Prevalence of antiphospholipid antibodies in patients with primary Sjögren's syndrome

The aim of this study was to determine prevalence of antiphospholipid antibodies (aPL) including anticardiolipin antibodies (aCL), and anti-beta2GP1 in a cohort of 32 patients with primary Sjogren's syndrome (pSS) diagnosed according to revised European criteria. aPL were found in 9/32 (28%) patients (IgG in 8 and IgM in one case). Anti-beta2GPI antibodies were detected only in two patients. Titres were usually low.     

Anticentromere antibody-positive primary Sjögren's syndrome: Epitope analysis of a subset of anticentromere antibody-positive patients

Objectives: Anticentromere antibody (ACA) is generally considered to be a serological marker for systemic sclerosis (SSc). ACA-positive patients with primary Sjögren's syndrome (pSS) have also been reported. ACA often recognizes centromere proteins (CENPs): CENP-A, CENP-B, and CENP-C, and sometimes reacts to heterochromatin protein 1 (HP1)α. We compared the reactivity against six different epitopes for three ACA-positive clinical subgroups: 29 patients with pSS, 36 SSc patients with sicca symptoms, and 28 SSc patients without sicca symptoms.

Methods: We utilized enzyme-linked immunosorbent assays (ELISAs) with recombinant proteins covering six different epitope regions of ACA (the amino terminus (Nt) of CENP-A, CENP-B, and CENP-C, the carboxyl terminus (Ct) of CENP-B and CENP-C, and HP1α).

Results: The patients with pSS were found to have IgG-class autoantibodies against CENP-C-Nt and HP1α, and IgA-class autoantibodies against CENP-C-Ct with significantly higher frequencies than the SSc patients with or without sicca symptoms. The positive predictive value and the negative predictive value of the combination of these three autoantibodies for pSS were 73% and 82%, respectively, for pSS.

Conclusions: Based on the result that reactivities against CENP-C and HP1α in patients with pSS differ from those in patients with SSc, we propose ACA-positive pSS as a clinical subset of SS that is independent of SSc.     

Monozygotic twins with primary Sjögren's syndrome

Sj?gren's syndrome (SS) is a chronic autoimmune disease mainly characterized by dry mouth and dry eyes due to an inflammatory process in the exocrine glands. We describe a pair of Caucasian monozygotic twin sisters and their mother, all having primary SS. The twins had very similar clinical presentation and almost identical serological data, and histological examination of lower labial salivary glands gave a focus score of 3 in both twins. We also present their family medical history, which shows aggregation of immunological disorders among family members, although the twins and their mother were the only individuals with primary SS.     

Sjögren's syndrome associated with systemic lupus erythematosus: clinical and laboratory profiles and comparison with primary Sjögren's syndrome

OBJECTIVE: To address the clinical, serologic, pathologic, and immunogenetic features of sicca syndrome that occurs in systemic lupus erythematosus (SLE), as well as its similarities to, and differences from, sicca syndrome that occurs in primary Sj?gren's syndrome (SS). METHODS: A cohort of 283 consecutive unselected SLE patients was evaluated for the presence of associated SS using the American-European classification criteria. Clinical and laboratory parameters in SLE patients with SS (SLE-SS) were compared with those in SLE patients without SS (SLE-no SS) and with a group of 86 unselected patients with primary SS. RESULTS: SS was identified in 26 SLE patients (9.2%); the SS preceded the development of lupus in 18 of them (69.2%). Compared with the SLE-no SS group, patients with SLE-SS were significantly older, had a higher frequency of Raynaud's phenomenon, anti-Ro/SSA, anti-La/SSB, and rheumatoid factor, but had a significantly lower frequency of renal involvement, lymphadenopathy, and thrombocytopenia. Compared with the primary SS group, SLE-SS patients displayed a clinically similar sicca syndrome, but were significantly younger and had an increased frequency of perivascular infiltrates in the salivary glands associated with anticardiolipin antibodies in the serum. SLE-SS patients had a high frequency of the DRB1*0301 allele. This HLA profile distinguished the SLE-SS group from the SLE-no SS group, who had an increased frequency of DRB1*1501 and DQB1*0602 alleles, but was similar to the HLA profile of the primary SS group, who had an increased frequency of DRB1*0301. CONCLUSION: SLE-SS appears to constitute a subgroup of patients with distinct clinical, serologic, pathologic, and immunogenetic features, in whom SS is expressed as an overlapping entity and is largely similar to primary SS.     

Hematologic manifestations of primary Sjögren's syndrome

Sj?gren's syndrome (SS) is a chronic autoimmune disorder, primarily characterized by the mononuclear cell infiltration of exocrine glands exiting in parenchymal damage and secretory impairment. The spectrum of the disease extends from an autoimmune exocrinopathy to a systemic process with extraglandular manifestations. SS is defined as primary (pSS) when isolated, or secondary when associated with another autoimmune disease. Patients with pSS may present hematologic abnormalities, such as anemia, hemocytopenias, monoclonal gammopathies and lymphoprolipherative disorders, predominantly non-Hodgkin's lymphoma of B-cell origin. The increased prevalence of B-cell malignancies suggests that SS may be a boundary disease between autoimmunity and lymphoproliferation. In this paper, the hematologic manifestations of pSS are reviewed.     

Pulmonary manifestations of primary Sjögren's syndrome

Sj?gren's syndrome (SS) is a systemic disease with a predilection for the exocrine glands. It also is considered to be an autoimmune epitheliitis, and, as the respiratory system is lined throughout with epithelial cells, it should not be surprising that patients who have SS may develop pulmonary disease. This article describes these manifestations.     

HLA markers and clinical characteristics in Caucasians with primary Sjögren's syndrome

OBJECTIVE: To explore the association between HLA genotypes and clinical and immunological characteristics in Caucasians with primary Sj?gren's syndrome (pSS). METHODS: HLA genotyping for DRB1, DQA1 and DQB1 was carried out in 62 single case patients with pSS and 64 healthy controls. The specific amino acid residues at DQA1 position 34 (DQalpha-34Q) and DQB1 position 26 (DQbeta-26L) in addition to the DQ-DI (AA59-AA69) motif were deterrmined. Subsequently, the relative contribution of individual HLA markers to clinical and immunologic characteristics of pSS was assessed by group comparisons. RESULTS: No significant associations were seen between HLA markers and histopathological or clinical features of pSS. Significant positive associations with HLA Class II markers were restricted to the formation of different autoantibodies. Formation of an anti-Ro/SSA and anti-La/SSB autoantibody response was positively associated with DRB1*03, DQB1*02 and DRB1*03/DRB1*15-DQB1*02/DQB1*0602 heterozygosity. Patients positive for anti-La/SSB also showed a strong positive anti-La/SSB association with DQA1*0501. Considering the contribution of individual DQA1 and DQB1 amino acids and sequence motifs to the formation of anti-Ro/SSA and anti-La/SSB autoantibodies, a dose dependent positive influence was detected for DQalpha-34Q and DQbeta-26L. For DQbeta-DI, the largest difference between patients and controls was seen for the presence of a single copy of this motif after selecting patients with either anti-Ro/SSA or anti-La/SSB autoantibodies. CONCLUSION: The association of HLA Class II markers with pSS may concern the anti-Ro/La response rather than the disease itself. The strongest contributors to the formation of an anti-Ro/La response included components of the DRB1*03-DQB1*02-DQA1*0501 haplotype also encompassing the transethnically-associated DQbeta-DI motif. In addition, the dose dependent contribution of DQalpha-34Q and DQbeta-26L argue for a recessive contribution of HLA-DQ to the formation of an anti-Ro/La response. Given the prominent associations with DRB1*03 and the complex dose dependent interactions at HLA-DQ, a joint contribution of HLA-DR and DQ is likely to be relevant for the formation of anti-Ro/La autoantibodies in patients with pSS.     

Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjögren's syndrome

Objective: To investigate the prevalence of anti-cyclic citrullinated peptide (anti-CCP) and anti-keratin antibodies (AKA) in patients with primary Sjögren''s syndrome. Methods: 149 patients with a diagnosis of primary Sjögren''s syndrome according to the European/American consensus criteria were recruited from three French medical centres. The presence of anti-CCP was determined by enzyme linked immunosorbent assay and of AKA antibodies by indirect immunofluorescence. Radiographs of hands and feet were evaluated at the time of anti-CCP analysis. Results: Six patients with radiological erosions and nine patients with non-erosive arthritis fulfilling ACR criteria for rheumatoid arthritis were thought to have rheumatoid arthritis and secondary Sjögren''s syndrome, while 134 were considered to have primary Sjögren''s syndrome (mean (SD) disease duration, 11.1 (6.6) years). Of these, 80 tested positive for IgM rheumatoid factor (RF) (59%), 10 (7.5%) for anti-CCP, 7 (5.2%) for AKA, and 5 (3.7%) for both anti-CCP and AKA. There was no difference in clinical and biological features, including prevalence of RF, between anti-CCP positive and negative patients. The nine Sjögren patients with non-erosive arthritis, fulfilling ACR criteria for rheumatoid arthritis, were all CCP positive. Their response to disease modifying antirheumatic drugs could be different from classical rheumatoid patients. Conclusions: Most patients with primary Sjögren''s syndrome are negative for AKA and anti-CCP, but positive test results should not rule out this diagnosis. Anti-CCP positive patients, who may be prone to developing rheumatoid arthritis, require cautious clinical and radiographic follow up.     

Diagnosis and definition of primary Sjögren's syndrome

During the last years, several sets of criteria for the diagnosis and classification of primary Sj?gren's syndrome (SS) have been promulgated. So far none has achieved universal acceptance. It is conceivable that the lack of pathognomonic features of SS and the frequent coexistence of SS with other connective tissue di-seases partly explain the lack of agreement. Regardless of criteria preference the final diagnosis of SS should reflect the definition of the syndrome, being an inflammatory and autoimmune rheumatic disease. It is therefore suggested that any criteria employed should include a mandatory combination of measurements of exocrine dysfunction. histological confirmation of inflammation, serological evidence of autoimmunity and exclusion or diseases mimicking primary Sj?gren's syndrome.     

Immunogenetics of primary Sjögren's syndrome in Colombians

OBJECTIVE: Data concerning the immunogenetic characteristics of primary Sjogren's syndrome (SS) in Latin-Americans are scarce. A research project centered on primary SS in Colombians was initiated in January 1996 to better define these characteristics. METHODS: TAP, HLA, IL-10, and microsatellites on 6p21.3 genotyping was performed by polymerase chain reaction techniques. Immunohistochemistry for Bcl-2 antagonist/killer (Bak) was performed. Autoantibodies and serum level of cytokines (IL-10, TNF-alpha, IFN-gamma, IL-4, and IL-12p70) were determined by enzyme-linked immunosorbent assay. RESULTS: The HLA-DRB1*0301-DQB1*0201 haplotype was associated with disease (OR = 4.3, 95% CI: 1.6 to 11.9, P = 0.002), with a more severe histopathologic picture, and with the presence of anti-Ro and anti-La antibodies. D6S439 microsatellite polymorphism was associated with primary SS in an HLA-independent manner. The most likely gene related to the D6S439 chromosomal location appears to be BAK-1 , which codes for Bak protein, expressed in salivary gland's infiltrate from patients with primary SS but not in controls. IL-10 and IFN-gamma concentrations were significantly higher in patients than in controls ( P < 0.01). IL-10 correlated with titers of IgA rheumatoid factor, anti-Ro, and anti-La antibodies, and with the severity of lymphocytic infiltrate (r > 0.3, P < 0.04). Patients who produced high IL-10 levels had significantly more episodes of cutaneous vasculitis and a higher proportion the IL-10.G9 allele. CONCLUSIONS: The HLA-DRB1*0301-DQB1*0201 haplotype and IL-10 participate in the histopathological progression of SS, autoantibody production, and clinical manifestations. Bak protein and its gene polymorphism may participate in the pathology and susceptibility of disease. HLA and cytokine (IL-10 and IFN-gamma) manipulation may be helpful in treating patients with primary SS.     

Gluten sensitivity in patients with primary Sjögren's syndrome

Objective. To evaluate the rectal mucosal response to gluten as an indication of gluten sensitivity in patients with primary Sjögren's syndrome (pSS). Material and methods. Rectal challenges with wheat gluten were performed in 20 patients with pSS and 18 healthy control subjects. Fifteen hours after challenge the mucosal production of nitric oxide (NO) was measured. Results. Five patients with pSS had a significant increase in the luminal release of NO after the rectal gluten challenge, indicating gluten sensitivity. All were HLA-DQ2 and/or -DQ8-positive. Two of the patients with increased NO had antibodies against transglutaminase and a duodenal biopsy showed an absolutely flat mucosa consistent with coeliac disease in one of the patients. Before gluten challenge, 15 of the Sjögren's syndrome (SS) patients reported gastrointestinal symptoms, and 8 reported intolerance to various food products. No correlation was found between gluten sensitivity and self-reported food intolerance or gastrointestinal symptoms. Conclusions. Rectal mucosal inflammatory response after gluten challenge is often seen in patients with pSS, signifying gluten sensitivity. However, this reactivity is not necessarily linked to coeliac disease.     

Successful treatment of a patient with primary Sjögren's syndrome with Rituximab

We report the course of a 55-year-old woman, the first patient with primary Sjögren's syndrome and distal renal tubular acidosis but without lymphoma to be treated with B-cell depletion using Rituximab. Rapidly after B-cell depletion, remarkable improvement in xerostomia occurred, while serological findings and tubular acidosis have been unchanged. In labial salivary gland biopsy, lymphocyte infiltration and particularly CD20-positive cells decreased strikingly. Aquaporin 1 (AQP-1) expression in myoepithelial cells was very low before treatment and increased noticeably. Apical AQP-5 in acinus cells likewise increased following Rituximab. In contrast, basolateral NKCC1 was expressed at unchanged intensity before and following Rituximab. The improvement has been sustained and still is most gratifying 10 months after treatment. B-cell depletion may be effective treatment in Sjögren's syndrome. Likewise, it may now be possible to separate the immunologic phenomena in Sjögren's syndrome from the consequences of prolonged hyposalivation when studying the pathophysiology of xerostomia.