Differences in immunochemical characteristics of cryoglobulins in rheumatoid arthritis and systemic lupus erythematosus and their complement binding properties.

Cryoglobulins isolated from sera of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were analysed for their immunoglobulin, antibody, and complement components. In both disease categories the cryoglobulins contained predominantly IgG with lesser amounts of IgM and IgA, but relative to serum more IgM was concentrated in the cryoglobulins. IgM rheumatoid factor was found in 65% of RA cryoglobulins but in only 17% of SLE cryoglobulins (p less than 0.02), whereas SLE cryoglobulins contained more DNA binding activity than RA cryoglobulins (p less than 0.01). C1q binding activity was detectable in the majority of SLE and RA sera and SLE cryoglobulins. Paradoxically only two out of 34 RA cryoglobulins bound C1q, although rheumatoid factor activity was present in both cryoglobulins and sera. When isolated from serum the rheumatoid factor fraction strongly bound C1q. Both RA and SLE cryoglobulins contained similar small amounts of C3 and C4. Differences in antibody composition and complement binding activity of cryoglobulins from RA and SLE sera may reflect properties of immune complexes which affect their tissue localisation and pathogenicity.

Antibodies to extractable nuclear antigens in rheumatoid arthritis: relationship to vasculitis and circulating immune complexes.

Antibodies to extractable nuclear antigens (ENA) were analysed in the sera of fifty-two patients with severe rheumatoid arthritis (RA) who were divided into two categories: twenty-five with arthritis only and twenty-seven with extra-articular disease. Using haemagglutination, counterimmunoelectropheresis (CIE) and double diffusion, antibodies to ENA were detected in three (12%) of the patients with arthritis only. In the group with extra-articular disease, antibodies were found in sixteen (59%) of the patients. In ten patients the antibodies reacted with an RNase and DNAse resistant, but trypsin sensitive protein component of ENA. These patients all had extraarticular disease with digital vasculitis being a particularly common feature. Their sera also contained circulating immune complexes detected by elevated cryoprecipitate protein levels associated with relatively low complement levels. It is suggested that antibodies to soluble proteins of nuclear origin may be markers of circulating immune complexes in extra-articular RA.

Neutrophilic dermatosis in association with rheumatoid arthritis.

Extra-articular involvement of the skin in patients with rheumatoid arthritis is not uncommon. A patient with this condition is reported who developed an unusual cutaneous eruption associated with systemic upset. Skin biopsy showed a dense dermal neutrophilic infiltrate and after treatment with standard immunosuppressive agents had failed he responded to dapsone. The rash recurred on withdrawal of the dapsone but has responded to sulphamethoxypyridamine. It is proposed that this condition is a rare but specific entity of unknown cause associated with rheumatoid arthritis.

The association of cryoglobulinaemia with nodules, vasculitis and fibrosing alveolitis in rheumatoid arthritis and their relationship to serum C1q binding activity and rheumatoid factor.

Two measurements of serum immune complexes, cryoglobulinaemia and 125I-C1q binding, have been performed in patients with severe rheumatoid arthritis (RA) and compared with normal levels. Cryoglobulinaemia was present in 20 out of 28 patients (71%) with extra-articular disease (mean level 17 micrograms/ml) including nodules, digital vasculitis, cutaneous ulcers, rash, neuropathy, lung disease and scleritis, but in none of 32 patients with joint disease alone (uncomplicated RA) (mean level 3 micrograms/ml). Cryoglobulinaemia correlates with, but probably does not antedate, extra-articular disease, and may be useful in predicting morbidity and mortailty in this group of patients. In contrast, serum 125I-Clq binding was raised in patients with uncomplicated RA and those with extra-articular disease, although levels were higher in the latter group. Both tests showed a negative correlation with serum haemolytic complement and a positive correlation with IgM rheumatoid factor although there were some sera with raised levels of rheumatoid factor without cryoglobulinaemia. These results suggest that cryoglobulinaemia is a better test than Clq-binding for demonstrating the presence of circulating immune complexes involved in the pathogenesis of extra-articular lesions.

The painful shoulder: can consultants agree?

As a two-phase exercise in inter-district audit, with the emphasis on critical evaluation of routine clinical practice, three rheumatologists each examined the same 44 patients with shoulder pain, and recorded their diagnosis and the investigations and treatment they would carry out. In the first phase, 26 patients were seen by each rheumatologist separately; there was complete diagnostic agreement in only 46%, with wide variation in the frequency of requests for standard investigations, but all three rheumatologists recommended steroid injections for most patients. In the second phase, all three rheumatologists examined a further 18 patients together, discussed the symptoms and signs, and recorded their diagnoses separately. There was complete agreement in 78%. The presence of more than one lesion, and differences in the interpretation of certain physical signs, partly explain the lack of agreement in Phase 1. Treatment of specific shoulder lesions is highly concordant, with injection the major treatment modality, followed by physiotherapy. Perhaps the different diagnoses reached, and the fact that treatment might therefore be administered for the wrong diagnosis, may explain some treatment failures. Also, recruitment of patients for studies of the treatment of shoulder lesions requires care to avoid selection of a heterogeneous group.

IgE and IgE-rheumatoid factors in circulating immune complexes in rheumatoid arthritis.

The sera of 21 patients with rheumatoid arthritis (RA), 11 patients with systemic lupus erythematosus (SLE), and 20 healthy subjects were analysed for the presence of IgE in immune complex fractions. These fractions were isolated by polyethylene glycol precipitation and gel filtration. Thirteen sera from RA patients contained IgE immune complexes (IC) and 11 of these were from patients with extra-articular manifestations. One SLE and none of the control sera contained such material. The serum IgE level did not correlate with IgE content of the IC fractions. Higher mean serum IgE levels were found in RA patients with extra-articular complications than in controls or RA patients with joint disease only, but the differences did not reach statistical significance. IgE anti-rabbit IgG (IgE rheumatoid factors) could be demonstrated in some IgE positive IC fractions. Antibodies to IgE, in 2 instances characterised as belonging to IgG class, were also found in ICs. This suggests the presence of anti IgE complexes. It is suggested that IgE, including some with rheumatoid factor activity, is contained in complexes which may be involved in some extra-articular manifestations of RA.

Factors predicting a poor life prognosis in rheumatoid arthritis: an eight year prospective study.

This prospective study evaluates the usefulness of clinical features and measurements of circulating immune complexes and autoantibodies for identification of patients with rheumatoid arthritis with a poor life prognosis. One hundred and seven hospital clinic patients, 64 with extra-articular manifestations, were followed up for a mean period of eight years, during which 50 deaths occurred. Comparison with an age and sex matched control population showed an increased incidence of deaths from myocardial infarction, pneumonia, and complications of rheumatoid arthritis. Patients with cutaneous ulcers, vasculitic rash, neuropathy, and scleritis had a higher mortality than patients whose disease was confined to the joints. Positive serological tests for precipitating antibodies to soluble cellular antigens and cryoglobulinaemia also predicted a poor prognosis. Eleven out of 12 patients (92%) with antibodies to soluble cellular antigens died compared with 21 out of 64 patients (33%) without antibodies. The presence of cryoglobulinaemia was associated with almost a twofold higher mortality. The laboratory measurements may reflect immunopathogenic mechanisms which lead to the occurrence of extra-articular disease features and reduce life expectancy.

Titers of antibodies to RANA in rheumatoid arthritis and normal sera. Relationship to Epstein-Barr virus infection.

The disease specificity of antibodies to rheumatoid arthritis nuclear antigen (RANA) was examined by comparing anti-RANA titers in sera from 100 patients with rheumatoid arthritis (RA) with sera from 93 healthy controls. Anti-RANA antibodies were found in 86% of the RA sera and 56% of the controls. The higher titers in the RA sera were unrelated to clinical features or to measurements of circulating immune complexes or rheumatoid factors. To study the relationship of these antibodies to previous Epstein-Barr virus (EBV) infection, antibodies to the EB virus capsid antigen (VCA) were examined and found in 94% of the RA sera and 97% of the adult controls. Four of the six RA sera without anti-VCA antibodies had detectable anti-RANA antibodies, so that we might suggest anti-RANA can arise in the absence of EBV infection. From absorption experiments with non-EBV transformed extracts, we inferred that high anti-RANA titers could be due to reactions with non-Epstein-Bar virus related nuclear antigens. These data cast doubt on current speculation about a possible pathogenic role for Epstein-Barr virus in this disease.

Dialysis arthropathy: amyloid or iron?

The clinical, biochemical, radiological, and pathological features in five cases of dialysis arthropathy were analysed. All patients were receiving long term haemodialysis and had had multiple blood transfusions. The arthropathy affected both large and small joints, was predominantly bilateral, and in all cases was associated with the carpal tunnel syndrome. In some instances joint pain was exacerbated during dialysis. In four cases the serum ferritin concentration was raised. Radiological examination showed a few juxta-articular cysts and erosions but most affected joints looked normal. All synovial tissue examined showed amyloid, which stained immunohistochemically for beta 2 microglobulin. Large amounts of iron were present in synovial tissue from affected joints. It is suggested that the deposits of iron, rather than amyloid, in synovial tissue may be the cause of the arthropathy. Iron may be derived locally as a result of haemarthrosis or it may be a manifestation of systemic iron overload.

Dialysis arthropathy: a clinical, biochemical, radiological and histological study of 36 patients.

Out of a population of 97 haemodialysis patients, 36 patients with dialysis arthropathy were identified. Dialysis arthropathy is a chronic symmetrical polyarthritis which affected 97 per cent of the patients who had been undergoing cuprophane haemodialysis for more than 10 years. It commonly affected the shoulders, hips, hands, knees and wrists, worsening with time and extending to other joints. Fifty-eight per cent of the patients complained of morning stiffness and 47 per cent complained of exacerbation of shoulder pain during or after haemodialysis. Half of the patients also suffered from carpal tunnel syndrome, which recurred and was associated with a long-lasting disability. The most common radiological abnormality was periarticular bone cysts, followed by articular erosions and a destructive spondyloarthropathy, but clinical symptoms were more common than radiological signs. Patients with dialysis arthropathy had a higher C-reactive protein level than patients without arthropathy (18.6 mg/l versus 11.4 mg/l), indicative of an inflammatory process. Some of the clinical manifestations of the disease correlated with levels of C-reactive protein and ferritin. Serum ferritin levels correlated strongly with the units of blood transfused in the past five years (RS = 0.83), and the logarithm of ferritin level correlated weakly with C-reactive protein (r = 0.32). Haemarthroses were documented in 19 per cent of patients. Mean serum beta 2-microglobulin was elevated in the patients with (57.3 mg/l) and without arthropathy (50.7 mg/l), and there was no difference in the parathormone or aluminium levels between these groups. Articular tissue was obtained in 25 patients; beta 2-microglobulin amyloid was present in 24. Larger deposits were present in the capsular tissue, and these appeared to replace collagen bundles in eight cases. Amyloid deposits replaced the lining layer in six cases. It is likely therefore that amyloid disrupts normal joint function by replacing normal joint tissue. Mild chronic synovitis with haemosiderin deposition were found in approximately 60 per cent of cases. These findings suggest that amyloid derived from beta 2-microglobulin has a primary role in the pathogenesis of dialysis arthropathy, but there was also evidence of inflammatory processes. It is suggested that iron overload or haemarthroses might contribute to the inflammation, but other factors, such as dialysis-related bioincompatibility reactions, may also have a role.

In vivo fate of 125I SS-B (La) injected into mice.

The fate of the radiolabelled soluble cellular antigen SS-B (La) was compared with that of other 125I-labelled proteins of known molecular weight (MW) and electrostatic charge, following i.v. injection into BALB/c mice. The plasma half-life of 125I-SS-B was 3 min, while that of 125I-bovine serum albumin (similar MW and electrostatic charge) was 270 min. 125I-heat-aggregated IgG (MW greater than 1 x 10(6)) and 125I-7S human IgG (MW 168,000) had plasma half-lives of 40 min and greater than 300 min, respectively. Liver and kidney showed preferential uptake of 125I-SS-B, followed by a rapid decrease in radioactivity. During this time low MW, trichloroacetic acid (TCA) soluble, material appeared in urine. This suggests a specific uptake mechanism followed by a catabolic phase. These studies demonstrate that normal mice remove 125I-SS-B rapidly from the circulation and then degrade it. This rapid antigen elimination may protect against the induction of potentially harmful autoantibody responses.