Inflammatory conditions of the esophagus: an update.

A variety of inflammatory disorders involve the esophagus. This commentary discusses the pathology of some forms of esophagitis, with an emphasis on recent developments. The initial section focuses on some common forms of nonreflux esophagitis, including lymphocytic esophagitis and eosinophilic esophagitis. Recent studies suggest that lymphocytic esophagitis may be associated with esophageal motility disorders and gastroesophageal reflux disease. Immunophenotypic features of intraepithelial lymphocytes may be helpful in distinguishing these conditions. Updates on the criteria and the limitations of histologic approach to the diagnosis of eosinophilic esophagitis are presented and new diagnostic adjuncts are discussed. In the remaining section, novel entities, such as IgG4-related esophagitis, are discussed. IgG4-related esophagitis has been recognized as a cause of esophageal lymphoplasmacytic inflammation. Increased understanding of esophageal inflammation remains an important goal that likely will lead to new approaches in the therapy of inflammatory esophageal diseases.

Autonomic neuropathy-in its many guises-as the initial manifestation of the antiphospholipid syndrome.

Autonomic disorders have previously been described in association with the antiphospholipid syndrome. The present study aimed to determine the clinical phenotype of patients in whom autonomic dysfunction was the initial manifestation of the antiphospholipid syndrome and to evaluate for autonomic neuropathy in these patients. This was a retrospective study of 22 patients evaluated at the University of Colorado who were found to have a disorder of the autonomic nervous system as the initial manifestation of antiphospholipid syndrome. All patients had persistent antiphospholipid antibody positivity and all patients who underwent skin biopsy were found to have reduced sweat gland nerve fiber density suggestive of an autonomic neuropathy. All patients underwent an extensive evaluation to rule out other causes for their autonomic dysfunction. Patients presented with multiple different autonomic disorders, including postural tachycardia syndrome, gastrointestinal dysmotility, and complex regional pain syndrome. Despite most having low-titer IgM antiphospholipid antibodies, 13 of the 22 patients (59%) suffered one or more thrombotic event, but pregnancy morbidity was minimal. Prothrombin-associated antibodies were helpful in confirming the diagnosis of antiphospholipid syndrome. We conclude that autonomic neuropathy may occur in association with antiphospholipid antibodies and may be the initial manifestation of the syndrome. Increased awareness of this association is important, because it is associated with a significant thrombotic risk and a high degree of disability. In addition, anecdotal experience has suggested that antithrombotic therapy and intravenous immunoglobulin therapy may result in significant clinical improvement in these patients.

Lymphocytic Esophagitis in Nonachalasia Primary Esophageal Motility Disorders: Improved Criteria, Prevalence, Strength of Association, and Natural History.

Lymphocytic esophagitis (LE) is a histologic pattern with no established clinical correlates in the majority of patients. The goal of this study was to evaluate the association between nonachalasia primary esophageal motility disorders (PEMD) and LE. Sixty-nine patients with PEMD and esophageal biopsies, including 22 with nutcracker esophagus, 33 with ineffective motility, and 14 with diffuse spasm, constituted the study group. The control group consisted of 70 patients with severe dysmotility-negative gastroesophageal reflux disease requiring referral for Nissen fundoplication. To improve the criteria for LE, a lymphocyte reference range at different esophageal levels was first established in 17 healthy volunteers. The cutoffs for normal intraepithelial lymphocytes, defined as lymphocyte levels not exceeding mean level±2 SDs, were set at 62, 46, and 41 lymphocytes per high-power field at 0 to 2, 5, and 10 cm above the gastroesophageal junction, respectively. Predominantly focal peripapillary LE was observed in approximately 40% of patients with nutcracker esophagus or diffuse spasm and in 20% of patients with ineffective motility, in comparison with 4% of patients with dysmotility-negative gastroesophageal reflux disease (P<0.035 vs. any subtype of PEMD). Overall, LE was strongly associated with PEMD in multivariate analysis (adjusted odds ratio, 7.93; 95% confidence interval, 2.26-27.9; P=0.001). LE had a chronic course in 56% of the patients with follow-up biopsies. In conclusion, LE has a strong association with PEMD, suggesting the utility of LE in raising the possibility of PEMD.

Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis.

OBJECTIVE: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. METHODS: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. RESULTS: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. CONCLUSION: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.

Patients with irritable bowel syndrome and dysmotility express antibodies against gonadotropin-releasing hormone in serum.

BACKGROUND: The etiology of irritable bowel syndrome (IBS) and dysmotility is in most cases unknown. Organic, pathognomonic changes have not been described. We have previously demonstrated sporadic expressions of antibodies against gonadotropin-releasing hormone (GnRH) in serum from these patients. The aim of this study was to screen for the presence of GnRH antibodies in healthy subjects and patients with gastrointestinal (GI) diseases. METHODS: Consecutive patients suffering from either IBS, idiopathic dysmotility, GI complaints secondary to diabetes mellitus, celiac disease or inflammatory bowel disease (IBD) were included. Healthy blood donors served as controls. Blood samples were taken for analyzing IgM and IgG antibodies against GnRH using an ELISA method. Medical records were scrutinized with respect to duration of symptoms, co-existing diseases, drug treatments, hereditary factors, and laboratory analyses. KEY RESULTS: Healthy controls expressed low levels of GnRH IgM antibodies in a prevalence of 23%. The prevalence of GnRH IgM antibodies in IBS and dysmotility patients was 42% (P = 0.008), and the levels were higher (P = 0.000). Patients with diabetes mellitus expressed GnRH IgM antibodies in the same prevalence as controls (25%), but in higher levels (P = 0.02). Patients with celiac disease or IBD had the same or lower levels of antibodies. There were no associations between antibodies, other co-existing diseases or laboratory analyses. CONCLUSIONS & INFERENCES: Higher levels of GnRH IgM antibodies were detected in patients with IBS and dysmotility, but not organic GI diseases, compared with healthy controls. These findings suggest that IBS and dysmotility to some extent may be of an autoimmune origin.

Histological analysis of esophageal muscular layers from 27 autopsy cases with mixed connective tissue disease (MCTD).

Esophageal symptoms in mixed connective tissue disease (MCTD) have been investigated radiologically. We investigated the esophageal lesions in MCTD histopathologically, and analyzed relationships between these lesions and autoantibodies extracted from the serum of MCTD patients. Esophageal tissues from 27 MCTD patients submitted to autopsy were examined. We compared histopathological features of the esophagus in different wall layers from the mucosa, submucosa, and muscular layer to the adventitia, and in the upper, middle, and lower portions of esophagus. The most striking change observed was severe atrophy and occasional loss of smooth muscle cells in the muscular layer, followed by fibrosis. These muscular changes were particularly prominent in the inner layer of the lower esophagus. Immunohistochemically, degenerated muscular tissues of the esophagus were positive for anti-IgG and anti-C3 antibodies, but not for anti-IgM antibodies. IgG fractions extracted from three MCTD patients were immunohistochemically used to examine whether some antibodies in MCTD patients showed reactivity for esophageal components. The IgG fractions isolated from MCTD patients reacted with smooth muscle from non-connective tissue disease cases, suggesting that some serum antibodies may trigger esophageal changes. These findings suggest that esophageal lesions associated with clinical dysphagia in MCTD may be related to autoantibodies.

Esophageal manometry in 28 systemic sclerosis Brazilian patients: findings and correlations.

Systemic sclerosis (SSc) is a multisystem disease of unknown etiology. Esophageal involvement affects 50-90% of patients and is characterized by abnormal motility and hypotonic lower esophageal sphincter. Data on the association of esophageal abnormalities and age, gender, SSc subset or duration, autoantibody profile, esophageal symptoms, and medication are lacking or conflicting. The aim of this study was the evaluation of these associations in Brazilian sclerodermic patients from the Rheumatology Division, Clinics Hospital, Federal University, Minas Gerais. They underwent medical records review, clinical interview, and esophageal manometry. The normal cutoff level for lower esophageal sphincter pressure was 14 mmHg. Abnormal peristalsis occurred when less than 80% of peristaltic waves were propagated. P-values less than 0.05 were considered significant. Twenty-eight patients were included: 71% were women. The population presented medium age and disease duration of 46 years and 12 years, respectively. Cutaneous diffuse SSc occurred in 39% and its limited form in 61%. Dysphagia, pyrosis, and regurgitation occurred, respectively, in 71%, 43%, and 61% of patients. Lower esophageal sphincter pressure and number of peristaltic waves-propagated medias were, respectively, 17.2 mmHg and 2.3. SSc-related manometric abnormalities were present in 86% of patients. Manometry revealed distal esophageal body hypomotility, hypotonic lower esophageal sphincter, or both, respectively, in 82%, 39%, and 36% of patients. One patient presented the manometric pattern of esophageal achalasia. Male patients more frequently presented hypotonic inferior esophageal sphincter. Manometric findings have had no relationship with the other variables. Nifedipine use did not influence manometric findings.

Systemic sclerosis-rheumatoid arthritis overlap syndrome: a unique combination of features suggests a distinct genetic, serological and clinical entity.

OBJECTIVE: To determine the genetic, clinical and serological characteristics of systemic sclerosis (SSc)-rheumatoid arthritis (RA) overlap syndrome. METHODS: Clinical manifestations and immunolaboratory features of 22 SSc-RA patients were assessed. The HLA-DR genotype of the 22 SSc-RA patients determined by SSP-PCR was compared with that of 38 SSc patients, 100 RA patients and 50 healthy controls. RESULTS: All overlap patients fulfilled the American College of Rheumatology (ACR) criteria for SSc and RA. Five of the 22 patients (23%) had diffuse cutaneous SSc (dcSSc) and 17 patients (77%) had limited cutaneous SSc (lcSSc). Antinuclear antibody, anti-Scl70, IgM rheumatoid factor and anti-CCP antibody positivity were detected in 22 (100%), 5 (23%), 16 (73%) and 18 patients (82%), respectively. Seventeen patients (77%) had pulmonary fibrosis, 12 (55%) had oesophageal dismotility, 11 (50%) had cardiac and five (23%) had renal involvement. Hand joint destruction was observed in 18 patients (82%). Significantly increased frequencies of HLA-DR3 (36% vs 5%), HLA-DR7 (9% vs 4%), HLA-DR11 (36% vs 7%) and HLA-DRw53 (23% vs 5%) were observed in SSc-RA compared with RA patients (P < 0.05). Allele frequencies of the 'shared epitope' (HLA-DR1 and -DR4) were significantly increased in SSc-RA (32% and 27%, respectively) and RA patients (46% and 31%, respectively) in comparison with SSc patients (10.5% and 16%, respectively) or healthy controls (16% and 14%, respectively) (P < 0.05). CONCLUSIONS: To date this is the largest SSc-RA overlap cohort. Genetics, clinical and immunolaboratory features suggest a mixed phenotype. Our data suggest that SSc-RA overlap syndrome may be a distinct genetic, immunological and clinical entity.

Gastroesophageal reflux disease-associated esophagitis induces endogenous cytokine production leading to motor abnormalities.

BACKGROUND & AIMS: Gastroesophageal reflux disease is a condition frequently associated with esophagitis and motor abnormalities. Recent evidence suggests that proinflammatory cytokines, such as interleukin (IL)-1beta and IL-6, may be implicated because they reduce esophageal muscle contractility, but these results derive from in vitro or animal models of esophagitis. This study used human esophageal cells and tissues to identify the cellular source of cytokines in human esophagitis investigate whether cytokines can be induced by gastric refluxate, and examine whether esophageal tissue- or cell-derived mediators affect muscle contractility. METHODS: Endoscopic mucosal biopsy specimens were obtained from patients with and without esophagitis, organ-cultured, and undernatants were assessed for cytokine content. The cytokine profile of esophageal epithelial, fibroblast, and muscle cells was analyzed, and esophageal mucosa and cell products were tested in an esophageal circular muscle contraction assay. RESULTS: The mucosa of esophagitis patients produced significantly greater amounts of IL-1beta and IL-6 compared with those of control patients. Cultured esophageal epithelial cells produced IL-6, as did fibroblasts and muscle cells. Epithelial cells exposed to buffered, but not denatured, gastric juice produced IL-6. Undernatants of mucosal biopsy cultures from esophagitis patients reduced esophageal muscle contraction, as did supernatants from esophageal epithelial cell cultures. CONCLUSIONS: The human esophagus produces cytokines capable of reducing contractility of esophageal muscle cells. Exposure to gastric juice is sufficient to stimulate esophageal epithelial cells to produce IL-6, a cytokine able to alter esophageal contractility. These results indicate that classic cytokines are important mediators of the motor disturbances associated with human esophageal inflammation.

Oesophageal manometry in early and definite systemic sclerosis.

The objective of this study was to evaluate the oesophageal dysfunction in patients with "early" systemic sclerosis (SSc), as defined by LeRoy and Medsger, to compare it with that of patients with definite SSc, and to correlate it with other features of the disease. Oesophageal manometry results were retrospectively evaluated in 181 patients classified by the 2001 LeRoy and Medsger criteria and the 1980 American College of Rheumatology (ACR) criteria: group 1: limited SSc: Raynaud's phenomenon plus specific nailfold capillaroscopy abnormalities and/or autoantibodies; group 2: limited cutaneous SSc not satisfying the ACR criteria (lcSSc ACR-); group 3: lcSSc ACR+; group 4: diffuse cutaneous SSc. Peristaltic abnormalities in the oesophageal body were present in 73 of 125 patients with SSc ACR+ (groups 3 and 4) compared with 13 of 56 with SSc ACR- (groups 1 and 2) (p < 0.0001). They were more severe in patients with more advanced disease (1 vs 2; 1 vs 3; 1 vs 4; 2 vs 4; p < 0.05) and in patients anti-Scl-70+ than in patients anticentromere positive (p = 0.02). Abnormalities of the lower oesophageal sphincter (LES) were present in 35 of 125 patients with SSc ACR+ and 11 of 56 with SSc ACR- (not statistically different). They were correlated with forced vital capacity (FVC) (LES pressure: p = 0.0005; LES length: p = 0.0004). Abnormalities of the oesophageal body and of the LES were found in 21 and 16% of 46 patients without oesophageal symptoms. Oesophageal manometry can detect abnormalities in a sizeable proportion of patients with "early SSc" not fulfilling the ACR criteria, including asymptomatic patients. The correlation between LES abnormalities and FVC suggests a possible causal relationship between these disease manifestations.

Cytokine and chemokine levels in systemic sclerosis: relationship with cutaneous and internal organ involvement.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive collagen deposition in the skin and internal organs. Several cytokines and chemokines have been implicated in the induction of fibrosis, but a definitive relationship between specific cytokines and organ involvement has not been established yet. Serum samples, PBMC and T cell lines (TCL) obtained from 54 patients affected by SSc and 20 healthy donors (HD) were examined by ELISA for Interferon-gamma (IFN-gamma ), interleukin (IL)-4, IL-6, IL-10, IL-18, Transforming growth factor (TGF)-beta1, Tumour necrosis factor (TNF)-alpha, sCD30, Macrophage derived chemokine (MDC), Monocyte chemoattractant protein (MCP)-1, Macrophage inflammatory protein (MIP)-1alpha and Regulated on activation normal T-cell expressed and secreted (RANTES). In all the SSc serum samples, we found significantly increased levels of IL6, TNFalpha and MCP-1 but reduced amounts of gamma-IFN and MDC. IL6, IL10, IL18, MIP-1alpha and TNFalpha measured in supernatants from PHA-stimulated PBMC and IL6, MCP-1 and RANTES in supernatants from stimulated TCL were also increased in patients. MDC was decreased in all the biological SSc sources studied. TGF-beta1, IL10, and sCD30 were produced at a significantly lower level by SSc TCL. Serum IL6 and sCD30 levels were significantly increased in dc-SSc patients compared to lc-SSc as were levels of MCP-1 produced by PBMC and IL10 from TCL. We observed a strict relationship between pulmonary fibrosis and IL10, MCP-1 (both from TCL) and serum IL6. Kidney involvement was related to serum MCP-1 levels and IL18 production from PBMC. Oesophageal involvement correlated with MDC production from PBMC and IL10 synthesis by TCL. We showed that IL-6, IL-10, MDC and MCP-1 are variably associated with internal organ involvement and allow the discrimination between limited and diffuse forms of the disease.

Autoantibody profile in progressive systemic sclerosis as markers for esophageal involvement.

We investigated the relationship between the severity and extent of esophageal involvement in patients with progressive systemic sclerosis (PSS) and the autoantibody profile. We studied 37 consecutive patients with PSS and compared their results to 25 healthy volunteers. Patients with PSS were separated into three subgroups: group 1 (antinuclear antibody [ANA] [+/-], anti-Sc170 antibody [Scl70] [-], and anticentromere antibody [ACA] [-]), group 2 (ANA [+], Scl70 [+], and ACA [-]), and group 3 (ANA [+], Scl70 [-], and ACA [+]). The lower esophageal sphincter pressure and the mean proximal esophageal amplitude were significantly lower in group 3 when compared with group 1, group 2, and the healthy controls. Distal esophageal aperistalsis was noted in 85% of group 3, 40% of group 2, and 30% of group 1. An involvement of esophageal motility was found in 100% of the patients with ACA. Our results suggest that esophageal involvement is more pronounced in patients with PSS with ACA as compared with patients with only Sc170 or ANA.

Anti-centromere antibody and CREST syndrome in patients with primary biliary cirrhosis.

Anti-centromere antibodies (ACA) in 41 sera from patients with primary biliary cirrhosis (PBC) were analyzed by an immunoblotting method and the correlation between the presence of ACA and the clinical features in these PBC patients was studied. In 10 of 16 ACA-positive PBC patients, one or more clinical features of CREST syndrome (PBC-CREST) were found. Statistical differences were observed in age at disease onset, serum levels of IgM and total bilirubin and titer of anti-M2 antibody, between PBC-CREST patients and the PBC patients without CREST symptoms (PBC-non CREST). By immunoblotting analysis, three major epitopes of ACA were identified at 18 kD, 80 kD and 140 kD polypeptides. The 18 kD polypeptides were detected in all 16 ACA-positive PBC patients. From these results, it is suggested that ACA-positive PBC-CREST patients can be separated from ACA-negative PBC-CREST and PBC-non CREST patients.

Antibodies to hn-RNP protein A1 in systemic lupus erythematosus: clinical association with Raynaud's phenomenon and esophageal dysmotility.

Antibodies to recombinant hn-RNP protein A1 were found by ELISA in sera from 26 out of 67 unselected patients with systemic lupus erythematosus. A higher number of anti-A1 positive patients had Raynaud's phenomenon (50% vs 7%) and esophageal dysmotility (42% vs 5%) than the anti-A1 negative patients. All 8 patients with both Raynaud's phenomenon and esophageal dysmotility had a positive anti-A1 assay. No association was found with other clinical findings, nor with disease activity and treatment regimes. Anti-A1 antibodies did not correlate with anti-RNP and anti-Sm antibodies, which were present in 30% and 12% of the anti-A1 positive cases and in 22% and 7% of the anti-A1 negative cases, respectively. Our results indicate that antibodies to hn-RNP protein A1 may be associated with a subset of SLE patients with clinical features overlapping those of progressive systemic sclerosis and quite distinct from the group identified by anti-RNP antibodies.

Anticentromere antibody positive CREST syndrome associated with polyarthritis, renal impairment and mixed cryoglobulinaemia.

We describe a 63-year-old female who developed the CREST syndrome within two years. Even though she was anticentromere antibody positive, her illness followed a very aggressive course and was associated with severe polyarthritis, renal impairment, hypocomplementaemia and mixed cryoglobulinaemia.

Coexistence of CREST syndrome and primary biliary cirrhosis. Serological studies of two cases.

Two patients with characteristic features of CREST syndrome and primary biliary cirrhosis are reported. Sera of both patients contained autoantibodies to centromere and mitochondrial antigens. Immunodiffusion analysis identified the specificities of precipitating antibodies to mitochondria of the first case as anti-M-A and M-C, and of the second case as anti-M-A and M-B antibodies. Simultaneous occurrence of 2 marker antibodies in an individual patient indicates that the 2 patients reported here have CREST syndrome and primary biliary cirrhosis, both of which are considered as a distinct clinical entity.