Primary Sjögren's syndrome, ulcerative colitis and selective IgA deficiency.

A 24-year-old man with primary Sjögren's syndrome presented with xerophthalmia, xerostomia, and marked parotid swelling. He had a previous history of selective IgA deficiency and ulcerative colitis treated with sulphasalazine. Immunosuppression and withdrawal of sulphasalazine resulted in rapid resolution of the parotitis and disappearance of autoantibodies. A possible role for sulphasalazine in the induction of autoimmunity in this case is discussed.

Erythema elevatum diutinum associated with Wegener's granulomatosis and IgA paraproteinemia.

A 69-year-old man had erythema elevatum diutinum for several years before he developed IgA paraproteinemia and a limited form of Wegener's granulomatosis. This is the first report of an association between erythema elevatum diutinum and Wegener's granulomatosis. IgA paraproteinemia has been reported in association with erythema elevatum diutinum but not with Wegener's granulomatosis.

Juvenile dermatomyositis associated with partial lipoatrophy.

A 26-year-old woman developed partial lipoatrophy 12 years after juvenile dermatomyositis was diagnosed. Renal function was normal, but she had other features typically associated with partial lipoatrophy, including hepatomegaly, acanthosis nigricans, hypertrichosis, and hyperinsulinemia.

Abnormalities in the glycosylation of IgG in spouses of patients with rheumatoid arthritis. A family study.

Forty-seven members of eight families with a rheumatoid proband were analysed for abnormal glycosylation of IgG. The results (%G(o) which is the percentage of oligosaccharide chains lacking galactose) were corrected for age and expressed as SD units about the mean for the normal population. Seven of 8 probands, 3/8 spouses, 3/5 RA relatives and 4/26 non-RA relatives had %G(o) values greater than 1SD above the age corrected mean for the normal control population (P less than 0.001, less than 0.01, less than 0.005 and greater than 0.5 respectively). A further 13 spouse pairs were studied. Ten of 13 probands and 8/13 spouses had %G(o) values greater than 1SD above the mean (P less than 0.001 and less than 0.001 respectively). Thus in total, a strikingly high number of unaffected spouses had high %G(o) values (11/21). IgM, IgA and IgG rheumatoid factors were studied. While RA patients' sera showed a correlation between IgM and IgA rheumatoid factors and %G(o), (IgM, r = 0.41 0.05 greater than P greater than 0.02, IgA, r = 0.36, P = 0.05), no correlation between IgG RF and %G(o) was noted in the RA patients. No correlation was found between any of the RF classes and %G(o) in spouses and non-RA relatives.

Deficient repair of O6-methylguanine in lymphocytes from rheumatoid arthritis families may be an acquired defect.

Deficient repair of the premutagenic DNA lesion O6-methylguanine (O6-MeGua) has been reported in lymphocytes from patients with autoimmune diseases. This was confirmed in the present study of probands with rheumatoid arthritis (RA) and their families. We also noted a significant deficiency in 9/19 spouses (P less than 0.05) and a statistically non-significant deficiency of repair of O6-MeGua in 14/42 first and second degree relatives in comparison with healthy and non-autoimmune disease controls, respectively. A significant correlation of the repair status of O6-MeGua in DNA between individual probands with RA and respective spouses (P less than 0.01) and probands and respective family members (P less than 0.001) supported the idea that an environmental, transmissible agent could influence the expression of the protein, O6-methylguanine-DNA-transferase (O6-MT), involved in the repair of O6-MeGua. The present results, however, cannot entirely exclude an additional hereditary influence.

Familial lupus anticoagulants.

Three families having more than one affected member with SLE or lupus-like disease were investigated by global coagulation tests as well as methods based on dilute thromboplastin, Russell's viper venom and thermal stability/absorption, and by RIA for anticardiolipin (CL) antibodies. Of the 19 persons, 11 had SLE or lupus-like disease. Eight of these 11 had a prolonged KPTT and other evidence of LA, while only 5/11 had high anticardiolipin titres. Four healthy spouses of affected females, and three asymptomatic siblings also had prolonged non-correctable KPTTs. These persons had no bleeding or thrombotic history and normal clotting factor levels. Further clotting tests were negative, although one had raised anti-CL antibody. Such cases may account for some of the patients one finds during routine haemostatic screening with unexplained prolonged KPTT. Although anticardiolipin levels are raised in subjects with LA, there was no close correlation between length of KPTT and anticardiolipin titre. These findings would support a hypothesis of transmissible agents or other environmental factors being involved in lupus-like disorders.

Anti-cardiolipin antibodies in neurological disorders: cross-reaction with anti-single stranded DNA activity.

Antiphospholipid (PL) antibodies have been detected in sera from patients with chronic neurological diseases associated with disorders of immunity. In an isotype specific radioimmunoassay for anti-cardiolipin (CL) antibodies, we found IgM anti-CL (greater than 2 s.d. above mean of controls) in 17/25 (68%) patients with myasthenia gravis (MG), 8/25 (32%) with the Lambert-Eaton myasthenic syndrome (LEMS), 5/17 (29%) with multiple sclerosis and 3/11 (27%) cases of migraine. IgG anti-CL was only found in low titres in sera from 10 patients with MG and three with LEMS. Significant anti-CL activity could not be detected in sera from nine patients with acute Guillain-Barré Syndrome (GBS), 12 chronic cases of epilepsy, 8/9 with oat cell carcinoma and 9/10 with acute stroke. Further tests on 39 sera with the highest anti-CL activity, from all of the above disease groups, showed a significant correlation between IgM anti-CL and IgM anti-ss DNA activities. In a series of competitive inhibition assays six sera from patients with MG were shown to have a proportion of both specific and cross-reactive IgM anti-CL and IgM anti-ss DNA antibodies. Anti-phospholipid antibodies occur in certain neurological diseases, at lower titres than seen in SLE, yet their cross-reactive binding to ss DNA suggests similar antibacterial origins as have been proposed for lupus auto-antibodies. In the absence of overt infection they might reflect a breakdown of tolerance for non-organ specific membrane antigens in diseases with predominantly organ specific membrane bound putative autoimmunogens.

A common anti-DNA idiotype in sera of patients with active pulmonary tuberculosis.

The sera of 57 patients with active, untreated pulmonary tuberculosis were examined for the presence of a common anti-DNA idiotype, 16/6. Thirty-four of the 57 sera (60%) had an increased level of the idiotype, as measured by enzyme-linked immunosorbent assay using a specific rabbit anti-16/6 serum. Of 28 matched control sera, only 1 (4%) was found to be positive for the idiotype. The sera of patients with tuberculosis also showed increased activity against a variety of antigens with which lupus autoantibodies are known to crossreact (e.g., single-stranded DNA, double-stranded DNA, polynucleotides, and cardiolipin). A correlation was observed between serum IgG and IgM levels and the 16/6 idiotype levels.

HLA frequency and haplotype analysis in a family study of adult onset rheumatoid arthritis.

Twenty-five families with probands who have rheumatoid arthritis (RA) were studied for clinical evidence of disease and for HLA status. This confirmed an association between RA and DR4 in 19/25 probands (76 per cent, p = 0.008). These 19 probands carried 24 haplotypes which contained DR4. There was no significant increase of DR4 haplotypes bearing B15(Bw62) or B44 when compared with published control haplotype data. The rare complement allele C4 B3 was detected as part of the extended haplotype A2 Cw3 B15(Bw62) DR4 C4 A*3B*3 in three probands with severe RA. Further studies to examine disease severity and autoantibody expression are in progress.

The relationship of anti-DNA antibody idiotypes and anti-cardiolipin antibodies to disease activity in systemic lupus erythematosus.

The detection of anti-cardiolipin antibodies and anti-DNA antibody idiotypes has shown utility in a prospective assessment of 42 lupus patients over a 1-year study period. However, so broad is the range of clinical and serological features included in the diagnostic category of SLE that even a combination of tests will often inadequately reflect disease activity at a given time. For the foreseeable future the value of laboratory investigations will probably lie in supporting clinical judgment of the nature of a patient's illness and the severity of the target organ's dysfunction.

Repair of chemical carcinogen-induced damage in DNA of human lymphocytes and lymphoid cell lines--studies of the kinetics of removal of O6-methylguanine and 3-methyladenine.

The removal of O6-methylguanine by human lymphoid cells corresponded, with certain assumptions, to a second-order chemical reaction in any given cell. There was a spectrum of proficiency in this respect for a considerable number of cells originating from different individuals and it was found that patients with diseases associated with autoimmunity tended to fall into the less proficient groups. E-B virus-induced lymphoid cell lines, derived from proficient, but not relatively deficient, peripheral blood lymphocytes, always (in 9/9 cases) reflected the level of proficiency of the donor lymphocytes with respect to removal of O6-methylguanine. Thus while proficient lymphocytes always produced proficient cell lines, deficient lymphocytes, in 3/8 cases, gave rise to more proficient cell lines. No evidence was found that groups of individuals exist who lack ability to remove 3-methyladenine from DNA, either from their blood lymphocytes or derived lymphoid cell lines.

Antikeratin antibodies in serum and synovial fluid show specificity for rheumatoid arthritis in a study of connective tissue diseases.

Tests for antikeratin antibodies (AKA) were performed on 2152 disease-associated and control sera by indirect immunofluorescence (IF) on rat oesophagus substrate. The incidence of AKA was significantly raised in rheumatoid arthritis (37%) in comparison with systemic sclerosis (8%), psoriasis (7%), ankylosing spondylitis (6%), systemic lupus erythematosus (3%), and normal controls (2%). AKA were detected in synovial fluid obtained from patients with rheumatoid arthritis (RA) (48%) but not from patients with other conditions. Further experiments on AKA-positive sera showed reactivity with stratum corneum of rabbit prepuce and lips. A specific rabbit antihuman keratin antiserum was shown, by IF and inhibition studies, to have a different specificity from that of spontaneous human AKA. AKA were associated with the presence of subcutaneous nodules in RA (p = 0.05), but not with Raynaud's phenomenon, Sjögren's syndrome, or HLA-DR4 positivity. Rheumatoid factor (RF) was not associated with AKA either in RA or in RF-positive disease controls.

Anti-phospholipid antibodies in syphilis and a thrombotic subset of SLE: distinct profiles of epitope specificity.

In a study of connective tissue and infectious disease sera, we have demonstrated IgM and IgG anti-cardiolipin activity, in a solid phase radioimmunoassay, in systemic lupus erythematosus (SLE), rheumatoid arthritis, syphilis and in acute malaria caused by four different species of Plasmodium. The highest values were noted in SLE (IgM anti-cardiolipin P less than 0.005, IgG anti-cardiolipin P less than 0.01), but there was no correlation with anti-dsDNA, rheumatoid factor or VDRL titres in any disease group. Anti-cardiolipin binding was significantly associated with the lupus anticoagulant, thrombocytopenia, spontaneous abortions and thromboses in the SLE patients. Ten SLE sera from this thrombotic subset and 10 syphilitic sera with similar anti-cardiolipin activity, were tested against four phospholipid antigens and showed significantly different anti-phosphatidyl ethanolamine/anti-phosphatidyl serine binding ratios (P less than 0.001). These differences in phospholipid epitope specificity could explain the specificity of the VDRL antigen in syphilis serology, and we discuss a putative role for anti-phosphatidyl serine in the thrombotic diathesis of SLE.

The lupus anticoagulant. A disease marker in antinuclear antibody negative lupus that is cross-reactive with autoantibodies to double-stranded DNA.

The lupus anticoagulant (LA) was demonstrated in 37% of 52 consecutive systemic lupus erythematosus (SLE) patients and patients with lupus-like syndromes, who were referred to our unit. The LA was found to be associated with a biologic false-positive VDRL (P less than 0.005), and the apparently paradoxical association of LA with vascular thromboses was confirmed (P less than 0.05). The presence of LA and a biologic false-positive VDRL defined a group of 7 antinuclear antibody negative patients with characteristic features of recurrent thromboses, spontaneous abortions, neurologic involvement, and renal disease. Further studies on 6 selected sera demonstrated LA in all 6 IgM fractions and in 3 of 6 IgG fractions. Inhibition of LA was shown in 6 of 9 Ig fractions after absorption with double-stranded DNA (dsDNA). Anticardiolipin antibody was shown by immunodiffusion in 3 LA positive IgG fractions from VDRL negative sera. Cardiolipin micelles partially inhibited anti-dsDNA binding of 4 IgG fractions, 3 of which were LA negative. In this report we discuss the overlapping specificities due to cross-reactivity between LA, anticardiolipin, and anti-dsDNA antibodies in human SLE, and we suggest that LA be considered equivalent to the biologic false-positive VDRL as a criterion for the diagnosis of SLE.