Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group.

Classification criteria for Sjögren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

Immunogenetics of Sjögren's syndrome.

The etiology for SS remains unknown where multifactorial influences contribute to the pathogenesis of subsequent development of the disease. The genetic influence is also multifactorial and the data suggests a familial component indicative of autosomal-dominant genes as well as genetic contributions associated with class-I and class-II HLA alleles. Various auto-antibodies found with increased frequency in SS (anti-Ro and anti-La) were shown to be associated with HLA class-II alleles at the DQA1 and DQB1 loci that were also found to have in common specific amino acid residues (10). Ethnic groups have also been studied and show varying HLA associations with primary SS. Multiple ethnic groups, however, share a DQ allele supporting the idea that the majority of SS patients carry a common allele which may predispose to primary SS. In some cases, the HLA-DR antigen may be induced and cause to appear on epithelial cells where they present antigen to CD 4+ T-cells, which then go on to aid in the destruction of salivary gland epithelial cells specifically. The further elucidation of disease associations as well as possible immunogenetic pathogenic mechanisms may help to explain the causes for the development of various autoimmune diseases such as Sjögren's Syndrome. This may eventually result in the ability to immunomodulate these abnormal immune responses. In so doing, an approach to treatment by genetic engineering may also be possible once a further understanding of the genetic influences and mechanisms in the causation of autoimmune disease is further elucidated.

Fibrin(ogen)olysis in polymyalgia rheumatica and temporal arteritis: preliminary findings on association with disease activity.

Postulating an increased production of fibrin(ogen)olytic degradation products (FDP) and an abnormality of fibrinogen metabolism in polymyalgia rheumatica (PMR) and temporal arteritis (TA), we studied 16 PMR/TA patients and 10 control subjects using a sensitive radioimmunoassay for a specific type of FDP, namely, fibrin(ogen)-related D-antigen. Median serum D-antigen levels were increased five-fold in those 11 PMR/TA patients who were untreated compared with control subjects. In the five PMR/TA patients who were treated with prednisone the median D-antigen levels were not significantly different from those of the healthy controls. D-antigen concentration correlated significantly (r = 0.83) with ESR in the seven untreated PMR patients. In PMR patients prednisone therapy was followed by a reduction of serum D-antigen levels.

Pulmonary immune complex deposition in Wegener's granulomatosis.

Two male patients with pulmonary manifestations of Wegener's granulomatosis are presented. One had an elevated rheumatoid factor, and both had elevated levels of immunoglobulin E. Both demonstrated characteristic necrotizing granulomatous lesions on light microscopy of lung tissue. Immunohistologic analysis of lung tissue demonstrated a granular deposition of immunoglobulin G and complement. Raji cell assay of sera demonstrated elevated levels of circulating immune complexes in the sera of the one patient tested prior to any therapy. These findings support the hypothesis that immune complex deposition contributes to the pathogenesis of Wegener's granulomatosis.

Lactic acid levels in cerebrospinal fluid from patients with systemic lupus erythematosus.

Cerebrospinal fluid (CSF) samples from 22 patients with systemic lupus erythematosus (SLE) and 20 samples from normal controls were studied for lactic acid levels. Ten samples were obtained from SLE patients with active central nervous system (CNS) involvement and 12 from SLE patients with inactive CNS disease. The mean CSF lactic acid level in patients with SLE was 17.24 +/- 1.25 mg/dl (range 31-10.2 mg/dl) which was not statistically different to the normal control mean of 14.75 +/- 0.9 mg/dl (range 9-28 mg/dl). Thus, lactic acid levels in active or inactive CNS disease of SLE appear to be normal. Due to the fact that lactic acid levels are elevated in the CSF of patients with bacterial meningitis, lactic acid levels can be of potential value in the differentiation between bacterial meningitis and CNS involvement of SLE.

Central nervous system lupus erythematosus: measurement of cerebrospinal fluid cyclic GMP and other clinical markers of disease activity.

Cyclic-GMP (C-GMP), a normal constituent of the central nervous system, was found to be present in increased amounts in the cerebrospinal fluid (CSF) of systemic lupus erythematosus (SLE) patients with active neurologic disease. Twenty-four CSF samples from 17 patients with SLE were evaluated for C-GMP concentration by radioimmunoassay. This study extends our initial observations and examines three groups of SLE patients based on their clinical status at the time of each lumbar puncture: those with active neurologic and psychologic abnormalities (group I), active neurologic abnormalities (group II), and psychologic abnormalities without active neurologic involvement (group III). Groups I and II had mean CSF C-GMP values of 3.1 nM +/- 0.64 (SE) and 4.1 nM +/- 0.10 respectively, which were both significantly higher than the mean for group III (1.2 nM +/- 0.43) (P less than 0.05). Other CSF findings did not display this close correlation with activity of neurologic disease. In 4 SLE patients, significantly higher levels of CSF C-GMP were found on serial sampling during times when neurologic abnormalities were active. Thus elevated CSF C-GMP concentration may be a marker of active neurologic disease in SLE.

Increased toxoplasma antibodies in idiopathic inflammatory muscle disease. A case-controlled study.

Antibodies to Toxoplasma gondii were measured in sera from 69 patients with polymyositis, dermatomyositis, and myositis associated with other connective tissue diseases and compared to 69 age-, race-, and sex-matched controls with unrelated diseases. Complement fixation toxoplasma antibodies were significantly more frequent in polymyositis and correlated with high IgM levels. Other distinguishing clinical or laboratory features of these patients were not found. The high toxoplasma antibodies were not associated with generally hyperactive humoral immunity. The serologic data suggested that inflammatory muscle disease was associated with recent active toxoplasma infection in certain patients. The pathogenetic role of the microorganism remains uncertain.

Increased risk of lymphoma in sicca syndrome.

The risk of cancer was ascertained in 136 women with sicca syndrome followed at the National Institutes of Health (NIH). Seven patients developed non-Hodgkin's lymphoma from 6 months to 13 years after their first admission to NIH. This was 43.8 times (P less than 0.01) the incidence expected from the rates of cancer prevailing among women of the same age range in the general population during this time. In addition, three cases of Waldenström's macroglobulinemia occurred in this study group. Eight patients developed cancers other than lymphoma, similar to the number expected based on the rates prevailing in the general population. Patients with a history of parotid enlargement, splenomegaly, and lymphadenopahy had an increased risk of lymphoma. These clinical conditions did not appear to be early manifestations of undiagnosed lymphoma but rather seemed to identify a subgroup of patients with sicca syndrome with marked lymphoid reactivity, who had a particularly high risk of subsequently developing lymphoma.

Elevated levels of cerebrospinal fluid guanosine 3',5'-cyclic monophosphate (C-GMP) in systemic lupus erythematosus.

Cerebrospinal fluid samples from patients with systemic lupus erythematosus (SLE) and neurologic involvement were evaluated for guanosine 3',5'-cyclic monophosphate (C-GMP) and cyclic adenosine monophosphate (C-GMP) content by radioimmunoassay and radioassay, respectively. Twenty-five samples from 15 patients with SLE had an average C-GMP level of 2.4 nM +/- 0.44 (average +/- SE) compared with 0.68 nM +/- 0.14 in a control group with lumbosacral pain (p less than 0.0002). No significant difference was noted in C-AMP content between patients with SLE and control subjects. C-GMP levels in cerebrospinal fluid samples from patients with SLE who had changing neurologic disease were higher than in those with stable neurologic disease. Elevated C-GMP levels in cerebrospinal fluid correlated with the leukocyte number in cerebrospinal fluid (r = 0.53 p less than 0.01), but not with the initial pressure, protein concentration or daily prednisone dosage. Experimental results suggested that leukocytes in the cerebrospinal fluid were not the source of elevated C-GMP levels. Thus, elevated C-GMP levels in cerebrospinal fluid of patients with SLE appeared to reflect neurologic involvement. C-GMP levels were alos found to be elevated in five patients with other active neurologic diseases; thus, measurement of C-GMP in cerebrospinal fluid may have more general diagnostic value.

Demonstration of activation of B lymphocytes in New Zealand black mice at birth by an immunoradiometric assay for murine IgM.

We have developed a highly specific and sensitive "two-site" immunoradiometric assay for murine IgM in which antigen bound to immobilized antibody reacts with affinity-purified radiolabeled antibody. We utilized the sensitivity of this assay to study the rate of IgM secretion in short-term cultures by spleen cells from the autoimmune strains, New Zealand Black (NZB) and New Zealand Black by New Zealand White F1 hybrid (BW), and from normal (C57BL/6, DBA/2, NZW) mice. The temperature dependence of IgM secretion in short-term cultures, its pentameric structure, and the similar viability of NZB and normal strain spleen cells indicate that active IgM synthesis is being measured. We observed that the splenic B lymphocytes of NZB and BW mice, in contrast to normal strains, produce IgM in vitro at birth. By 6 to 8 weeks of age NZB and BW spleen cells produce 40 times more IgM than spleen cells from normal strains of mice. The IgM produced in vitro by splenic lymphocytes from NZB and BW mice is not absorbed by synegeneic or allogeneic thymocytes or erythrocytes.

Sjögren's syndrome associated with HLA-Dw3.

Sjögren's syndrome is associated with a serologically defined histocompatibility antigen of the HLA-B locus, HLA-B8. Another closely linked locus, HLA-D, determines lymphocyte-defined cell-surface antigens. In laboratory animals such antigens are closely linked to immune response genes. To determine whether Sjögren's syndrome is primarily associated with an HLA-D antigent or with HLA-A and HLA-B antigens as well as HLA-Dw3, which is known to be in linkage disequilibrium with HLA-B8. We found the primary association of association of Sjögren's syndrome to be with HLA-Dw3, which we observed in 84 percent of patients with Sjögren's syndrome in the absence of rheumatoid arthritis as compared to 24 percent in controls (P less than 0.00001). The frequency of HLA-B8 and HLA-Dw3 in patients with both Sjögren's syndrome and rheumatoid arthritis did not differ from that in controls. Patients with Sjögren's syndrome and rheumatoid arthritis comprise genetically distinct groups.

Macrophage requirement for the in vitro response to TNP Ficoll: a thymic independent antigen.

The in vitro antibody-forming cell response of mouse spleen cells to the thymic independent synthetic polymer, TNP-Ficoll, was found to require the presence of either macrophages or 2-mercaptoethanol. The TNP-Ficoll response and that to the thymic dependent antigen, sheep erythrocytes, demonstrated the same degree of macrophage dependence. However, macrophage-depleted spleen cells which did not produce plaque-forming cells responded normally to T and B cell mitogens. Comparison of the antibody-forming cell response of macrophage-depleted spleen cells in the presence and absence of 2-mercaptoethanol indicated that either macrophages function 10 to 100 times more efficiently in its presence or that 2-mercaptoethanol partially replaces the function of macrophages.