Suppressor T cell function in patients with rheumatoid arthritis complicated by vasculitis

Concanavalin A (Con A)-induced suppressor T cell activity was determined in 10 rheumatoid arthritis (RA) patients with vasculitis, 34 RA patients without vasculitis, and 10 healthy individuals. The percent Con A-induced suppression in RA patients with vasculitis was 24.6. In contrast, it was 68.4% in those RA patients without vascular lesions. Further, the proportion of T cells reactive with OKT8 monoclonal antibody was also decreased in RA patients with vasculitis. Accordingly, the reduced Con A-induced suppressor T cell activity in these RA patients resulted, in part, from the reduction in the number of cells of the suppressor T cell subset. Those patients with vascular lesions also had a higher percentage of positive antilymphocytotoxic antibodies than RA patients without vasculitis. Since the differences in Con A-induced suppressor T cell activity and frequency of positive antilymphocytotoxic antibodies were so great, we believe RA patients with vasculitis could be recognized as a disease group distinct from RA patients without vasculitis.     

Characterization of anti-endothelial antibodies in patients with rheumatoid arthritis complicated by vasculitis.

Anti-endothelial antibodies (AEA) have been described in patients with rheumatoid arthritis (RA) complicated by vasculitis. In this study we made use of an ELISA and immunoblot technique (IBT) to further characterize AEA of the IgG class in serum of patients with rheumatoid vasculitis (RV) and to investigate the relationship between the presence of IgG-AEA and vasculitis. IgG-AEA as measured by ELISA or IBT could be detected in the serum from 20 of the 23 (87%) RV patients, in 2 out of 13 (15%) patients with RA and in one of 15 healthy donors. The IBT revealed reactivity of IgG-AEA against a total of 12 bands of endothelial antigens ranging in size from 16 to 68 kD. IgG-AEA as measured by ELISA and IBT in serum samples of patients followed longitudinally were present more frequently and in higher titres in patients with active RV as compared to patients with vasculitis in remission. A significant correlation was found between the presence of clinical signs of vasculitis and serum IgG-AEA reactivity against an endothelial membrane antigen of 44 kD. These data show that the pattern of IgG-AEA reactivity in the serum of RV patients is heterogeneous and suggest that IgG-AEA against one particular antigen is involved in the pathogenesis of RV.     

Prednisone treatment of elderly-onset rheumatoid arthritis

Objective. Prednisone is frequently used in the treatment of elderly-onset rheumatoid arthritis (RA), but the balance between efficacy and toxicity, including the effect on bone mass, has not been investigated in long-term studies. This prospective, randomized study was undertaken to compare disease activity and bone mass during long-term treatment with prednisone versus chloroquine in this patient population. Methods. Patients with active RA diagnosed at age ≥ 60 were randomized to receive prednisone (15 mg/day for 1 month, with the dosage tapered as low as possible thereafter) (n = 28) or chloroquine (n = 28). Patients who did not show a response received other second-line drugs as an adjunct to prednisone or as a replacement for chloroquine. Bone mass was measured by dual-energy x-ray absorptiometry. The study duration was 2 years. Results. During the 2 years, treatment with other second-line drugs was needed for 12 patients in the prednisone group (43%) and 8 in the chloroquine group (29%). Functional capacity and disease activity improved significantly in both groups and did not differ significantly between the groups, except for a greater improvement in the prednisone group at 1 month. Radiographic scores for joint destruction progressed similarly in both groups. There was a nonsignificant excess bone loss of 1.8% in the spine and 1.5% in the hip in the prednisone group, compared with the chloroquine group. Conclusion. Neither treatment was entirely satisfactory since a significant number of patients needed an additional second-line drug over the 2-year period.     

A study on soluble intercellular adhesion molecule-1 and selenium in patients with rheumatoid arthritis complicated by vasculitis

Clinical manifestations of vasculitis, as a complication of rheumatoid arthritis (RA), can be postulated as a consequence of immune response abnormalities and endothelial cell dysfunction. In this study we searched for the relationship between the extent of vascular involvement and either serum sICAM-1 or selenium concentrations. We also explored the possible interaction of serum selenium with sICAM-1 to provide a greater understanding of their role in rheumatoid vasculitis (RV). For the study, we measured the serum titers of sICAM-1 using an ELISA assay and the serum selenium concentrations using the ETAAS method in 37 women suffering from RA and 18 normal women serving as controls. All the RA patients were evaluated by extensive clinical, laboratory and capillaroscopic studies. In all patients with extra-articular manifestations, severe or moderate changes in nailfold capillaroscopy were found. Serum sICAM-1 titers in RA patients with mild vasculitis on nailfold capillaroscopy did not differ significantly from those of the healthy subjects, whereas a higher sICAM-1 level seemed to reflect the more intensive vascular changes in capillaroscopy. These data suggest that sICAM-1 serum levels may reflect the extent of the microvascular involvement in RA patients. Compared with controls, all the RA patients had markedly lower serum selenium concentrations, irrespective of the degree of the capillaroscopic vascular changes. A significant inverse correlation between sICAM-1 and selenium was found in the controls (r = –0.54; P<0.02). By contrast, no correlation was noted in RA patients (r=0.10, P not significant). This suggests that the sICAM-1 shedding in RV does not appear to be influenced by selenium, presumably owing to its low serum concentration.Abbreviations CRP Serum C-reactive protein - DAS Disease activity score - ESR Erythrocyte sedimentation rate - GSH-Px Glutathione peroxidase - NSAIDs Non-steroidal anti-inflammatory drugs - RA Rheumatoid arthritis - RV Rheumatoid vasculitis - TR Thioredoxin reductase     

Abnormal plasma fibrinolysis in patients with rheumatoid arthritis and impaired endothelial fibrinolytic response in those complicated by vasculitis.

OBJECTIVES--(a) To assess plasma fibrinolytic parameters in patients with rheumatoid arthritis (RA) and to determine whether there are differences between patients with RA alone and those with RA complicated by vasculitis. (b) To determine if patients with RA respond differently to venous occlusion compared with normal subjects and to assess whether such a response differs in patients with RA alone and those with rheumatoid vasculitis. (c) To determine the extent of vascular damage in patients with rheumatoid vasculitis and if this correlates with the levels of plasma fibrinolytic parameters. METHODS--Sixty three patients with RA (38 had RA only and 25 had evidence of rheumatoid vasculitis) were recruited. Plasma levels of tissue plasminogen activator antigen (t-PA Ag), plasminogen activator inhibitor (PAI) activity, and factor VIII von Willebrand factor (vWF) were measured before and 10 minutes after venous occlusion. RESULTS--Patients with RA, with or without rheumatoid vasculitis, had higher baseline PAI levels than control subjects. The difference was statistically significant for patients with RA alone but was not statistically significant for patients with rheumatoid vasculitis. After venous occlusion, t-PA Ag levels increased significantly in normal subjects and patients with RA alone, but not in patients with rheumatoid vasculitis. Plasma levels of vWF were significantly higher in patients with rheumatoid vasculitis than in normal subjects and those with RA alone. In patients with RA alone, baseline vWF correlated positively with t-PA Ag levels, whereas a negative correlation was found between these two parameters in patients with rheumatoid vasculitis. A negative correlation between vWF and t-PA Ag levels after venous occlusion was also found in patients with rheumatoid vasculitis. CONCLUSIONS--Patients with rheumatoid vasculitis showed evidence of vascular damage with increased levels of vWF and impaired t-PA Ag release after venous occlusion, a useful measurement of endothelial reserve to remove fibrin. This may be of pathophysiological importance in the development of vasculitis in these patients.     

Prednisone and azathioprine compared to prednisone plus low-dose azathioprine and cyclophosphamide in the treatment of diffuse lupus nephritis

A 1-year double-blind crossover study comparing prednisone and azathioprine to prednisone plus low-dose azathioprine and cyclophosphamide was carried out in 14 patients with diffuse lupus nephritis. Low-dose triple therapy had no apparent therapeutic advantage over prednisone plus azathioprine. Cyclophosphamide-induced ovarian failure and hematuria were not avoided by its use in low dose.     

Antilactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis

Objective. To determine the occurrence of antineutrophil cytoplasmic antibodies (ANCA) and the specificity of these antibodies (Ab) in serum from patients with rheumatoid arthritis (RA) and patients with rheumatoid arthritis complicated by vasculitis (rheumatoid vasculitis [RV]). Methods. ANCA was detected with an indirect immunofluorescence test on ethanol-fixed granulocytes. Ab against the cytoplasmic antigens proteinase-3, elastase, lactoferrin (LF), and myeloperoxidase were measured by enzyme-linked immunosorbent assay. Results. ANCA were found in the serum of 43% of 49 patients with RV and in 36% of 50 patients with RA. Anti-LF Ab occurred more frequently in RV patients (45%) than in RA patients (4%), whereas reactivity against the other cytoplasmic antigens did not differ significantly between these groups. Conclusion. Anti-LF Ab in serum of patients with RA may be useful in the diagnosis of vasculitis in RA.     

Antilactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis.

OBJECTIVE. To determine the occurrence of antineutrophil cytoplasmic antibodies (ANCA) and the specificity of these antibodies (Ab) in serum from patients with rheumatoid arthritis (RA) and patients with rheumatoid arthritis complicated by vasculitis (rheumatoid vasculitis [RV]). METHODS. ANCA was detected with an indirect immunofluorescence test on ethanol-fixed granulocytes. Ab against the cytoplasmic antigens proteinase-3, elastase, lactoferrin (LF), and myeloperoxidase were measured by enzyme-linked immunosorbent assay. RESULTS. ANCA were found in the serum of 43% of 49 patients with RV and in 36% of 50 patients with RA. Anti-LF Ab occurred more frequently in RV patients (45%) than in RA patients (4%), whereas reactivity against the other cytoplasmic antigens did not differe significantly between these groups. CONCLUSION. Anti-LF Ab in serum of patients with RA may be useful in the diagnosis of vasculitis in RA.     

Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis

Systemic vasculitis in rheumatoid arthritis shows similarities to polyarteritis nodosa and may require equally aggressive therapy. Forty-five patients with systemic rheumatoid vasculitis were studied during treatment with either cyclophosphamide plus methylprednisolone given by intermittent bolus intravenous injection (21 patients) or a variety of other more conventional drug regimens (24 patients). In this open study, the intravenous treatment group had more severe initial disease, a higher incidence of neuropathy, and more frequent evidence of necrotizing arteritis on biopsy than the other treatment group. Despite this, intravenous cyclophosphamide plus methylprednisolone resulted in more frequent healing of vasculitic lesions including leg ulcers and neuropathy, a lower incidence of relapse, fewer serious complications, and a lower mortality than did other treatments. Toxic effects were similar in both study groups. Intravenous cyclophosphamide plus methylprednisolone is a useful early treatment for systemic rheumatoid vasculitis.     

Immunological studies in patients with rheumatoid arthritis receiving azathioprine and myocrisin in combination

Summary Thirty-one patients with classical or definite rheumatoid arthritis (RA), on treatment with azathioprine and sodium aurothiomalate in combination were studied. Absolute lymphocyte counts and IgA levels were reduced but this did not reach statistical significance. Lymphocyte transformation with phytohaemagglutinin (PHA) showed no significant difference from a control group. However, antibody dependent cell-mediated cytotoxicity was significantly impaired compared to rheumatoid controls (p<0.001). There was no relation to the degree of impairment of ADCC and the current dose of azathioprine nor to the total dose or duration of therapy. Inhibiting material to cell-mediated cytotoxicity was present in the sera of 23 patients but its presence showed no relation to the degree of cytotoxicity exhibited by cells in the same patient. Our studies of cellular cytotoxicity have revealed alterations in cellular function possibly attributable to azathioprine.     

The mortality of rheumatoid vasculitis compared with rheumatoid arthritis

Objective. To determine whether the mortality of patients with rheumatoid vasculitis (RV) is increased in comparison with that of patients with rheumatoid arthritis (RA). Methods. The mortality of all RV patients identified in 1980–1992 (n = 61) was compared with that of 244 RA controls matched for the year the diagnosis was made in the RV cases. Hazard ratios (HR) of death were calculated with a multivariate survival analysis, adjusting for age, sex, comorbidity, treatment, and parameters of RA severity. Results. The unadjusted risk of death (HR) in RV patients compared with RA controls was 1.65 (95% confidence interval [95% CI] 1.05–2.58). After adjustment for prognostic factors, the HR was reduced to 1.26 (95% CI 0.79–2.01), mainly due to removal of the effects of age and sex. No excess mortality was seen in RV patients with severe organ involvement when compared with RV patients without severe organ involvement, although the former patients were treated more often with cytostatic and immunosuppressive drugs. Infection was the main cause of death in the RV patients, and cardiovascular disease in the RA controls. Vasculitis was reported as the cause of death in only 1 RV patient. Conclusion. After allowance for general risk factors such as age and sex, there remains only a slight excess mortality in RV patients compared with RA controls.     

Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis

Objective. To examine the clinicopathologic features of the noncompressive neuropathies in rheumatoid arthritis (RA). Methods. We studied 32 patients with RA and peripheral neuropathy whose nerve and/or muscle biopsy specimens exhibited necrotizing vasculitis. Morphologic analysis of nerve specimens included light and electron microscopy studies and teased fiber preparation. Survival was evaluated, and the prognostic values of clinical, biologic, and pathologic features were assessed by Cox proportional hazards model. A prognostic assessment based on the significant variables was devised to estimate the probability of survival of any individual patient. Results. Epi and/or perineurial vasculitis was observed with the same frequency in the 17 patients with sensory and motor deficit and the 15 patients with sensory neuropathies and was associated with axonal degeneration of an average of 77.7% of the nerve fibers. The mean followup was 7.2 years, and the overall survival rate at 5 years was 57%. A full prolonged remission of the vasculitis was observed in 53% of the patientsrelapse occurred in 25%. The factors correlated with mortality, in decreasing order of significance, were clinical cutaneous vasculitis (P = 0.0003), neuropathy affecting 3 or 4 limbs (P = 0.03), and depressed level of C4 (P < 0.05). The prognostic assessment indicated a wide range of 5-year probabilities of survival, from <1% to 93%. Conclusion. Necrotizing vasculitis is responsible for the different patterns of noncompressive neuropathies in RA, including mononeuritis multiplex and distal symmetric sensory or sensorimotor neuropathy. Cutaneous vasculitis, multifocal neuropathy, and depressed C4 level were the 3 independent variables which best predicted mortality. We propose a prognostic assessment according to these variables, to stratify patients to receive more aggressive or less aggressive therapy.