Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

BACKGROUND: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. PATIENTS AND METHODS: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. RESULTS: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. CONCLUSIONS: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.

Correction: PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

A multicentre case control study on complicated coeliac disease: two different patterns of natural history, two different prognoses.

BACKGROUND: Coeliac disease is a common enteropathy characterized by an increased mortality mainly due to its complications. The natural history of complicated coeliac disease is characterised by two different types of course: patients with a new diagnosis of coeliac disease that do not improve despite a strict gluten-free diet (type A cases) and previously diagnosed coeliac patients that initially improved on a gluten-free diet but then relapsed despite a strict diet (type B cases). Our aim was to study the prognosis and survival of A and B cases. METHODS: Clinical and laboratory data from coeliac patients who later developed complications (A and B cases) and sex- and age-matched coeliac patients who normally responded to a gluten-free diet (controls) were collected among 11 Italian centres. RESULTS: 87 cases and 136 controls were enrolled. Complications tended to occur rapidly after the diagnosis of coeliac disease and cumulative survival dropped in the first months after diagnosis of complicated coeliac disease. Thirty-seven cases died (30/59 in group A, 7/28 in group B). Type B cases presented an increased survival rate compared to A cases. CONCLUSIONS: Complicated coeliac disease is an extremely serious condition with a high mortality and a short survival. Survival depends on the type of natural history.

Assessment of Nutritional Status by Bioelectrical Impedance in Adult Patients with Celiac Disease: A Prospective Single-Center Study.

The gluten-free diet [GFD] has been linked to an increased risk of weight gain and the development of metabolic disorders. Most of the studies have focused on the effect of GFD on the Body Mass Index [BMI]. We aimed to evaluate the nutritional status using specific nutritional parameters in patients with celiac disease [CeD] at diagnosis and on a GFD compared to healthy controls. We recruited subjects at our outpatient clinic at the University of Padua. We collected demographic and clinical data and values obtained with bioelectrical impedance analysis. A total of 24 CeD patients and 28 healthy controls were enrolled. CeD patients at diagnosis had a lower body cell mass index [BCMI, p = 0.006], fat-free mass index [FFMI, p = 0.02], appendicular skeletal muscle index [ASMI, p = 0.02], and phase angle [PA] [p < 0.001] compared to controls. Their percentage of extracellular water [ECW] was also higher [p < 0.001]. Considering CeD patients after GFD, nutritional status significantly improved after 6 months of GFD. We did not observe differences in BMI among groups [p = ns]. CeD patients at diagnosis were found to have a poorer nutritional status than healthy controls, with a positive effect of the GFD on their nutritional status, underlining the inefficacy of evaluating this aspect through only BMI evaluation.

Clinical features and psychological impact of celiac disease at diagnosis.

BACKGROUND AND AIM: We aimed to describe the socio-demographic, behavioral and clinical profiles of adult patients with newly diagnosed celiac disease (CeD) and their possible association with QoL and psychological symptoms. METHODS: Adults newly diagnosed with CeD and residents in the Veneto region were included. Their sociodemographic characteristics, clinical presentation, mode of diagnosis, duration of symptoms before diagnosis and comorbidities were recorded. All patients completed the Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI) and Short Form Health Survey (SF-36) questionnaires. RESULTS: Between 2016 and 2019, 110 CeD patients (81% females, mean age 37.5) were recruited. At diagnosis, patients were categorized into classical (n = 56), nonclassical CeD (n = 49) and asymptomatic (n = 5) groups. Patients with classical presentation had a lower QoL than nonclassical patients, who were found to be more depressed. We observed a diagnosis delay of more than 7 months in more than 60% of patients with both classical and nonclassical presentations and we found that a longer duration of GI symptoms decreased the self-reported SF36 scores in the physical health (p = 0.002), social functioning (p = 0.03) and general health (p = 0.009) domains. Women had an overall lower self-perceived QoL. CONCLUSIONS: Symptomatic presentation at CeD diagnosis, diagnostic delay and sex may affect QoL and psychological disorders.

Quality of Life and Psychological Disorders in Coeliac Disease: A Prospective Multicentre Study.

Coeliac disease (CeD) has been associated with psychological disorders and reduced quality of life. Our prospective study evaluated the changes in the quality of life, anxiety and depression in CeD patients up to two years after diagnosis. We recruited adult patients residing in the Veneto region with a new diagnosis of CeD. Several validated questionnaires were administered to measure quality of life, psychological symptoms and adherence to a gluten-free diet (GFD) at the time of diagnosis and after 1 and 2 years. Ninety-three patients reached the 1-year follow-up (81.7% were females with a median age at diagnosis of 35 years), and 55 patients reached the 2-year follow-up. We observed a significant improvement in quality of life, anxiety and depression scores at 1 year after diagnosis, particularly in patients who complied with a GFD. The improvements among classical CeD patients were similar to those observed in nonclassical patients except for anxiety, which improved only in patients with a classical presentation at diagnosis. Age, sex and other disease factors did not affect the change in quality of life (QoL) or other mood disorders. Most of the improvements measured 1 year after diagnosis and 2 years after diagnosis were not significant. In conclusion, QoL and mood disorders must be considered, and psychological counselling should be used when needed.

The Risk of Malignancies in Celiac Disease-A Literature Review.

Celiac disease (CeD) is an immune-mediated enteropathy precipitated by ingestion of gluten in genetically predisposed individuals. Considering that CeD affects approximately 1% of the Western population, it may be considered a global health problem. In the large majority of cases, CeD has a benign course, characterized by the complete resolution of symptoms and a normal life expectancy after the beginning of a gluten-free-diet (GFD); however, an increased risk of developing malignancies, such as lymphomas and small bowel carcinoma (SBC), has been reported. In particular, enteropathy-associated T-cell lymphoma (EATL), a peculiar type of T-cell lymphoma, is characteristically associated with CeD. Moreover, the possible association between CeD and several other malignancies has been also investigated in a considerable number of studies. In this paper, we aim to provide a comprehensive review of the current knowledge about the associations between CeD and cancer, focusing in particular on EATL and SBC, two rare but aggressive malignancies.

COVID-19 pandemic perception in adults with celiac disease: an impulse to implement the use of telemedicine.

Background: Coronavirus Disease 2019 (COVID-19) causes severe complications and deaths all over the world. COVID-19 also has indirect effects from the lockdown and the possible lack of food. We aimed to evaluate the perception of this in Celiac Disease (CeD) patients who require a lifelong gluten-free diet as a therapy. Methods: We invited by e-mail CeD adult patients from the University of Salerno (Campania, South Italy) and the University of Padua (Veneto, North Italy) to answer an ad hoc COVID-19 survey. Results: We sent the web survey to 651 email addresses and we received 276 answers (42,4%). CeD patients did not feel more vulnerable because they had CeD (not at all 56.6%) and they did not worry much about the possible shortness of gluten-free food during the epidemic (not at all 48.5%). The most worried were the elderly patients, patients with other comorbidities and females. Finally, CeD patients were happy with remote consultations and explicitly asked to have them. Discussion: The COVID-19 pandemic has impacted a proportion of patients with CeD; in particular, women, elderly patients, patients with other comorbidities. COVID-19, although a challenging experience from the medical and the psychological point of view, has offered an opportunity to practice, on a large-scale, a remote consultation approach for CeD healthcare.

Quality-of-Life Evaluation in Coeliac Patients on a Gluten-Free Diet.

The treatment for coeliac disease (CD) has a considerable psychological impact on patients, which may vary depending on subjects and clinical characteristics. The aim of this study was to describe the quality of life (QoL) in CD patients during follow-up, evaluating which factors can influence it. Patients with CD who consecutively visited the outpatient clinic of CD Unit of the University Hospital of Padua from January to September 2019 were enrolled. Demographics and clinical information were collected, and all patients were asked to answer the CD-QoL and Biagi's validated questionnaires. Student's t-test and chi-square test were used to compare the continuous and categorical variables, respectively. One hundred patients were enrolled (86 females, mean age at test ± SD: 39.73 ± 13.51; mean age at diagnosis ± SD: 33.09 ± 12.92), with 61% of them having been diagnosed with CD within the previous 5 years. At the time of diagnosis, 43 CD patients reported classical CD presentation, 32 non-classical features, 16 only anaemia and 9 were asymptomatic. The mean CD-QoL value was overall high (80.54 ± 11.91). We found that the "health concerns" subscale score was significantly lower in subjects aged more than 35 years compared to younger subjects (p = 0.03). We also observed that the CD-QoL score in gluten-free diet (GFD)-adherent patients tended to be higher compared to subjects who were non-compliant, with a significantly higher percentage of patients with low score for the "dysphoria" subscale (p = 0.05). This study showed an overall good QoL in subjects on a GFD. However, subjects older and non-compliant to GFD appear to experience more health concerns and suffer from dysphoria, respectively.

A Survey on Nutritional Knowledge in Coeliac Disease Compared to Inflammatory Bowel Diseases Patients and Healthy Subjects.

Background and aim: Nutritional deficiencies are frequent in coeliac disease (CeD), mostly because of the nutritional deficits in gluten-free foods and because of wrong behaviors. We aimed to investigate the level of nutritional knowledge in a cohort of CeD patients in comparison with patients with inflammatory bowel disease (IBD) and healthy subjects. Materials and methods: We consecutively recruited CeD patients and matched-sex and -age IBD patients between April and December 2019 at the University Hospital of Padua outpatient clinic. Healthy subjects were also recruited from family and friends of the hospital staff. The CeD patients were asymptomatic on a gluten-free diet, whereas the IBD patients were in remission. All of the subjects completed the Moynihan validated questionnaire to measure their nutritional knowledge. Results: We included 96 CeD patients, 96 IBD patients, and 65 healthy controls. We found that CeD patients were less aware of nutritional recommendations compared with healthy subjects (HS), and were less able to identify nutrient sources compared with IBD patients and to choose healthy food compared with both groups. The Moynihan questionnaire mean total score was not significantly different between CeD and IBD groups (mean 22.5 ± 2.3 for CeD, 22.0 ± 2.2 for IBD), while it was statistically significantly worse in CeD compared with healthy subjects (mean 21.2 ± 2.3 for HS, p = 0.001). Conclusions: CeD patients tend to focus their diet on gluten avoidance, while IBD patients tend to follow a healthier diet, probably because they believe that diet plays a major role in regulating inflammation and, therefore, their symptoms. A dietitian consultation at CeD diagnosis is recommended.

Insights into the pathogenesis of catastrophic antiphospholipid syndrome. A case report of relapsing catastrophic antiphospholipid syndrome and review of the literature on ischemic colitis.

We present the case of a woman with a severe clinical history of antiphospholipid syndrome and persistent positivity for lupus anticoagulant, IgG anticardiolipin and IgG anti-ß2Glycoprotein I antibodies. An acute clinical onset characterized by severe abdominal pain immediately followed by circulatory shock and histological colonic small vessel thrombosis pattern pointed to a diagnosis of ischemic colitis. The subsequent rapid onset of pulmonary alveolitis and heart failure associated to subendocardial hypoperfusion led to a diagnosis of definite catastrophic antiphospholipid syndrome (CAPS). Conventional triple therapy together with a broad-spectrum preventive antibiotic therapy were quickly initiated, and the outcome was favorable. We evaluated the patients with ischemic colitis in CAPS described in the literature between 1992 and May 2019 and our CAPS case. In accordance with the "two-hit" hypothesis and on the basis of the patients' data, we would like to speculate that the colonic wall necrosis related to ischemic colitis damaged the intestinal barrier causing loss of resistance to bacteria and leading to endotoxemia and bacteremia with bacteria translocation through the circulatory stream to the lungs and heart. The bacteria acted as the priming factor which favored the binding of ß2Glycoprotein I to the endothelium vessels in the colon, lungs, and heart following activation of anti-ß2Glycoprotein I antibodies which attached to the domain I of ß2Glycoprotein I. This was followed by complement activation which triggered the thrombotic and cytokine storm. If further clinical studies confirm this hypothesis, the treatment of CAPS could be more targeted and effective.

Neurological complications of celiac disease and autoimmune mechanisms: a prospective study.

Humoral immune mechanisms may have a role in the neurological complications of celiac disease (CD). We assessed 71 CD patients for neurologic manifestations and presence of serum antibodies to neural antigens. Sixteen patients (22.5%) were found to have neurological deficits including headache, depression, entrapment syndromes, peripheral neuropathy, and epilepsy. Antibody reactivity to neural antigens was detected in 30/71 (42.2%) patients. There was no clear correlation between anti-neural reactivity and neurologic dysfunction. Follow-up of 62 patients did not reveal change in electrophysiology or antibodies, regardless of diet. However, in 2 patients with neuropathy, symptoms improved or worsened depending on the diet.

IL-4 -588C>T polymorphism and IL-4 receptor alpha [Ex5+14A>G; Ex11+828A>G] haplotype concur in selecting H. pylori cagA subtype infections.

BACKGROUND: The Th2 cytokine IL-4 might limit H. pylori associated gastric inflammation and favour H. pylori clearance. The aim of the study was to verify whether IL-4 -588C>T SNP, or two SNPs of the gene coding the alpha chain of IL-4 receptor (IL-4RA Ex5+14A>G, IL-4RA Ex11+828A>G) considered singly or as haplotypes, are correlated with H. pylori virulence genes or H. pylori associated diseases. METHODS: We studied 144 patients with non-cardia gastric cancer (NCGC)(41/50 with present or past H. pylori infection), 75 with duodenal ulcer (DU)(66 H. pylori infected) and 171 with gastritis (CG)(107 H. pylori infected). cagA gene was present in 24/28 NCGC, 45/59 DU and 56/107 CG. RESULTS: All SNPs were in Hardy-Weinberg equilibrium. IL-4RA haplotypes frequencies were estimated using Arlequin software. Neither the SNPs nor the IL-4RA haplotype correlated with disease diagnosis, H. pylori infection, degree of mucosal inflammation or intestinal metaplasia. IL-4 -588T allele (OR=3.69, 95% CI:1.34-10.16) and IL-4RA GA haplotype (p<0.05) enhanced the risk for cagA positive infections. IL-4RA GA haplotype correlated with IL-4 protein levels in H. pylori infected gastric mucosa. CONCLUSIONS: IL-4 and IL-4RA gene polymorphisms concur in selecting the H. pylori infecting strain, probably influencing the IL-4 signalling pathway.

Clarithromycin resistance, tumor necrosis factor alpha gene polymorphism and mucosal inflammation affect H. pylori eradication success.

Several bacterial and host-related factors concur in causing Helicobacter pylori eradication failure. We ascertained the role of bacterial virulence genes (cagA, vacA), clarithromycin resistance [Cla(R), 23S ribosomal RNA (rRNA) mutations], host polymorphism of CYP2C19 (polyphosphoinositide, PPI, metabolism) and of the cytokines IL-1B-31C>T, IL-1RN VNTR, IFN-gamma+874A>T, TNF-alpha-1031T>C, TNF-alpha-857C>T, TNF-alpha-376G>A, TNF-alpha-308G>A, TNF-alpha-238G>A, IL-10-1082A>G, IL-10-819C>T, IL-10-592C>A, IL-12A+6686G>A, IL-12B+15485A>C. Two groups of H. pylori-infected and H. pylori-treated patients were retrospectively identified: 45 not eradicated and 57 eradicated. Treatment failure was significantly correlated with Cla(R) (all resistant strains in non-eradicated patients); with TNF-alpha-238, IL10-819, IL10-592, IL-12B+15485 single nucleotide polymorphism (SNP); with IL10 ATA/ATA haplotype; and with antral inflammatory grade. On considering Cla(S)-infected patients only, logistic regression analysis (eradication = dependent; TNF-alpha-238, IL12B + 15485 genotypes, IL10 ATA/ATA as present or absent, antral gastritis grade = covariates) confirmed as significantly correlated with eradication antral gastritis grade only (Exp(B) = 6.48; 95% CI, 1.2-35.01). In conclusion, the bacterial determinant causing triple therapy failure is clarithromycin resistant, being virulence genes not involved. The host related factors that favor eradication are those linked to inflammation: a higher inflammatory infiltrate in the mucosa, possibly favored by genotypes able to down regulate the anti-inflammatory cytokine response, enhance the chance of eradication success.

PROgnosticating COeliac patieNts SUrvivaL: the PROCONSUL score.

INTRODUCTION: It has been shown that mortality rates of coeliac patients correlate with age at diagnosis of coeliac disease, diagnostic delay for coeliac disease, pattern of clinical presentation and HLA typing. Our aim was to create a tool that identifies coeliac patients at higher risk of developing complications. METHODS: To identify predictors of complications in patients with coeliac disease, we organised an observational multicenter case-control study based on a retrospective collection of clinical data. Clinical data from 116 cases (patients with complicated coeliac disease) and 181 controls (coeliac patients without any complications) were collected from seven European centres. For each case, one or two controls, matched to cases according to the year of assessment, gender and age, were selected. Diagnostic delay, pattern of clinical presentation, HLA typing and age at diagnosis were used as predictors. RESULTS: Differences between cases and controls were detected for diagnostic delay and classical presentation. Conditional logistic models based on these statistically different predictors allowed the development of a score system. Tertiles analysis showed a relationship between score and risk of developing complications. DISCUSSION: A score that shows the risk of a newly diagnosed coeliac patient developing complications was devised for the first time. This will make it possible to set up the follow-up of coeliac patients with great benefits not only for their health but also for management of economic resources. CONCLUSIONS: We think that our results are very encouraging and represent the first attempt to build a prognostic score for coeliac patients.

Trefoil peptides, E-cadherin, and beta-catenin expression in sporadic fundic gland polyps: further evidence toward the benign nature of these lesions.

Sporadic fundic gland polyps (FGP) are the most common type of gastric polyps and their pathogenesis is still unclear, although a beta-catenin gene mutation has been described. They are regarded as benign lesions but low-grade dysplasia has been observed, arising more debate on their potential progression to a malignant phenotype. We investigated in FGP the role of factors involved in cell integrity, proliferation, and intercellular adhesion: trefoil peptides (TFF1, TFF2), MIB1, E-cadherin, and beta-catenin. We selected randomly 24 patients with FGP, 24 with normal gastric mucosa and 12 with atrophic gastritis with diffuse intestinal metaplasia (IM-gastritis), all Helicobacter pylori negative. The expression of all factors was examined by immunohistochemistry. In polyps and normal mucosa, TFF1 is expressed only in foveolar compartment whereas in IM-gastritis the signal is reduced in all the compartments. TFF2 is expressed in polyps and normal mucosa, in proliferative and basal compartment, whereas in IM-gastritis the expression is reduced or absent. E-cadherin is expressed in the entire zone: with a medium signal in normal mucosa and polyps, and weaker in IM-gastritis. The beta-catenin's signal in normal mucosa and polyps is moderate-to-intense in proliferative and basal compartments, whereas in IM-gastritis signal is significantly reduced in all the compartments. MIB1 in normal mucosa and polyps is expressed only in proliferative compartment, whereas its expression is stronger in IM-gastritis and involves also basal compartment. In conclusion all the factors considered were normally expressed in FGP and this, especially considered against the findings in IM-gastritis, supports the benign nature of FGP.

Celiac disease in North Italian patients with autoimmune thyroid diseases.

BACKGROUND: Patients with autoimmune thyroid diseases (AITDs) are prone to develop other autoimmune manifestations and to display autoimmune polyendocrine syndromes. An increased prevalence of celiac disease (CD) was demonstrated in adult European and Italian patients with AITDs; conversely, an increased prevalence of AITDs was demonstrated in patients with CD. An IgA deficiency is the most frequent immunodeficiency in humans and, in general, high frequency of this disorder was demonstrated in those with autoimmune diseases. AIM: To define the prevalence of both CD and IgA deficiency in North Italian patients with AITDs. METHODS: 276 Italian patients with AITD were enrolled (mean age 42.6 years range 12-89, 186 of whom had chronic thyroiditis and 90 had Graves' disease). The tissue transglutaminase autoantibodies of the IgA class (IgA-tTGAbs) were evaluated using an ELISA method in these patients. Furthermore, the serological levels of the IgA were determined. RESULTS: Five of the patients (1.8%) were affected by previously diagnosed CD and were on a gluten-free diet. Ten out of the remaining 271 patients (3.6%) were found to be positive for celiac-related autoantibodies. All of these patients agreed to undergo endoscopy and duodenal biopsies and silent CD was found in 5 of them but 5 had not histopathological signs of CD. CD (clinical, silent or latent) was present in 15/276 (5.4%) of the North Italian patients with AITD; this prevalence is significantly higher with respect to the general population (p < 0.00001). The genetic pattern of the 10 patients with both AITDs and CD was characterized by the presence of DQ2 in 8 patients and DQ8 in 2. An IgA deficiency was present in 2/276 of the patients (0.72%). CONCLUSIONS: CD is significantly increased in patients with thyroid autoimmune disorders for this reason it is important to screen for CD in patients with AITDs.

Antibodies to muscle and ganglionic acetylcholine receptors (AchR) in celiac disease.

BACKGROUND: About 2.5% of patients with idiopathic peripheral neuropathy or idiopathic dysautonomia have underlying celiac disease (CD). Antibodies to ganglioside have been reported in CD patients with neuropathy. No data are so far available on the presence in CD of acetylcholine receptor (AChR) antibodies. Muscle AChR antibodies are found in patients with myasthenia gravis, and ganglionic AChR antibodies in patients with autoimmune autonomic neuropathy. OBJECTIVE: To determine the frequency of AChR antibodies in CD patients and assess possible correlations with neurological manifestations. METHODS: Seventy CD patients (16 M, 54 F, mean age 36 years) underwent neurological and electrophysiological evaluation. AChR antibodies were detected with radioimmunoprecipitation assay. Sera from 15 age-matched patients with systemic lupus erythematosus (SLE) and 10 with Sjogren syndrome were studied as controls. RESULTS: None of our CD patients complained of autonomic symptoms or fatigable weakness. Borderline titres (0.03-0.05 nmol/l) of ganglionic AChR antibodies were present in 4 patients, one affected with type I diabetes and one with subclinical neuropathy. Three of the 4 patients underwent cardiovascular autonomic function tests, which showed no abnormalities. Low levels of ganglionic AChR antibodies (0.05-0.10 nmol/l) were found in 2 SLE control patients, one of whom had a severe sicca complex. Muscle AChR antibodies (>1.0 nmol/l) were found in two CD patient and one control patient with SLE. Neither had symptoms or signs of myasthenia gravis. DISCUSSION AND CONCLUSIONS: CD is occasionally associated with neurologic disease, and with antibody reactivity to neuronal antigens. None of our CD patients had autonomic failure or significant levels of ganglionic AChR antibodies. Two CD patient and one control with SLE had muscle AChR antibodies without clinical evidence of myasthenia. The presence of antibodies in CD and in SLE patients may reflect a non-specific autoimmune response in these patients or may indicate subclinical autoimmune autonomic and neuromuscular involvement.