Antibodies to cellular antigens in Greek patients with autoimmune rheumatic diseases: anti-Ro(SSA) antibody a possible marker of penicillamine-D intolerance.

One hundred and twenty-four sera from Greek patients with autoimmune rheumatic diseases (29 with systemic lupus erythematosus (SLE), 24 with scleroderma, 11 with primary Sjögren's syndrome (SS), and 60 with rheumatoid arthritis (RA) were tested for antibodies to nRNP, Sm, Scl-70, Ro(SSA), and La(SSB) cellular antigens. The incidence of these antibodies in the different groups of patients examined, did not differ overall from that described previously. It was noted, however, that antibodies to Sm were very infrequently found in Greek patients with SLE and anti-Ro positive patients with SLE did not have the clinical manifestations described by other workers. Finally, it was found that anti-Ro positive patients with RA experienced a high frequency of side effects from penicillamine-D. The significance of these findings is discussed.     

Serum soluble Fas/APO-1 is increased in patients with primary Sjögren's syndrome

The aim of the study was to elucidate the involvement of Fas antigen in human autoimmune disease, by analysing serum levels of soluble Fas/APO-1 protein in patients with various autoimmune diseases, including system lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), Behçet's syndrome and Sjögren's syndrome (SjS). The levels of soluble Fas/APO-1 in sera were quantitated by a sandwich enzymelinked immunosorbent assay. Soluble Fas/APO-1 levels were significantly increased in serum from patients with primary Sjögren's syndrome (1° SjS) compared with control subjects. However, no significant differences in soluble Fas/APO-1 levels were noted in patients with secondary Sjögren's syndrome (2° SjS) nor in patients with any of the other autoimmune diseases. The soluble Fas/APO-1 level in 1° SjS patients with extraglandular diseases was significantly higher than that in patients without extraglandular diseases. These results suggest that soluble Fas/APO-1 protein may play an important role in the pathogenesis of 1° SS.     

THYROID DISEASE AND OTHER AUTOIMMUNE PHENOMENA IN A FAMILY STUDY OF PRIMARY SJOGREN'S SYNDROME

Autoimmune diseases and autoantibodies have been documentedin 42 index cases with definite primary Sjögren's syndrome(1° SS), 207 relatives and 39 spouses. The results werecompared with control data from a local population survey. Thyroiddisease, 1° SS and their associated autoantibodies werethe commonest autoimmune abnormalities observed and found predominantlyin older female relatives. The HLA-DR3 phenotype associatedwith 1° SS, antinuclear factor, hypothyroidism, and thyroidmicrosomal antibody. Rheumatoid arthritis and systemic lupuserythematosus were not found in excess in the families. PrimarySjögren's syndrome is frequently associated with thyroiddisease and we suggest that there is a common genetic predispositionbetween these diseases which differs from 2° SS associatedwith rheumatoid arthritis and systemic lupus erythematosus.This includes MHC and non-MHC genes. KEY WORDS: Thyroid disease, Genetics, HLA-DR3, Sjögren's syndrome     

Antibodies to human immunodeficiency virus (HIV-1) in autoimmune diseases: Primary Sjögren's syndrome,systemic lupus erythematosus,rheumatoid arthritis and autoimmune thyroid diseases

Summary The aetiology of autoimmune diseases remains unknown. The relationship between virus, and more recently retrovirus, has been suggested with this group of diseases. Immunoblotting is a useful method for determining the presence of proteins coded by different retrovirus genes. Since the prevalence of these types of proteins in patients with primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and autoimmune thyroid diseases has not been fully established, the aim of this work was to determine the prevalence of antibodies to immunodeficiency human virus type 1 (HIV-1) proteins in these diseases and their possible relationship with the presence of anti-nuclear, anti-DNA, anti-SSA (Ro) and anti-SSB (La) autoantibodies. Antibodies to human immunodeficiency virus (HIV-1) were studied in a group of 341 patients with autoimmune diseases (77 SS, 98 SLE, 75 RA, 91 autoimmune thyroid diseases) and 126 blood donors as a control group. A Western blot was used to detect antibodies to HIV-1, and a double polymerase chain reaction (PCR) using nested primers in the gag and pol gene of HIV-1. Antinuclear antibodies, anti-DNA, anti-SSA (Ro) and anti-SSB (La) were determined by enzyme-linked immunosorbent assays.At least one band was shown on immunoblotting in 26% of patients with autoimmune diseases and 35% of controls. The presence of antibodies to p55 or p68 proteins in patients with SS or SLE proved to be the only statistically significant difference between the other autoimmune diseases studied and the control group. These antibodies were not associated with autoantibodies, ANA, DNA, SSA (Ro) or SSB (La). Initially, PCR assay was performed to rule out the presence of HIV-1 virus; results were always negative, as expected. Our results suggest that the presence of p55 and p68 in Western blot for HIV-1 helps differentiate patients with SS or SLE, from those with RA or autoimmune thyroid disease and from a control group.     

Anti-Ro (SSA)/La (SSB) antibodies and Sj?gren's syndrome

Antibodies to Ro (SSA) and La (SSB) cellular ribonucleoprotein complexes are found in the circulation of patients with Sjögren's syndrome (SS), mainly in those with the primary form of the syndrome. Their presence is associated with long disease duration, earlier disease onset, parotid gland enlargement, systemic manifestations and also with hypergammaglobulinemia, rheumatoid factors and monoclonal type II cryoglobulins. While anti-Ro (SSA) antibodies are not specific for SS, anti-La (SSB) antibodies seem to be specific. Studies of HLA class II molecules in Ss patients with and without these antibodies have shown that their production is under genetic control. Finally, there is no conclusive evidence relating pathogenetically these autoantibodies to tissue destruction in SS.     

Purification of the Ro/SSA antigen and enzyme-linked immunosorbent assay for quantitation of the antibody

Antibodies to the Ro/SSA antigen occur in patients with Sj?gren's syndrome and other collagen diseases. In this study, we used ammonium sulfate precipitation, anti-Ro/SSA immunoaffinity chromatography and gel filtration to purify the Ro/SSA antigen from pig spleen. In addition, the normal human IgG affinity column chromatography was also used to adsorb nonspecific reacting materials as heterophile antigens which contaminated in preparations after immunoaffinity chromatography. On SDS-PAGE the purified Ro/SSA antigen migrated as 60K and 53K polypeptides bands and the antigenicity was observed on 60 K band. An enzyme-linked immunosorbent assay (ELISA) using the purified antigen was developed for quantitation of the antibody which was found to be sensitive, precise and specific. By the method, anti-Ro/SSA antibodies were detected in SLE (44%), MCTD (71%), PSS (50%), SjS (83%), RA (16%), PBC (23%), lupoid hepatitis (23%) but only 4% in normal controls. The purified antigen and ELISA method will provide beneficial tools for the investigation of autoimmune diseases.     

Leucocytoclastic vasculitis as presenting feature of primary Sjögren's syndrome

Summary Described are two patients whose primary Sjögren's syndrome presented as leucocytoclastic vasculitis of the skin. One patient initially admitted complaints of dryness of the eyes and the mouth after direct questioning, and serologic testing revealed the presence of Ro/SS-A and La/SS-B antibodies. In the other patient the presence of antinuclear antibodies and rheumatoid factors in serum were the only suggestions of the presence of primary Sjögren's syndrome. Primary Sjögren's syndrome should be considered in patients presenting with leucocytoclastic vasculitis.     

Can B cell epitopes of 60 kDa Ro distinguish systemic lupus erythematosus from Sj?gren's syndrome?

Antibodies binding components of the Ro/La (or SSA/SSB) ribonucleoprotein particle are found in the sera of patients with systemic lupus erythematosus (SLE) and Sj?gren's syndrome (SS) as well as mothers who give birth to babies with neonatal lupus. Anti-La occurs in a subset of sera that contain anti-Ro, and anti-La is found more commonly in sera of patients with SS than in sera from SLE patients. The fine specificity of autoantibodies binding 60 kDa has been studied extensively. Recent data have suggested that there are disease-specific epitopes which identify patients with either SLE or SS. Alternatively, other data suggest that the B cell epitopes of 60kDa Ro vary according to the presence of anti-La. The present study was undertaken to determine whether binding of putative disease-specific 60 kDa Ro epitopes is associated with the diagnosis of SLE vs SS, or instead associated with the presence of anti-La. Anti-60 kDa Ro positive sera from 24 SLE patients and 44 SS patients were studied for antibodies binding two epitopes of 60 kDa Ro. We find the epitope defined by residues 171-190 is associated with anti-60 kDa Ro without anti-La, regardless of diagnosis. Meanwhile, binding of the epitope defined by residues 215-232 is not commonly found in anti-60 kDa Ro sera, especially in those sera with both anti-60 kDa Ro and anti-La. Thus, the fine specificity of antibody binding to 60 kDa Ro varies according to the presence of anti-La, not to the diagnosis of either SLE or SS.     

Fine specificity of the Ro/SSA autoantibody response in relation to serological and clinical findings in 96 patients with self-reported cutaneous symptoms induced by the sun

Anti-Ro/SSA assays assist the clinician in distinguishing autoimmune diseases such as Sj?gren? syndrome (SS), systemic lupus erythematosus (SLE) and subacute cutaneous lupus erythematosus (SCLE). The objective of the study was to investigate the fine specificity of the autoantibodies in relation to clinical presentation as well as environmental and endogenous factors such as photosensitivity, smoking and immunoglobulin (Ig) levels in patients with Ro/SSA autoantibodies. Serum samples from 96 anti-Ro/SSA positive photosensitive patients were tested for autoantibody levels by enzyme-linked immunosorbent assay (ELISA) using purified recombinant Ro52 kd, Ro60 kd and La proteins as antigens. The highest levels of anti-Ro52 and anti-La were observed in patients with primary SS, and the lowest levels of anti-Ro52 in chronic cutaneous lupus erythematosus (CCLE). SCLE patients with systemic disease (SLE and/or SS) showed higher levels of anti-Ro52 than SCLE limited to the skin. A correlation between high serum levels of IgG and anti-Ro52 (P < 0.01) and between IgA and anti-Ro52 (P < 0.05) and anti-Ro60 (P < 0.05) was found. Polymorphic light eruption (PLE) was common in all diagnostic groups but did not correlate with autoantibody levels. Smoking was more common in lupus patients than in SS patients. Our findings thus propose different mechanisms for different clinical presentations of Ro/SSA positive patients. The testing of anti-Ro52 antibodies might serve as a prognostic tool in photosensitive cutaneous diseases.     

ASSOCIATION OF DR3 WITH SUSCEPTIBILITY TO AND SEVERITY OF PRIMARY SJOGREN'SYNDROME IN A FAMILY STUDY

A study of HLA and primary Sjögren's syndrome (1°SS)was performed in 40 index cases and 180 relatives all of whomwere Caucasian. The association of DR3 and 1°SS was confirmed.In probands, DR3 associated with extraglandular manifestationsof 1°SS and homozygosity for DR3 associated with youngeronset of disease. Familial clustering of 1°SS was evident.Definite or probable 1°SS (Fox criteria) occurred with aprevalence of 4.4% in the relatives, exclusively in older femalefirst degree relatives and was associated with DR3. The relativerisk was greatest in those who expressed antinuclear factor,rheumatoid factor or Ro and DR3. We identified a group of youngfemales expressing some criteria for 1°SS and the same immunogeneticmarkers. They may be at risk of full expression of 1°SSas they become older. Milder forms of 1°SS were common inolder relatives but not DR3 associated. 1°SS in males wasrare and mild irrespective of immunogenetic status. Symptomsof 1°SS in relatives were mild or absent. Such individualswill only be identified through a family study or a communitysurvey KEY WORDS: Genetics, HLA, Ro and La antibodies     

Multicentric Castleman's disease in a patient with primary Sjögren's syndrome

Summary A 38-year-old woman suffering from primary Sjögren's syndrome for 2 years developed angiofollicular hyperplasia (multicentric Castelman's disease). In Sjögren's syndrome (SS) a number of findings indicate the presence of a B-cell hyperactivity that may evolve to a lymphoproliferative disorder. This report adds another pathological event to the complex spectrum of lymphoproliferative diseases in SS.Deccased     

Undifferentiated connective tissue disease with antibodies to Ro/SSa: clinical features and follow-up of 148 patients

OBJECTIVE: To evaluate the clinical and serologic profile, the rate of progression to well defined CTD and the possible predictors of disease evolution in patients affected by UCTD with antibodies anti-RoISSA. METHODS: 148 patients diagnosed as UCTD were retrospectively evaluated. Antibodies to SSA/Ro were determined by counter-immunoelectrophoresis and ELISA. RESULTS: Thirty-six patients (24.3%) developed a well-defined CTD after a mean follow-up of 4.5 years. Most patients developed primary Sj?gren's syndrome (SS) (50%) or systemic lupus erythematosus (SLE) (30.5%). Leukopenia and xerophthalmia developed more frequently in the group of patients evolving to defined CTDs (p < 0.0032 and p < 0.0063). Leukopenia independently predicted the evolution in CTD by multivariate regression analysis (p < 0.019). Anti-dsDNA predicted the evolution in SLE (p < 0.0207), while the presence of additional anti-ENA specificity to anti-Ro/SSA was not associated with the outcome. CONCLUSION: 24.3% of patients with UCTD and antibodies to Ro/SSA can progress in a relatively short period of time to well-defined CTDs. The development of primary SS could be predicted by xerophthalmia and SLE by the appearance of anti-dsDNA antibodies.     

SJOGREN'S SYNDROME PRESENTING AS A SEVERE SENSORY NEUROPATHY INCLUDING INVOLVEMENT OF THE TRIGEMINAL NERVE

Primary Sjögren's syndrome (SS) can be associated and maypresent with neurological complications. We describe a 32-year-oldwoman with a debilitating sensory neuropathy, including trigeminalnerve involvement which was the initial manifestation of thisdisease. KEY WORDS: Sjögren's syndrome, Sensory neuropathy, Trigeminal neuropathy     

Antibodies to Sm and SS-A demonstrated by enzyme immunoassay

Summary Using commercially available antigens, enzyme-linked immunosorbent assays (ELISAs) were set up to demonstrate antibodies of IgG class against Sm and SS-A. Anti-Sm antibodies were demonstrated in 40% of patients with systemic lupus erythematosus (SLE), in 12% of patients with Sjögren's syndrome, in 6% of patients with rheumatoid arthritis (RA) and in 12% of patients with miscellaneous rheumatic disorders. Anti-SS-A antibodies were seen in 63% of the SLE patients, in 37% of the patients with Sjögren's syndrome and in 23% of the patients with RA. In the patients with SLE, high levels of anti-Sm antibodies were related to the presence of Raynaud's phenomenon, whereas patients with a malar rash tended to have high levels of anti-SS-A antibodies. In 17 SLE patients followed over a period of time a correlation was seen between the levels of the anti-Sm antibodies and the disease activity. We concluded that it is useful to include ELISAs for the demonstration of anti-Sm and anti-SS-A antibodies in determining the serological profile and in the follow-up of patients with SLE.     

The clinical significance of the detection of anti-Ro/SS-A and anti-La/SS-B autoantibodies using purified recombinant proteins in primary Sjögren's syndrome

Summary Recently, an enzyme-linked immunosorbent assay (ELISA), using purified recombinant non-fusion proteins, has been introduced to detect and quantify Ro/SS-A and La/SS-B autoantibodies. We compared this method with anti-Ro/SS-A and anti-La/SS-B detection by means of counterimmunoelectrophoresis and immunoblotting in patients with primary Sjögren's syndrome (SS), patients suspected of the syndrome and controls. The sensitivity and specificity of the newly developed ELISA for anti-Ro/SS-A were 53% and 100%, respectively, and for anti-La/SS-B, 40% and 98%, respectively. No significant difference was found between these results and those obtained from both other assays. Titres of Ro/SS-A and La/SS-B autoantibodies correlated with the presence of an abnormal parotid gland sialogram and hypergammaglobulinaemia. We concluded that the new ELISA did not enhance the diagnostic yield in cases of suspicion of primary Sjögren's syndrome. Longitudinal studies of large groups of patients with primary Sjögren's syndrome are necessary to demonstrate whether following the course of the titres of these autoantibodies would be of value for prediction of disease exacerbations.     

Elevated levels of TRAIL in systemic lupus erythematosus are associated to the presence of anti-SSA/SSB antibodies

The objective of this study was to determine potential relationship between the levels of serum TNF-related apoptosis inducing ligand (TRAIL) and osteoprotegerin (OPG) and clinical markers in systemic lupus erythematosus (SLE) patients. Forty SLE patients with inactive disease were enrolled in this study. For comparison, 20 Sj?gren's syndrome (SS) patients and 30 normal controls were also analysed. Serum levels of TRAIL and OPG were determined by ELISA. Serum TRAIL and OPG concentrations in SLE patients were significantly (P < 0.05) higher than those in healthy volunteers. Of note, serum TRAIL but not OPG was significantly (P < 0.05) higher in the SLE patient subset characterized by the presence of anti-SSA/SSB antibodies. The relationship between high levels of TRAIL and SSA/SSB antibodies was further supported by the analysis of SS patients characterized by SSA/SSB antibodies positivity, in which TRAIL levels resulted comparable to the subgroup of anti-SSA/SSB positive SLE patients. The presence of SSA/SSB antibodies, targeting a specific subset of SLE and SS patients, is related to increased serum levels of TRAIL but not of OPG.     

Complete congenital heart block followed by anti-Ro/SSA in adult life. Studies of an informative family

A family is described in which an asymptomatic woman gave birth to a male child with complete congenital heart block. Precipitating antibodies to the Ro/SSA antigen have developed in this child, now aged 33, who is clinically well. In the mother, features of both systemic lupus erythematosus and Sj?gren's syndrome developed 26 years after the birth of her son. Her serum currently has precipitating antibodies to both the Ro/SSA and La/SSB antigens. The presence of anti-Ro/SSA in the child with complete congenital heart block and the extremely long delay of 26 years between the delivery of the child and the development of clinical disease in the mother are discussed in light of investigators' developing knowledge of both neonatal and adult systemic lupus erythematosus.     

Flares of systemic disease in primary Sjögren's syndrome

SIR, Rheumatic disorders such as rheumatoid arthritis (RA) orsystemic lupus erythematosus (SLE) are characterized by a relapsing–remittingcourse, with flares of disease activity [1, 2] amenable to therapy.This has not been well studied for the systemic features ofprimary Sjögren's syndrome (PSS). We report our observationsfrom 59 consecutive patients with PSS, fulfilling the revisedEU–USA criteria [3], who attended a multidisciplinarySjögren's syndrome clinic in Birmingham, UK between 1 January1997 and 31 December 2001. Six further     

Autoantibodies against alpha-fodrin in Sjögren's syndrome with neurological manifestations

OBJECTIVE: To investigate the diagnostic value of autoantibodies against alpha-fodrin in patients with Sj?gren's syndrome (SS) with neurological manifestations compared to SS patients without neurological manifestations, a control group, and patients with other neurological autoimmune diseases including systemic lupus erythematosus (SLE) with neurological manifestations and multiple sclerosis (MS). METHODS: We evaluated alpha-fodrin autoantibodies in 31 patients with SS with neurological manifestations, 53 SS patients without neurological symptoms, 38 patients with SLE, 60 with MS, and 160 controls. RESULTS: Twenty of the 31 SS patients with neurological manifestations (64.5%) had an increased concentration of IgA and/or IgG anti-alpha-fodrin. This was not statistically different from that of SS patients without neurological symptoms (73.6%), but was higher than the number with SSA/SSB antibodies, which were found in 15 (48%) of our SS patients without neurological manifestations. When the results of the 2 tests were combined, 28 of the 31 (90.3%) patients had positive autoantibodies (alpha-fodrin and/or SSA/SSB). Alpha-fodrin antibodies were increased in 8 (13.3%) of the 60 patients with MS, in 6 (15.7%) of 38 patients with SLE, and in 10 (6.3%) of 160 controls. CONCLUSION: Our results confirm that alpha-fodrin antibodies are an additional diagnostic tool for SS. This test is of particular interest for patients with SS with neurological manifestations, in whom anti SSA/SSB antibodies are less frequently found.