal volume (CV) measurements were significantly decreased, while anterior chamber angle width (ACA) values were significantly increased on both sides in all IBD patients compared to those in controls (p < .05). In addition, several anterior segment parameters were altered unilaterally in CD or UC patients. Negative correlations were found between corneal parameters and Schirmer I test values.Conclusions: Our investigations suggest that IBD patients have thinner corneas compared to that of controls. The coexistence of reduced tear quantity seems to have an additional impact on the thinning of the cornea in IBD patients. Early recognition of corneal impairments, a possible extraintestinal manifestation of IBD, should be included in the disease checkup to reduce vision-threatening developments.

[Staphylococcus-induced immunglobulin E-dependent allergic anaphylaxis in Crohn's disease. First description of an association of symptoms]. / Staphylococcus által kiváltott, immunglobulin-E-alapú anafilaxiás reakciók Crohn-betegségben. Egy tünetegyüttes elso leírása.

Immunglobulin E (IgE)-based, irregularly recurring, severe anaphylactic reactions occurred in a 50-year-old European white male patient suffering also from Crohn's disease. On the base of immunologic laboratory tests concerning the mechanism of the phenomenon, the idea arose whether molecules derived for certain microbial derivatives could enter the blood circulation via the damaged bowel walls in the patient with Crohn's disease and they might act as allergens. The microbial analysis diagnosed atypical Staphylococcus in the stool. The serum level of IgE was very high. The concomitant use of targeted antibiotics and anti-allergy and immunosuppressive agents resulted in a complete remission during a couple of months. Not only Crohn's disease has improved, but also the total serum IgE level has decreased significantly, and the unpredictable anaphylactic attacks have been completely eliminated. In Crohn's disease, the anaphylactic complications induced by atypical microbial allergens (e.g., derivatives of Staphylococcus) can be effectively treated after the recognition of this pathological mechanism. This is the first description of such a pathologic state. Orv Hetil. 2019; 160(38): 1514-1518.

[The extraintestinal spectrum of gluten sensitivity]. / A gluténérzékenység extraintestinalis spektruma.

Although celiac disease (gluten-sensitive enteropathy) is a relatively well known malady, yet is surrounded by several misconceptions. It is in fact, a multi-systemic autoimmune disorder with a wide spectrum of possible presentations, though most clinicians regard it as a solely gastrointestinal disease. Another misconception that it is a disease of paediatric age group. Thus, the diagnosis of adult or elderly patients is often delayed. Recognition of the disease in the adults can be challenging, as there are less pronounced gastrointestinal symptoms, and patients present with other manifestations (i.e., neurologic, cardiovascular, hepatobiliary, or hematologic involvement are common). As these extraintestinal manifestations are less well known among practicing physicians, here we propose a brief overview of these. We aimed to summarize the available literature on the extraintestinal manifestations associated with gluten sensitivity. Orv Hetil. 2019; 160(34): 1327-1334.

Evaluation of Objective Signs and Subjective Symptoms of Dry Eye Disease in Patients with Inflammatory Bowel Disease.

AIM: To evaluate tear film parameters and relationship of objective clinical signs and subjective symptoms of dry eye disease (DED) in inflammatory bowel disease (IBD) subgroups. METHODS: 39 patients with Crohn's disease (CD), 26 patients with ulcerative colitis (UC), and 39 control persons with no ocular symptoms or surface disorders were included in this prospective, case-control, and cross-sectional study. The ocular surface disease index (OSDI) questionnaire was applied to evaluate dry eye symptoms, and objective tests of DED were performed on both eyes of each subject. RESULTS: The average of OSDI scores was 30.59 (±16.68) in CD patients, 24.67 (±23.48) in UC patients, and 11.19 (±5.8) in controls. Except for tear film breakup time (tBUT) and Schirmer-I values other objective parameters were better in UC patients, than in CD patients. CD patients rather than UC patients tend to develop DED. This was associated with immunosuppressant and TNF-α inhibitor use. CONCLUSIONS: Clinicians must be aware of the spectrum of DED involvement in IBD and suggest using artificial tears in order to decrease severity of ocular complications.

Increased IL-21 Expression Induces Granzyme B in Peripheral CD5(+) B Cells as a Potential Counter-Regulatory Effect in Primary Sjögren's Syndrome.

Recently, we reported elevated proportions of circulating follicular T helper cells and higher levels of interleukin- (IL-) 21 in primary Sjögren's syndrome (pSS). Interaction of invariant natural killer T (iNKT) cells with B cells and granzyme B (GrB) production may be also important in pSS. Thirty-two pSS patients and 24 healthy controls were enrolled in our study. We investigated the expression of intracellular GrB and IL-21 receptor (IL-21R) of CD19(+)CD5(+) and CD19(+)CD5(-) B cells; furthermore, we determined the IL-21 expression of iNKT cells as well. We also assessed the proportion of transitional (CD19(+)CD24(high)CD38(high)), mature (CD19(+)CD24(int)CD38(int)) and primarily memory (CD19(+)CD24(high)CD38(-)) B cells. CD5(+) but not CD5(-) B cells showed elevated GrB and IL-21R expression in pSS; additionally IL-21 expression of iNKT cells was also elevated. The ratios of transitional and mature B cells were elevated in pSS, while primarily memory B cell percentages were decreased, which correlated with GrB and IL-21R expression of CD19(+) B cells. Our results suggest that enhanced IL-21R expression of CD19(+)CD5(+) B cells and production of IL-21 by iNKT cells may play an important role in the pathogenesis of pSS by regulating CD19(+)CD5(+) B cell functions and increasing GrB production, presumably leading to a counter-regulatory effect in the disease.

Increased levels of anti-heat-shock protein 60 (anti-Hsp60) indicate endothelial dysfunction, atherosclerosis and cardiovascular diseases in patients with mixed connective tissue disease.

Heat-shock protein 60 (Hsp60) has been shown to provoke inflammation, and anti-Hsp60 may facilitate the development of atherosclerosis. In this study, we have investigated 30 patients with mixed connective tissue disease (MCTD) and assessed anti-Hsp60 and their relationship to cardiovascular diseases (CVD). Out of 30 patients with MCTD, 15 had CVDs. Anti-Hsp60 antibody was determined by enzyme-linked immunosorbent assay. Since endothelial dysfunction and accelerated atherosclerosis are characteristic to MCTD, a wide array of MCTD-, endothelial dysfunction- and CVD-associated parameters was investigated: serum lipid levels, paraoxonase activity (PON1), rich nuclear ribonucleoprotein U1 (anti-U1RNP), anti-endothelial cell antibodies, anti-cardiolipin and anti-ß2-glycoprotein I antibody isotypes (anti-CL and anti-ß2GPI), endothelin-1 (ET-1) levels, also intima-media thickness (IMT), a quantitative indicator of atherosclerosis. In MCTD, anti-Hsp60 antibody levels were significantly higher than in healthy individuals (p < 0.02). MCTD patients with CVD had significantly higher levels of anti-Hsp60 compared to MCTD without CVD (p = 0.001). Patients with MCTD had significantly lower high-density lipoprotein cholesterol (p = 0.02) and PON activity (p < 0.001), and significantly increased systolic (p < 0.0002) and diastolic (p < 0.001) blood pressure compared to healthy individuals. Anti-U1RNP levels (p < 0.002) and IMT were higher in patients compared to controls (p = 0.002). The CVD-positive MCTD patients had increased anti-Hsp60 (p < 0.0013), anti-CL IgG (p = 0.0005), ET-1 serum concentration (p < 0.05) and IMT levels (p < 0.001) compared to MCTD patients without CVD. Anti-Hsp60 showed a strong correlation with anti-oxLDL (r = 0.36, p = 0.01) and serum ET-1 (r = 0.62, p < 0.001) and negative correlation with PON activity (r = -0.47, p = 0.01). Anti-Hsp60 indicates endothelial injury, CVD, and can function as a novel atherosclerotic risk factor, also a valuable diagnostic marker in patients with MCTD.

Clinical course, prognosis, and causes of death in mixed connective tissue disease.

OBJECTIVE: To study the survival rate and prognostic indicators of mixed connective tissue disease (MCTD) in a Hungarian population. METHODS: Two hundred eighty patients with MCTD diagnosed between 1979 and 2011 were followed prospectively. Clinical features, autoantibodies, and mortality data were assessed. Prognostic factors for survival were investigated and survival was calculated from the time of the diagnosis by Kaplan-Meier method. RESULTS: A total of 22 of 280 patients died: the causes of death were pulmonary arterial hypertension (PAH) in 9 patients, thrombotic thrombocytopenic purpura in 3, infections in 3, and cardiovascular events in 7. The 5, 10, and 15-year survival rates after the diagnosis was established were 98%, 96%, and 88%, respectively. The deceased patients were younger at the diagnosis of MCTD compared to patients who survived (35.5 ± 10.4 vs 41.8 ± 10.7 yrs; p < 0.03), while there was no difference in the duration of the disease (p = 0.835). Our cohort study showed that the presence of cardiovascular events (p < 0.0001), esophageal hypomotility (p = 0.04), serositis (p < 0.001), secondary antiphospholipid syndrome (p = 0.039), and malignancy (p < 0.001) was significantly higher in the deceased patients with MCTD. The presence of anticardiolipin (p = 0.019), anti-ß2-glycoprotein I (p = 0.002), and antiendothelial cell antibodies (p = 0.002) increased the risk of mortality. CONCLUSION: Overall, PAH remained the leading cause of death in patients with MCTD. The prevalence of cardiovascular morbidity and mortality, malignancy, and thrombotic events increased during the disease course of MCTD. The presence of antiphospholipid antibodies raised the risk of mortality.

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.

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.

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.

Successful use of adalimumab for treating fistulizing Crohn's disease with pyoderma gangrenosum: Two birds with one stone.

Crohn's disease (CD) is a chronic relapsing and remitting autoinflammatory disorder of the gastrointestinal tract that has many intestinal and extraintestinal complications. The purpose of treatment is long-term remission, reduction of complications, and improvement of patients' quality of life. In many cases, this can be quite challenging and it is necessary to have a well thought out management strategy. We present the case of a 38-year-old woman with fistulizing CD that manifested as diffuse abdominal pain and bloody diarrhea accompanied by arthralgia. In addition, there were ulcerative lesions surrounded by cutaneous inflammation and erythema on her extremities, indicative of pyoderma gangrenosum. The patient was treated with high doses of parenteral methylprednisolone without any improvement and was started on adalimumab. A positive response to adalimumab therapy was observed: after 2 mo of therapy, the ulcerative skin lesion healed completely and the enterogastric fistula was closed after 5 mo adalimumab treatment. Adalimumab might be a suitable initial as well as maintenance therapy in patients with complicated CD.