Gene variation at immunomodulatory and cell adhesion molecules loci impacts primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is an autoimmune disease triggered by a combination of environmental and host genetic factors, which results in the focal lymphocytic infiltration of exocrine glands causing eye and mouth dryness. Glandular infiltrates include T and B cell subsets positive for CD5 and/or CD6, two surface scavenger receptors involved in the fine-tuning of intracellular signals mediated by the antigen-specific receptor complex of T (TCR) and B (BCR) cells. Moreover, the epithelial cells of inflamed glands overexpress CD166/ALCAM, a CD6 ligand involved in homo and heterotypic cell adhesion interactions. All this, together with the reported association of functionally relevant single nucleotide polymorphisms (SNPs) of CD5, CD6, and CD166/ALCAM with the risk or prognosis of some immune-mediated inflammatory disorders, led us to investigate similar associations in a local cohort of patients with pSS. The logistic regression analyses of individual SNPs showed the association of CD5 rs2241002T with anti-Ro/La positivity, CD6 rs17824933C with neutropenia, and CD6 rs11230563T with increased leukopenia and neutropenia but decreased peripheral nervous system EULAR Sjögren's syndrome disease activity index (ESSDAI). Further analyses showed the association of haplotypes from CD5 (rs2241002T-rs2229177C) with anemia and thrombocytopenia, CD6 (rs17824933G-rs11230563C-rs12360861G) with cutaneous ESSDAI, and CD166/ALCAM (rs6437585C-rs579565A-rs1044243C and rs6437585C-rs579565G-rs1044243T) with disease susceptibility and several analytical parameters (anti-nuclear antibodies, neurological ESSDAI, and hematologic cytopenias). These results support the relevance of gene variation at loci coding for cell surface receptors involved in the modulation of T and B lymphocyte activation (CD5, CD6) and epithelial-immune cell adhesion (CD166/ALCAM) in modulating the clinical and analytical outcomes in patients with pS

How hepatitis C virus modifies the immunological profile of Sjögren syndrome: analysis of 783 patients.

Introduction: We conducted a study to analyze how infection by hepatitis C virus (HCV) may influence the immunological serum pattern of patients with Sjögren syndrome (SS). Methods: Since 1994, we have tested serum HCV-IgG antibodies in 783 patients with SS diagnosed according to the 1993 European classification criteria. The immunological profile at diagnosis was compared according to the presence or absence of HCV. Results: Of the 783 patients with SS, 105 (13.4 %) tested positive for HCV-IgG antibodies (88 females, 17 males,mean age at SS diagnosis: 62.9 years). Multivariate analysis showed that patients with SS-HCV had a higher mean age and a higher frequency of low C3/C4 levels, cryoglobulins, and hematological neoplasia compared with patients without HCV. The frequency of anti-La antibodies compared with anti-Ro antibodies was higher in patients with SS-HCV (17 % vs. 15 %) and lower in patients without HCV infection (30 % vs. 43 %). The frequency of concomitant detection of the three main cryoglobulin-related markers (cryoglobulins, rheumatoid factor activity, and C4 consumption) was threefold higher in patients with SS-HCV compared with patients without HCV. SS-HCV patients with genotype 1b showed the highest frequencies of immunological abnormalities related to cryoglobulins and the lowest frequencies of anti-Ro/La antibodies. Conclusions: We found HCV infection in 13 % of a large series of Spanish patients with SS. The HCV-driven autoimmune response was characterized by a lower frequency of anti-Ro/La antibodies, an abnormal predominance of anti-La among anti-Ro antibodies, and a higher frequency of cryoglobulinemic-related immunological markers in comparison with patients without HCV infection. This immunological pattern may contribute to the poor outcomes found in patients with SS-HCV

Auscultation of velcro crackles is associated with usual interstitial pneumonia

Auscultation of Velcro crackles has been proposed as a key finding in physical lung examination in patients with interstitial lung diseases (ILDs), especially in idiopathic pulmonary fibrosis (IPF). However, no studies have been carried out to assess the association of Velcro crackles with other clinical variables. We evaluated a cohort of 132 patients, prospectively and consecutively included in our ILD diagnostic program at a tertiary referral center. All patients were auscultated during the physical examination. The patients were divided into 2 groups: "presence" or "nonpresence" of bilateral Velcro crackles. Of all patients assessed, 83 (63%) presented Velcro crackles in the respiratory auscultation. Patients with Velcro crackles usually had more frequently cough and dyspnea at the moment of diagnosis. Forced vital capacity (P = 0.002) and lung diffusion capacity for carbon monoxide (P = 0.04) was lower in these patients. The ILD-GAP index was higher in the group with Velcro crackles (P = 0.01). All patients with usual interstitial pneumonia (UIP) in high-resolution computed tomography and all patients with final IPF diagnosis presented Velcro crackles. In multivariate analysis, the presence of Velcro crackles was independently associated with an UIP pattern. In patients suspected of having ILD, the auscultation of Velcro crackles was associated with UIP, a possibility which must be taken into consideration in early ILD detection in primary care

Impact of a systematic evaluation of connective tissue disease on diagnosis approach in patients with interstitial lung diseases

To date, there is no clear agreement regarding which is the best method to detect a connective tissue disease (CTD) during the initial diagnosis of interstitial lung diseases (ILD). The aim of our study was to explore the impact of a systematic diagnostic strategy to detect CTD-associated ILD (CTD-ILD) in clinical practice, and to clarify the significance of interstitial pneumonia with autoimmune features (IPAF) diagnosis in ILD patients. Consecutive patients evaluated in an ILD Diagnostic Program were divided in 3 groups: IPAF, CTD-ILD, and other ILD forms. Clinical characteristics, exhaustive serologic testing, high resolution computed tomography (HRCT) images, lung biopsy specimens, and follow-up were prospectively collected and analyzed. Among 139 patients with ILD, CTD was present in 21 (15.1%), 24 (17.3%) fulfilled IPAF criteria, and 94 (67.6%) were classified as other ILD forms. Specific systemic autoimmune symptoms such as Raynaud phenomenon (19%), inflammatory arthropathy (66.7%), and skin manifestations (38.1%) were more frequent in CTD-ILD patients than in the other groups (all P< .001). Among autoantibodies, antinuclear antibody was the most frequently found in IPAF (42%), and CTD-ILD (40%) (P= .04). Nonspecific interstitial pneumonia, detected by HRCT scan, was the most frequently seen pattern in patients with IPAF (63.5%), or CTD-ILD (57.1%) (P< .001). In multivariate analysis, a suggestive radiological pattern by HRCT scan (odds ratio [OR] 15.1, 95% confidence interval [CI] 4.7-48.3, P< .001) was the strongest independent predictor of CTD-ILD or IPAF, followed by the presence of clinical features (OR 14.6, 95% CI 4.3-49.5, P< .001), and serological features (OR 12.4, 95% CI 3.5-44.0, P< .001). This systematic diagnostic strategy was useful in discriminating an underlying CTD in patients with ILD. The defined criteria for IPAF are fulfilled by a considerable proportion of patients referred for ILD

IgG4-related disease: results from a multicenter Spanish registry

IgG4-related disease (IgG4-RD) is a rare entity consisting of inflammation and fibrosis that has been described in multiple organs. Concrete diagnostic criteria have been established recently and there is a lack of large series of patients.To describe the clinical presentation, histopathological characteristics, treatment and evolution of a series of IgG4-RD Spanish patients.A retrospective multicenter study was performed. Twelve hospitals across Spain included patients meeting the current 2012 consensus criteria on IgG4-RD diagnosis.Fifty-five patients were included in the study, 38 of whom (69.1%) were male. Median age at diagnosis was 53 years. Thirty (54.5%) patients were included in the Histologically Highly Suggestive IgG4-RD group and 25 (45.5%) in the probable IgG4-RD group. Twenty-six (47.3%) patients had more than 1 organ affected at presentation. The most frequently affected organs were: retroperitoneum, orbital pseudotumor, pancreas, salivary and lachrymal glands, and maxillary sinuses.Corticosteroids were the mainstay of treatment (46 patients, 83.6%). Eighteen patients (32.7%) required additional immunosuppressive agents. Twenty-four (43.6%) patients achieved a complete response and 26 (43.7%) presented a partial response (<50% of regression) after 22 months of follow-up. No deaths were attributed directly to IgG4-RD and malignancy was infrequent.This is the largest IgG4-RD series reported in Europe. Patients were middle-aged males, with histologically probable IgG4-RD. The systemic form of the disease was frequent, involving mainly sites of the head and abdomen. Corticosteroids were an effective first line treatment, sometimes combined with immunosuppressive agents. Neither fatalities nor malignancies were attributed to IgG4-RD

Marcadores inmunológicos como factores pronósticos en el síndrome de Sjögren primario

[spa] ANTECEDENTES DEL TEMA. El síndrome de Sjögren primario (SSp) es una enfermedad autoinmune sistémica que afecta a las glándulas exocrinas, principalmente las salivales y las lacrimales, originando síntomas de sequedad. La expresión clínica también incluye manifestaciones generales, afección extraglandular y desarrollo de linfoma. La influencia de los marcadores inmunológicos en la expresión clínica de la enfermedad aún no se conoce del todo y tampoco su papel como factores pronóstico de la enfermedad.JUSTIFICACIÓN UNITARIA DEL TEMA. Los artículos incluidos en esta Tesis Doctoral se centran en el estudio del SSp y describen las principales características de una cohorte de pacientes estudiada de forma estandarizada y prospectiva en el Servicio de Enfermedades Autoinmunes del Hospital Clínic de Barcelona.OBJETIVO. Analizar el papel de los marcadores inmunológicos en la expresión clínica y el pronóstico del SSp.RESULTADOS. En nuestros resultados describimos que los pacientes con SSp presentan porcentajes significativos de citopenias. La presencia de estas citopenias se asocian con los principales marcadores inmunológicos del SSp. El perfil inmunológico del paciente con SSp, junto con el estudio histológico también nos permite diferenciar la posible coexistencia o simulación de SS en un paciente con sarcoidosis. Cerca de un 20% de los pacientes con SSp presentan inmunoglobulinas monoclonales circulantes, siendo la IgGκ la más frecuente. La detección de estas inmunoglobulinas monoclonales circulantes se asocia a una mayor prevalencia de manifestaciones extraglandulares y marcadores inmunológicos respecto a aquellos pacientes que no presentan dichas inmunoglobulinas monoclonales. Otro de los marcadores inmunológicos frecuentes en el SSp es la hipocomplementemia, con una prevalencia de 24%. Su presencia se asocia estrechamente con mayor prevalencia de manifestaciones extraglandulares, autoanticuerpos, linfoma y menor supervivencia. Respecto al desarrollo de manifestaciones extraglandulares, los pacientes seguidos durante 5 años, el 18% desarrollaron manifestaciones extraglandulares y este porcentaje incrementaba al 67% en aquellos seguidos durante 20 años. El factor inmunológico que se asoció con la aparición de estas manifestaciones fue la positividad al FR en el momento del diagnóstico del SSp. Respecto al desarrollo de linfoma, la presencia de parotidomegalia, de gammagrafía parotídea grado III-IV e hipocomplementemia al momento del diagnóstico fueron factores predictores de desarrollo de linfoma. Por último, encontramos que la hipocomplementemia (en concreto el C3 y CH50) y la presencia de crioglobulinas en el momento del diagnóstico fueron factores inmunológicos asociados a una menor supervivencia.CONCLUSIONES. Nuestros estudios han demostrado el significativo papel de los marcadores inmunológicos (FR, inmunoglobulinas monoclonales, crioglobulinas e hipocomplementemia) en la expresión clínica del SSp y como factores pronóstico de la evolución de la enfermedad, por lo que sugerimos incluir estos parámetros inmunológicos en el seguimiento del paciente con SSp

Primary Sjogren syndrome.

Sjögren syndrome is a systemic autoimmune disease causing secretory gland dysfunction. This leads to dryness of the main mucosal surfaces such as the mouth, eyes, nose, pharynx, larynx, and vagina. 1 Sjögren syndrome may be a serious disease, with excess mortality caused by haematological cancer. 2 The cause of Sjögren syndrome is unknown, but factors postulated to play a role are both genetic and environmental ....

Primary Sjogren syndrome.

Sjögren syndrome is a systemic autoimmune disease causing secretory gland dysfunction. This leads to dryness of the main mucosal surfaces such as the mouth, eyes, nose, pharynx, larynx, and vagina. 1 Sjögren syndrome may be a serious disease, with excess mortality caused by haematological cancer. 2 The cause of Sjögren syndrome is unknown, but factors postulated to play a role are both genetic and environmental ....

How hepatitis C virus modifies the immunological profile of Sjögren syndrome: analysis of 783 patients.

Introduction: We conducted a study to analyze how infection by hepatitis C virus (HCV) may influence the immunological serum pattern of patients with Sjögren syndrome (SS). Methods: Since 1994, we have tested serum HCV-IgG antibodies in 783 patients with SS diagnosed according to the 1993 European classification criteria. The immunological profile at diagnosis was compared according to the presence or absence of HCV. Results: Of the 783 patients with SS, 105 (13.4 %) tested positive for HCV-IgG antibodies (88 females, 17 males,mean age at SS diagnosis: 62.9 years). Multivariate analysis showed that patients with SS-HCV had a higher mean age and a higher frequency of low C3/C4 levels, cryoglobulins, and hematological neoplasia compared with patients without HCV. The frequency of anti-La antibodies compared with anti-Ro antibodies was higher in patients with SS-HCV (17 % vs. 15 %) and lower in patients without HCV infection (30 % vs. 43 %). The frequency of concomitant detection of the three main cryoglobulin-related markers (cryoglobulins, rheumatoid factor activity, and C4 consumption) was threefold higher in patients with SS-HCV compared with patients without HCV. SS-HCV patients with genotype 1b showed the highest frequencies of immunological abnormalities related to cryoglobulins and the lowest frequencies of anti-Ro/La antibodies. Conclusions: We found HCV infection in 13 % of a large series of Spanish patients with SS. The HCV-driven autoimmune response was characterized by a lower frequency of anti-Ro/La antibodies, an abnormal predominance of anti-La among anti-Ro antibodies, and a higher frequency of cryoglobulinemic-related immunological markers in comparison with patients without HCV infection. This immunological pattern may contribute to the poor outcomes found in patients with SS-HCV