Interview with Haralampos M. Moutsopoulos. What's going to happen as far as the natural history of Sjögren's syndrome is concerned?. Interview by Pierre Youinou.
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Humans↗
Biomedical subjects
H M Moutsopoulos
Publications and source records attributed to H M Moutsopoulos.
Preliminary criteria for the classification of Sjögren's syndrome. Results of a prospective concerted action supported by the European Community.
OBJECTIVE: Different sets of diagnostic criteria have been proposed for Sjögren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community. METHODS: The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they included 13 questions and 7 questions, respectively. For part II a limited set of diagnostic tests was selected, and the exact procedure to be followed in performing these tests was defined. Part I of the study included 240 patients with primary SS and 240 age- and sex-matched controls. Two hundred forty-six patients with primary SS, 201 with secondary SS, 113 with connective tissue diseases but without associated SS, and 133 control patients were studied in part II. RESULTS: The study resulted in (a) the validation of a simple 6-item questionnaire for determination of dry eyes and dry mouth, which showed good discriminant power between patients and controls, to be used in the initial screening for sicca syndrome; and (b) the definition of a new set of criteria for the classification of SS. The sensitivity and specificity of the criteria in correctly identifying patients with either the primary or the secondary variant of SS were also determined. CONCLUSION: Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS. Final validation of the preliminary classification criteria for SS is underway.
Connective Tissue Diseases↗
Autoantibodies to HMG-17 nucleosomal protein in autoimmune rheumatic diseases. Correlation with systemic lupus erythematosus clinical activity and with antibodies to double-stranded DNA.
OBJECTIVE: Previous studies have shown that serum from patients with systemic lupus erythematosus (SLE) contains antibodies directed against HMG-17, a nucleosomal nonhistone high mobility group (HMG) protein found in chromatin. The aim of the present study was to investigate any associations between the presence of antibodies to HMG-17 and clinical and serologic features of SLE. METHODS: Using porcine thymus as a source, HMG-17 was purified by Sephacryl S-200 chromatography followed by high performance liquid chromatography. An enzyme-linked immunosorbent assay utilizing the purified HMG-17 as antigen was developed and was used to evaluate sera from patients with autoimmune rheumatic diseases, for the presence of autoantibodies. RESULTS: Anti-HMG-17 antibodies were found in the serum of 34.8% of the patients with SLE, compared with 11.5% of patients with primary Sjögren's syndrome, 4.4% of patients with rheumatoid arthritis, and 4.1% of normal blood donors. Analysis of the clinical features of SLE using 2 different lupus activity indices revealed that anti-HMG-17 antibodies were more frequently found in patients with active disease. A positive correlation was also observed between anti-HMG-17 and anti-dsDNA levels, and levels of both of these autoantibodies demonstrated a negative correlation with C4. Analysis of sequentially obtained serum samples from 4 SLE patients revealed that, in 2 patients, anti-HMG-17 levels fluctuated in parallel with both disease activity and anti-dsDNA levels, and in the remaining 2, anti-HMG-17 levels fluctuated in parallel with disease activity. CONCLUSION: Antibodies to HMG-17 are found in patients with many different autoimmune rheumatic diseases, although they are more frequently observed in those with SLE. Their presence appears to be associated with lupus disease activity as well as with anti-dsDNA and C4 levels.
Adolescent↗
Molecular analysis of HLA class II genes in primary Sjögren's syndrome. A study of Israeli Jewish and Greek non-Jewish patients.
In an attempt to define the role of HLA class II genes in predisposition to primary Sjögren's syndrome, patients of two different ethnic groups (Israeli Jews and Greeks of non-Jewish origin) suffering from this disorder were studied. Oligonucleotide genotyping revealed the majority in both groups to carry either DRB1*1101 or DRB1*1104, alleles that are in linkage disequilibrium with DQB1*0301 and DQA1*0501. The high frequency of the two alleles in these SS patients is in contrast with the accepted association of primary SS with HLA-DR3 in Italian and American individuals. Molecular analysis of DQB1 and DQA1 alleles found in American Caucasian and American black SS (or SLE) patients demonstrated high frequencies of DQB1*0201 and DQA1*0501. The fact that the majority of SS patients, across racial and ethnic boundaries, carry a common allele, DQA1*0501, implies its involvement in the predisposition to primary SS. Based on sequence analysis and the computer imaging of the HLA class II molecule structure, a hypothetical model for the role of the DQ molecule in promoting primary SS is proposed.
Alleles↗
Rare rheumatic disorders. A. Behçet's disease.
No more than 100 patients with respiratory involvement in Behçet's disease have been described in the literature. Haemoptysis, cough, dyspnoea and pleuritic chest pain are the main symptoms. Vasculitis and thrombosis of the great pulmonary vessels is the underlying condition in the majority of patients. Aneurysmal formation and rupture is possible and constitutes the most life-threatening aspect of the disease. Behçet's syndrome should be considered in the differential diagnosis of haemoptysis and veno-occlusive disease, especially where large vessels are involved. Early detection and treatment is mandatory to save the patient's life. Other pleuropulmonary manifestations described, such as fibrosing alveolitis and pleural disease, occur less frequently in Behçet's disease, and carry a better prognosis.
Behcet Syndrome↗
Patients with anticentromere antibodies, clinical features, diagnoses and evolution.
The sera of 1373 patients derived from a random population of 2627 individuals examined in a rheumatology outpatient clinic were found to be positive for antinuclear antibodies (ANA). Forty-seven of 1373 ANA positive patients (3.42%) presented a pattern of anticentromere antibodies (ACA), and of these 41 were followed-up. The predominant clinical features among ACA positive patients were Raynaud's phenomenon, arthralgias, scleroderma affecting the hands, feet, face and forearms, telangiectases and pulmonary involvement. There were 26 patients (64%) with limited cutaneous systemic sclerosis (lSSc), seven with primary Sjögren's syndrome (Ss) (17%), five with idiopathic Raynaud's phenomenon (IRPh) (12%) and three (7%) with other diseases. The lSSc subset was characterized by a significantly younger age for disease onset than for the IRPh patients. The Raynaud's phenomenon of lSSc patients lasted for many years before the onset of scleroderma, while their pulmonary involvement was mild and subclinical. The Ss patients with ACA were characterized by a lower incidence of parotid gland enlargement and anti-La (SSB) antibodies than described in the literature. Finally, the presence of ACA correlates with the clinical criteria proposed for the diagnosis of lSSc.
Adult↗
Detection of anti-Ro(SSA) antibodies in autoimmune diseases: comparison of five methods.
Counterimmunoelectrophoresis (CIE), RNA precipitation, ELISA and immunoblotting against cytoplasmic HeLa cell extract (IB-HeLa) and erythrocyte extract (IB-RBC) were applied to detect anti-Ro(SSA) antibodies in 93 sera selected from patients with various autoimmune diseases [47 were anti-Ro(SSA) positive by CIE]. The RNA precipitation assay, which demonstrated the highest sensitivity was selected as the reference method. CIE was found to be reliable with a specificity of 100% and a sensitivity of 89%. ELISA showed a comparable specificity (95%) but somewhat lower sensitivity (72%). Antibodies to 52 or 60 kDa Ro(SSA) proteins by IB-HeLa demonstrated a high specificity (95 and 97% respectively) but a low overall sensitivity (36 and 17% respectively). Anti-Ro(SSA) antibodies to 52, 54 and 60 kDa erythrocyte proteins by IB-RBC, had a variable overall specificity (95, 97 and 57%) and sensitivity (51, 13 and 34%). The anti-52 kDa antibodies detected by IB-HeLa correlated to those found by IB-RBC (P < 0.001) and occurred predominantly in primary Sjögren's syndrome (P < 0.001, sensitivity: 71 and 77%) as well as in sera with anti-Ro(SSA) and anti-La(SSB) antibodies (P < 0.001). These findings confirm that RNA precipitation assay has the highest sensitivity and specificity for anti-Ro(SSA) antibody detection. However, until a more sensitive ELISA is available, CIE because of its reliability appears to be the method of choice. Finally IB-RBC was found to be more sensitive than IB-HeLa for the detection of anti-Ro52 kDa antibodies.
Adult↗
Calreticulin synthetic peptide analogues: anti-peptide antibodies in autoimmune rheumatic diseases.
Autoantibodies in sera from patients with systemic lupus erythematosus (SLE) and onchocerciasis recognize calreticulin (CaR), a calcium-binding protein, as antigen. In this study we present the immunological properties of two synthetic peptides prepared to correspond to the 1-24 and 7-24 amino acid sequence of CaR. In contrast to information previously reported for the recombinant protein, the CaR-peptide analogues appeared immunoreactive to anti-Ro/SSA autoimmune sera. Human sera from patients with SLE, Sjögren's syndrome (SS), rheumatoid arthritis (RA), as well as mixed connective tissue disease (MCTD), demonstrated a positive autoimmune response (binding of antibodies), to the CaR-peptide analogues. These findings suggest that anti-calreticulin autoantibodies are not restricted to any disease specificity.
Amino Acid Sequence↗
Immunologic and viral markers in the circulation of anti-HIV negative heroin addicts.
To assess the degree of immune system activation associated with addiction or hepatotropic viruses infection, we examined 60 HIV-negative heroin addicts for the presence of hepatitis B virus (HBV) infection markers, hepatitis C virus antibodies (anti-HCV), various auto-antibodies, and serum levels of soluble interleukin-2 receptors (sIL-2R). In addition, 28 anti-HCV positive patients comprising the disease control group, were also examined. Our results demonstrated a high prevalence of anti-HCV antibodies (61.7% and 90% with 1st and 2nd generation ELISA, respectively). Eighty-seven percent (87%) of the addicts positive for anti-HCV by the latter and 92.8% of the disease control patients, were also positive with 2nd generation recombinant immunoblot assay (RIBA-II). In 88.9% of anti-HCV positive addicts, antibody to C22-3 was the predominant (anti-C33c in 81.5%). Antibodies to C33c and C22-3 polypeptides were also more frequent in disease control group (92.8% and 85.7%, respectively). Anti-HCV antibodies were associated with increased transaminases (ALT or AST, P < 0.05), as well as with longer duration of addiction (P < 0.005). HBV infection markers (HBsAg, anti-HBc only and anti-HBs) were also present in the addicts (5%, 28.3% and 26.7%, respectively). Rheumatoid factors (RF) were detected in 36.7%, antinuclear antibodies (ANA) in 11.7%, antibodies (IgG and/or IgM) against cardiolipin (anti-CL) and double stranded DNA (anti-ds DNA) in 20% and 50%, respectively. RF, ANA, anti-CL and anti-dsDNA antibodies were also detected in the disease control group (32.1%, 89.3%, 28.5% and 28.5% respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Examination of HLA-DR4 as a severity marker for rheumatoid arthritis in Greek patients.
OBJECTIVES: Previous reports have shown that HLA-DR4 may be a severity marker for rheumatoid arthritis (RA) in patients of northern European origin. The aim of the present study was to investigate this relation in Greek patients with RA, as RA in Greece differs from the RA described previously on clinical, serological, and immunological grounds. METHODS: Eighty four patients were studied in whom HLA-DR typing was performed by restriction fragment length polymorphism and the subtypes of HLA-DR4 were determined by the polymerase chain reaction. The absence or presence of HLA-DR4 and its subtypes was correlated with the clinical and serological characteristics of the patients and with the side effects due to disease modifying drugs. RESULTS: Twenty one of the 84 (25%) patients with RA were DR4+. There was no difference between the DR4+ and DR4-patients with respect to duration of disease, severity of arthritis, functional grade, and joint erosion score. The DR4+ group were more likely to have side effects due to disease modifying drugs (43%) than DR4- patients (36%), but this difference was not statistically significant. DR4-patients had more extra-articular manifestations, including Sjögren's syndrome (47 v 19%). Analysis of the DR4 subtypes showed that Dw15 was the most common variant (9/21 patients; 43%). There was no statistical difference in the clinical manifestations among patients with different DR4 subtypes. The same was also true when the clinical picture was correlated with the 'shared RA epitope' (QKRAA/QRRAA/RRRAA), which is common to all HLA-DRB1 alleles positively associated with RA. CONCLUSIONS: These results suggest that HLA-DR4 is not a severity marker in Greek patients with RA and further indicate differences in the clinical expression of RA in Greece.
Arthritis, Rheumatoid↗
Soluble interleukin-2 receptors, antineutrophil cytoplasmic antibodies, and other autoantibodies in patients with ulcerative colitis.
Ulcerative colitis (UC) is an inflammatory bowel disease of unknown aetiology. In this study, serum samples from 80 patients with UC were studied for the presence of various autoantibodies and soluble interleukin-2 receptor molecules (sIL-2Rs) in an attempt to determine the degree of activation of the immune system in this disease process. Autoantibodies detected included rheumatoid factors (in 5% of patients), antinuclear antibodies (in 51.3%), anti-Ro(SSA) (in 1.3%), anticardiolipin antibodies (IgG and/or IgM classes in 26.3%), anti-double stranded DNA (IgG or IgM classes in 45%), and antineutrophil cytoplasmic antibodies (ANCAs, in 30%). The ANCAs had a perinuclear pattern (p-ANCA) in 95.8%, without anti-myeloperoxidase activity, at least in an enzyme linked immunosorbent assay (ELISA) system. Raised concentrations of sIL-2R were found in 32.5% of patients (26/80, 18 with active and eight with inactive UC). The mean (SD) sIL-2R concentrations were significantly higher in patients with active UC (595 (219) u/ml v 406 (162) u/ml, p = 0.0001) and in patients with ANCAs (584 (177) u/ml in ANCA positive v 447 (212) u/ml in ANCA negative patients, p < 0.01). The sIL-2R concentrations were correlated with increased serum concentrations of C3c (r = 0.23, p < 0.05) or C4 (r = 0.4, p < 0.001) components of the complement system and erythrocyte sedimentation rate (ESR, r = 0.44, p = 0.0001). Platelets, ESR, and C3c were not associated with disease activity (p = 0.06, 0.33 and 0.86) whereas mean (SD) serum concentrations of C4 were higher in active disease (37.4 (11.9) mg/dl v 32.3 (10.3) mg/dl, p < 0.05). The sIL-2Rs had 53% sensitivity and 82.6% specificity for disease activity whereas platelet counts had 53% sensitivity and 58.7% specificity. To conclude, UC is accompanied by an autoimmune response that results in the production of several autoantibodies and cellular immune activation, as shown by the high sIL-2R concentration, is also present. The identification of the target antigen(s) of p-ANCA would possibly act as an indicator of disease activity if this distinct subset of ANCAs can be attributed to the pathogenesis of UC. The sIL-2R concentrations seem to be a useful laboratory marker for assessing activity of the disease.
Adolescent↗
Immunopathology of Sjogren's syndrome: more questions than answers.
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Humans↗
Systemic lupus erythematosus in Greece. Clinical features, evolution and outcome: a descriptive analysis of 292 patients.
The purpose of this study was the descriptive analysis of patients with systemic lupus erythematosus (SLE) with a particular focus on initial clinical features, evolution and outcome of disease, prevalence of clinical and serological manifestations and identification of clinicoserological associations indicative of renal and CNS involvement. The methodology applied was the following: retrospective analysis of the clinical charts of 292 unselected patients (246 female (84.2%) and 46 male (15.7%)) with SLE examined between 1982 and 1992. Multivariate analysis and hierarchical log linear models were used to examine for clinicoserological associations. Descriptive analysis was based on the prevalence of main clinicoserological features and disease outcome. The outcome was examined on the basis of the number of flares, the presence of chronic renal failure, the presence of central nervous system (CNS) involvement with subsequent disability and deaths. Flares were considered the severe alterations in disease status, requiring additional therapy to be controlled. The disease begins most frequently in the second and third decade of life with cutaneous and joint manifestations, while renal and CNS involvement developed later. The prevalence of serious renal, pulmonary and CNS involvement as well as the prevalence of RF, anti-Sm and anti-nRNP antibodies remain low. Multivariate analysis revealed the associations of renal involvement with leukopenia and serositis, of anti-Sm with leukopenia, of secondary Sjogren's syndrome with RF and of thromboembolic events with anticardiolipin antibodies. Patients with childhood onset SLE have a higher tendency for developing renal involvement than adult onset SLE patients. In addition, anti-Ro(SSA) antibodies were associated with anti-La(SSB) and RF, while anti-Sm antibodies were associated with anti-nRNP and RF. Flares occurred with a frequency of 0.07 per patient per year. Only 63.6% of flares were accompanied by positive anti-dsDNA reactivities. Reported deaths were 0.0047 per patient per year. Hierarchical log linear models indicated that the main variables of the disease were sufficient to describe our disease model and that the order of the interaction between the variables was insignificant. We conclude that the prevalence of various clinical features associated with SLE is similar, although the prevalence of CNS and pulmonary involvement as well as anti-Sm and anti-nRNP antibodies are less prominent in Greek SLE patients than that reported in the literature. The various clinicoserological associations detected do not appear to be of major significance as they are not powerful enough to subgroup the disease.
Adolescent↗
Antibodies to phosphatidylethanolamine in antiphospholipid syndrome and systemic lupus erythematosus: their correlation with anticardiolipin antibodies and beta 2 glycoprotein-I plasma levels.
The sera patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) were tested, by ELISA, for antibodies to phosphatidylethanolamine (aPE), as well as to cardiolipin (aCL) and compared to healthy blood donors (HBD). Both, SLE and APS patients presented a higher titre of IgM-aPE antibodies than normals, while the IgG and IgA aPE reactivity did not differ. APS patients were characterized by higher IgM-aPE antibody titres than SLE patients. In contrast, the predominant isotype of aCL antibodies in APS patients was IgG. The IgM aPE reactivity was correlated with IgM aCL reactivity, while no correlation was observed between the total IgM values and IgM-aPE binding units of sera tested. Since it was shown that beta 2-glycoprotein-I (beta 2-GPI) contributes to a complex antigen by binding to phospholipids and that this antigen is recognized by antiphospholipid antibodies from autoimmune patients, sera beta 2-GPI levels were measured and correlated to aCL and APE activity. Although APS patients had higher beta 2-GPI levels than SLE patients, no correlation was found between the beta 2-GPI levels and IgG/IgM aCL and IgM-aPE reactivities a finding suggesting that in addition to beta 2-GPI, other cofactors for aPE antibodies may exist. These findings indicate that aPE and aCL antibodies co-exist and that the IgM-isotype is predominant in APS. In addition, the IgA and IgG aPE antibodies appear to occur in low titres in these patients, as well as in normals and may exist as natural autoantibodies. We suggest that the high IgM-aPE antibodies may be viewed as a thymus independent process.
Antibodies, Anticardiolipin↗
Is central nervous system involvement a systemic manifestation of primary Sjögren's syndrome?
Central nervous system involvement in primary Sjögren's syndrome (pSS) is a controversial issue. Without an international criteria for the diagnosis of pSS, each research center must establish, publish, and strictly adhere to their own criteria. Therefore, patients should be made aware of professional uncertainties, particularly when therapeutic decisions are involved.
Central Nervous System Diseases↗
Rheumatoid arthritis in Greek and British patients. A comparative clinical, radiologic, and serologic study.
OBJECTIVE: To compare the clinical, radiologic, and serologic expression of rheumatoid arthritis (RA) in 2 different populations. METHODS: Standard protocols and assessment criteria were used in this study of 108 Greek and 107 British patients with RA. RESULTS: British patients had more severe articular involvement than did Greeks, as judged by the duration of morning stiffness (P less than 0.005), grip strength (P less than 0.0001), and the numbers of swollen (P less than 0.001) and tender (P less than 0.0001) joints. The British RA patients also had more severe joint damage on radiologic examination, as evidenced by Steinbrocker stage III (P less than 0.005) and IV (P less than 0.025) disease and had more extraarticular manifestations (P less than 0.0001), including rheumatoid nodules (P less than 0.0001) and Raynaud's phenomenon (P less than 0.05). Greek RA patients, however, more frequently presented with sicca manifestations (P less than 0.001) and serum antibodies to Ro/SS-A (P less than 0.025). Furthermore, Ro/SS-A antibodies were associated with a high incidence of side effects to D-penicillamine only in the Greeks. CONCLUSION: Genetic and environmental factors may be responsible for these striking differences in disease expression between these 2 European populations with RA.
Antibodies, Antinuclear↗
HLA class II sequence polymorphisms and susceptibility to rheumatoid arthritis in Greeks. The HLA-DR beta shared-epitope hypothesis accounts for the disease in only a minority of Greek patients.
OBJECTIVE: In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA-DR beta found notably in the HLA-DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen. METHODS: We characterized HLA-DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization. RESULTS: DNA analysis in the RA patients showed that although individual HLA-DR allelic associations were weak, a relatively conserved HLA-DR beta motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA-DR beta 1 of 43.5% of the RA patients versus 15.5% of the controls (uncorrected P = 0.00004). CONCLUSION: Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA-DR beta motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.
Amino Acid Sequence↗
Serum-soluble interleukin-2 receptors in B-cell lymphoproliferative malignancies.
The levels of soluble interleukin-2 receptors (sIL-2R) were determined in the serum of 53 patients with B-cell lymphoproliferative malignancies, including 31 patients with non-Hodgkin lymphomas (NHL), 16 with chronic lymphocytic leukemia (CLL), and 6 with multiple myeloma. In addition, serum samples from 40 patients with various solid tumors as well as from 53 healthy individuals were used as controls. It was found that the mean serum levels of sIL-2R were significantly increased (P less than 0.001) in NHL (mean +/- standard error of the mean 2,327 +/- 320 units/ml) and CLL patients (2517 +/- 451 units/ml) as compared to normal controls (207 +/- 17 units/ml). No such difference was observed when the serum sIL-2R levels of patients with multiple myeloma or solid tumors were analyzed. Serum sIL-2R levels were closely related to the clinical stage, the presence of B-symptoms, and the disease activity of patients with NHL and CLL. In fact, response to chemotherapy was followed by marked decrease or normalization of sIL-2R levels, while in a number of patients sIL-2R values were even able to predict disease relapse. Finally, no association with histologic grade in NHL patients, could be demonstrated. We conclude that serum sIL-2R (1) are increased only in B-NHL and B-CLL but not in myeloma patients, (2) are related to the tumor burden, and (3) can serve as a valuable tumor marker for the monitoring of patients treatment.
Female↗