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Objective: Evaluation of the prognostic value of immunogenetic markers in early rheumatoid arthritis (RA)., Methods: Ninety-nine patients with definite RA and disease duration 24 months or less were followed with standardized assessment. Disability was assessed by the HAQ index and radiographic changes in hands and feet by the Larsen method. The frequencies of HLA-DR genes were determined by serological typing, Gm allotype distribution by classical hemagglutination inhibition test, and occurrence of anti-Gm allotypes by use of anti-Rh coats. The immunogenetic findings were related to disease severity after 2 years' followup., Results: Functional capacity was well preserved, disease activity was less, but radiographic changes in hands and feet had increased considerably at study finish. A group of 13 patients had developed rapidly progressive changes of hip and/or shoulder joints, all requiring arthroplasty. There was a significantly increased frequency of HLA-DR4. Twenty-seven of the 68 HLA-DR4 positive patients were putatively homozygous. HLA-DR4 was not related to disability or to severe small joint destruction. However, progressive large joint damage was significantly more prevalent in homozygous patients (p < 0.01). Gm allotype distribution was normal and not related to clinical findings. Anti-Gm antibodies were common and frequently specific for nonhost Gm allotype. Fifty-six patients carried anti-G1m(a), and occurrence of this antibody was significantly associated with radiographic progression of small joints (p = 0.01), presence of nodules (p < 0.01) and number of active joints (p = 0.001)., Conclusion: Immunogenetic markers aided in identifying patients with early RA with more severe disease.

A 39-year-old woman was admitted with abdominal pain and dyspnea, and a diagnosis of systemic lupus erythematosus with renal involvement was established. Laboratory tests revealed highly elevated anticardiolipin antibody, thrombocytopenia and false positive VDRL. Generalized thrombus formation and Libman-Sacks endocarditis were found at postmortem examination. The pancreas showed chronic inflammation with thrombi in pancreatic arteries, but no vasculitic change was observed. Lowering of pancreatic blood flow because of arterial thrombi was a possible cause of pancreatitis in this patient. The spectrum of antiphospholipid antibody associated diseases may be extended to include pancreatitis as a thrombotic complication.

We have used neutralizing antibodies raised against murine recombinant interleukin 1 (IL-1) to demonstrate a role for IL-1 in the cartilage destruction and inflammation of antigen induced arthritis. Ex vivo production of IL-1 was demonstrated in tissue cultures of joint cross sections shortly after arthritis induction. Neutralizing antimurine IL-1 antibodies identified the activity to be about 80% IL-1 alpha 24 h after onset of arthritis. In animals receiving a single injection of anti-IL-1 antisera at Day -3, cartilage proteoglycan synthesis suppression during the first 2 days of arthritis was prevented. Normal proteoglycan synthesis was maintained until Day 4 when anti-IL-1 antisera was given at Days -2, 0, and 2 or arthritis. Dose response experiments showed that the reduction in inflammation was insufficient to account for the clearcut reduction in cartilage proteoglycan synthesis inhibition. Our results demonstrate that IL-1 plays a role in cartilage pathology in murine antigen induced arthritis.

The association between antiphospholipid antibodies (aPL) and venous and arterial thromboses has been well described. However the association between aPL and avascular necrosis has not been widely reported. We report the association of avascular necrosis with the primary anticardiolipin antibody syndrome in a patient with a history of hemiplegic migraine and cerebrovascular infarcts. This phenomenon appears to be secondary to hemostatic abnormalities associated with the presence of aPL.

Cartilage breakdown in rheumatoid arthritis results from (a) lytic action by synovial enzymes, and (b) release of synovial catabolin, now believed to be a form of interleukin 1 (IL-1), causing chondrocytes to degrade their matrix. Rheumatoid synovial culture media were tested for their ability to stimulate cartilage degradation (proteoglycan release from bovine nasal cartilage discs) and thymocyte proliferation (3H-thymidine incorporation) in the absence or presence of anti-IL-1. Degradation of living cartilage, stimulated 2-fold by synovial culture media, was inhibited up to 80% by anti-IL-1. Residual breakdown in living cartilage and synovial culture media induced breakdown in dead cultures were of similar magnitude, and both were unaffected by antibody treatment. Proteoglycan products released from synovial culture media treated cartilage were of smaller average molecular weight (Sepharose CL-2B), and such size reduction was inhibited by anti-IL-1 treatment. Synovial culture media that stimulated cartilage degradation also stimulated thymocyte proliferation; the latter was fully suppressible by anti-IL-1. One of 8 synovial culture media contained an inhibitor(s) of thymocyte proliferation, removable by dialysis. We conclude (1) rheumatoid synovial catabolin activity is due to a form of IL-1. (2) A minor nonsuppressible component of synovial culture media stimulated breakdown, identical in living and killed cartilage, is due to passive transfer of enzymic activity. (3) Cultured rheumatoid synovium releases both IL-1 and an inhibitor(s) of IL-1 action.

We studied the frequency of antiphospholipid antibodies (aPL) in patients undergoing cardiac valve replacement, and present the results in the context of the pathology of the valve lesions. Forty-eight consecutive patients undergoing valve replacement were studied. Of the whole group, 15 (31%) had antibody levels greater than 2 SD above the mean for a control group of healthy persons and 11 (23%) had a level of greater than 3 SD. There was an increased frequency of elevated antibody levels in patients with valves showing fibrocalcific change and a significant association between aPL and valve thrombus. The possible role of these antibodies in the pathogenesis of the valve lesions is discussed.

In order to define the behavior of the lupus anticoagulant and/or antiphospholipid antibodies, we investigated the possible association with protein C, protein S and thrombomodulin. In 19 patients with established diagnosis of an autoimmune disease and coexisting lupus anticoagulant protein C (antigen and activity), protein S (total and free), anticardiolipin and antiphosphatidylserine antibodies were estimated. In one case the IgG globulin fraction containing the inhibitor was separated. The activation rate of pure protein C to its activated form using thrombin/thrombomodulin as activator was then measured in the presence or absence of lupus anticoagulant. No overall decrease of protein C or protein S was detected in patients' plasma. Nevertheless, the lupus anticoagulant had a specific effect on the protein C system, inhibiting the catalytic activity of thrombomodulin without causing a functional protein C deficiency. This specific effect upon thrombomodulin can be a main cause, but not necessarily the only one, for the thrombophilic tendency of patients with the lupus anticoagulant.

A patient with relapsing polychondritis and Sjogren's syndrome is reported. Diagnosis was confirmed by ear cartilage biopsy. Antibodies against rat costal cartilage were present in the patient's serum. Antinative collagen type II antibodies were detected using a passive hemagglutination technique and the titer grossly correlated with the clinical course. Direct immunofluorescence using the patient's ear cartilage as a target suggested that anti-collagen antibodies might play a major pathogenic role in the course of relapsing polychondritis.

The presence of plasminogen activator (PA) inhibitor in human articular cartilage extracts was shown using a microtiter plate assay using immunofixed urokinase. Cartilage urokinase inhibitor had a molecular weight of 66,000 on gel chromatography. Cartilage extracts also contained alpha 1-proteinase inhibitor; however, the urokinase inhibitor was distinguishable from such serum inhibitors immunologically. In sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by fibrin overlay, inhibition of urokinase was observed accompanying higher molecular weight complex formation. The cartilage urokinase inhibitor was unstable with acid, heat and SDS treatment, and required the active site of urokinase for inhibition.

2-dimensional flow cytometric analysis of the peripheral blood T lymphocytes from 20 patients with systemic lupus erythematosus showed a significant increase in the percentage of Leu 2a+ 15- cytotoxic subset irrespective of disease activity compared to 35 age and sex matched healthy individuals. The percentage of Leu 2a+ HLA-DR + cells also increased significantly in both patients with active and inactive disease compared to the controls. In contrast, both the relative and absolute number of Leu 3a+ 8+ cell (suppressor/inducer T cell) showed a significant reduction in active and inactive disease if compared to controls. All of these changes were more drastic in the patients with active disease.

The immunoregulator human gamma interferon (IFN-gamma) suppressed the spontaneous in vitro synthesis and secretion of anti-DNA antibodies by peripheral blood mononuclear cells of patients with systemic lupus erythematosus (SLE-PBMC). Comparable level of suppression were observed with both natural human IFN-gamma and recombinant derived human IFN-gamma. In addition, the inhibitory effects of human IFN-gamma were completely neutralized by a monoclonal antibody directed against it. Human IFN-gamma also inhibited the antigen induced production of anti-DNA synthesis by SLE-PBMC. Based on the kinetics of inhibition, human IFN-gamma appeared to be acting directly on the B cell. Lastly, human IFN-gamma also suppressed the spontaneous production of IgG and IgM by SLE-PBMC. Our findings support the conclusion that SLE Ig production can be regulated and that human IFN-gamma may be clinically useful in the treatment of SLE as well as other immune complex diseases.