HLA antigens and seronegative rheumatoid arthritis.

HLA antigens and clinical features in a series of 46 Caucasian patients (40 females, 6 males) and definite repeatedly seronegative rheumatoid arthritis (RA) of more than two years' duration (mean 11.6 years) were compared with those in 77 seropositive RA patients and 110 controls of the same ethnic and geographic origin. Seronegative RA appeared to be less often erosive than seropositive RA, and seronegative patients had fewer extra-articular features. The frequency of the HLA antigen DR1 was raised in seronegative patients as compared with controls (p = 0.006, relative risk = 3) and with seropositive patients (p less than 0.05). HLA-DR4 was slightly increased in seronegative patients compared with controls (p less than 0.05) but was clearly less so than in seropositive patients (p less than 0.005). Early onset of disease was very significantly associated with HLA-DR1 in seronegative patients (p = 0.007), whereas HLA-DR4 was present more frequently in seropositive patients with onset prior to age 35 (p less than 0.05). No correlation between HLA antigens and intolerance to drugs was found in seronegative patients, whereas in seropositive patients side effects to gold salts were associated with DR3. These results suggest that seropositive and seronegative RA have distinct HLA-DR associations, especially in disease of early onset, in addition to well established clinical differences.     

Significance of rheumatoid factor isotypes in seronegative rheumatoid arthritis

Summary In a cross-sectional study of 124 patients with definite or classical rheumatoid arthritis (RA) and negative agglutination assays, rheumatoid factor (RF) isotypes were measured using an ELISA technique. Elevated levels of IgA-RF were found in 55 patients (44%), IgG-RF in 99 (80%), and IgM-RF in 20 (16%). The levels of IgA- and IgM-RF correlated with each other (P<0.001). Elevated levels of IgM-RF were associated with a more severe disease course. Elevated levels of IgA-RF correlated with the occurrence of bone erosions. The results of this study suggest that in patients with RA and negative agglutination assays, both IgM- and IgA-RF are markers of disease severity.     

Synovial fluid in seronegative juvenile rheumatoid arthritis

Synovial fluid of 20 children with seronegative juvenile rheumatoid arthritis (JRA) and 20 patients with other joint pathology was examined for levels of total hemolytic complement and selected components, immune complexes, and α₂-macroglobulin (α₂-M). When adjusted for total protein, synovial levels of total hemolytic complement, C3, C4, and α₂-M did not differ significantly in the two groups. The concentrations of IgM and IgG were elevated in the JRA synovial fluid, but immune complexes were not increased when compared with the non-JRA group as determined by the Raji cell technique. α₂-M activity against substrates of C1 esterase was absent. Therefore, evidence of specific increase in immune complexes and complement activation was sought but not found, suggesting that they may not be a major factor in the pathogonesis of seronegative, pauciarticular JRA.     

Selective lymphocyte deficiency in seronegative rheumatoid arthritis

Prior studies have shown that in vitro infection with the Epstein Barr virus (EBV) is able to induce IgM rheumatoid factor production by normal lymphocytes, with a higher degree of production by seropositive rheumatoid arthritis lymphocytes. The present investigation demonstrates that EBV-infected lymphocytes from patients with seronegative rheumatoid arthritis produce in vitro significantly less IgM rheumatoid factor than do normal lymphocytes. The results suggest that the peripheral blood of seronegative patients is deficient in the rheumatoid factor precursor B cells responsive to stimulation by Epstein Barr virus.     

ELISA determined IgM and IgA rheumatoid factors in seronegative rheumatoid and psoriatic arthritis

Previous studies have strongly suggested an association between rheumatoid factors (RF's), particularly IgA-RF, and the presence of erosions in rheumatoid arthritis (RA). The present study was aimed at studying this association in seronegative erosive arthritides. Forty-eight patients with seronegative arthritis were evaluated for the presence of IgM- and IgA-RFs using an enzyme linked immunosorbent assay (ELISA). Twenty-nine had seronegative RA and nineteen had psoriatic arthritis (PA). Twelve (41%) seronegative RA patients were found to be seropositive for IgM- or IgA-RF. Only 1 (7%) patient with PSA was positive for IgA-RF alone. Fifteen (51%) of the RA patients and eight (42%) of the PSA patients had erosive disease. A significant correlation between IgA-RF alone and erosive disease was found only in the seronegative RA patient (p less than 0.02). We conclude that in PSA patients there appears to be no need to define isotype specific RFs. On the other hand, our findings indicate that an early detection of IgA-RF can have clinical importance in seronegative rheumatoid arthritis, as it may constitute an indication for the timely institution of disease-modifying drugs in these patients.     

IgM rheumatoid factor estimation by ELISA in seronegative rheumatoid arthritis before and after IgM fractionation: does seronegative RA exist?

We looked for the presence of IgM rheumatoid factor (RF) using an enzyme-linked immunosorbent assay (ELISA) in 25 patients with active seronegative rheumatoid arthritis. In unfractionated sera, 12 patients (48%) were positive for IgM RF (classical), but after IgM fractionation of 23 samples (2 samples were not available) using high performance liquid chromatography for fractionating IgM, 12 patients were positive for RF by ELISA indicatingt the presence of hidden RF. Finally, three patients were labelled as truly seronegative for IgM RF. Classical IgM RF as deteced by ELISA correlated significantly with erosive disease. Hidden RF did not correlate with disease activity or severity in this cross-sectional study, and though its presence was associated with shorter disease duration. this did not reach statistical significance.     

Differing X-ray patterns in seronegative and seropositive rheumatoid arthritis

Clinical Rheumatology - Anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) status are important predictors for rheumatoid arthritis (RA) erosivity. Qualitative differences on...     

Constrictive pericarditis in severe seronegative rheumatoid polyarthritis]

Constrictive pericarditis is a rare complication of rheumatoid arthritis, with 78 published cases. We report a new typical case where the pericardial disease was associated with a severe seronegative rheumatoid arthritis of 17 years duration. Constrictive pericarditis generally occurs in men (62.8% of all cases) aged 52.4 +/- 11.5 years. Its clinical features are identical with those of constrictive pericarditis due to other causes. Diagnosis rests on echocardiography and, chiefly, on right heart catheterization. The arthritis is seropositive in 85.7% of the cases, frequently nodular (75%) and advanced. There is no relation between its duration (mean: 9.6 +/- 7.4 years) and the occurrence of the pericardial pathology. The pericardial fluid has no specific abnormality. Histology shows fibrosis and a non-specific inflammatory cell infiltrate. Immunoglobulin and complement deposits in the walls of the pericardial vessels are detected by immunofluorescence. The only treatment is pericardiectomy; without it the disease is constantly lethal.     

IgG and IgM rheumatoid factor in active seronegative nodular rheumatoid arthritis and in children with benign rheumatoid nodules

Summary Rheumatoid nodules in rheumatoid arthritis are usually associated with high levels of IgM rheumatoid factors and aggressive disease. IgM, IgG, and C3 have been identified in tissue sections of rheumatoid nodules, suggesting pathogenetic importance. The role of IgM and IgG rheumatoid factors in sero-negative RA is poorly understood. Seven patients with active seronegative RA and rheumatoid nodules and 10 seronegative children with the syndrome of benign rheumatoid nodules were studied for the presence of IgG and IgM rheumatoid factors by radioimmunoassay and for complement-fixing IgM rheumatoid factor by haemolytic assay. Elevated titres of hidden complement fixing IgM rheumatoid factor were found in 60 % of the patients with benign rheumatoid nodules studied but in none of the patients with active seronegative nodular RA. Serum IgG and IgM rheumatoid factor levels by radioimmunoassay and circulating immune complex levels in both groups were not significantly different from normal controls. These data suggest IgG and IgM rheumatoid factors do not participate in the pathogenesis of active seronegative rheumatoid arthritis with rheumatoid nodules.     

A comparison of patients with seropositive and seronegative rheumatoid arthritis

Summary It has recently been suggested that a subpopulation of patients with rheumatoid arthritis, diagnosed on clinical, radiologic and pragmatic grounds, but with negative rheumatoid factor tests, represents a clinical entity quite distinct from that of seropositve rheumatoid arthritis. We have studied 60 sequentially presenting patients, 30 of whom were selected because they were seronegative, and 30 selected because they were seropositive in regard to IGM rheumatoid factor. The only major differences detected between the two groups on blind assessment were a greater tendency to deformity, a greater degree of erosion and the presence of subcutaneous nodules in the seropositive group. Seronegative and seropositive rheumatoid arthritis appear to have very similar clinical features, but differing degrees of severity.     

IgG rheumatoid factor. Relationship to seropositive rheumatoid arthritis and absence in seronegative disorders.

IgG rheumatoid factor was detected in the sera of the majority of patients with seropositive rheumatoid arthritis. Values suggestive of IgG rheumatoid factor were noted in one-quarter of patients with seronegative inflammatory arthropathies. These determinations were always low and correlated with elevated IgG concentrations, suggesting nonspecific adherence of IgG rather than a true antigen-antibody reaction. In support of this conclusion, nonrheumatoid factor IgG was capable of concentration-dependent nonspecific adsorption to the solid phase. IgG, but not IgM, rheumatoid factor corresponded with disease activity in patients with seropositive rheumatoid arthritis, suggesting that IgG rheumatoid factor may be important in the pathogenesis.     

Differential patterns of in vitro IgM rheumatoid factor synthesis in seronegative and seropositive rheumatoid arthritis

The existence of a subpopulation of patients with rheumatoid arthritis (RA) who lack detectable rheumatoid factor (RF) is well documented. The cellular basis for nonexpression of RF in seronegative RA is not understood. In order to approach this problem, we compared mononuclear leukocytes (MNL) from 20 healthy adult controls, 20 seropositive RA and 22 seronegative RA patients to assess their capacity to synthesize IgM and IgM RF in vitro in the presence and absence of pokeweed mitogen (PWM). MNL from 10 of 20 seropositive RA patients spontaneously elaborated IgM RF (mean = 16.7 ng/10⁶ cells), whereas this was not observed with MNL from either controls or seronegative patients. Small quantities of IgM were spontaneously released by MNL from the seropositive (68.1 ng/10⁶ cells), seronegative (43.1 ng/10⁶ cells), and control (142.3 ng/10⁶ cells) groups. PWM induced IgM RF production by MNL from 10 of 20 controls (18.5 ng/10⁶ cells) and 8 of 22 seronegative RA patients (13.5 ng/10⁶ cells); however, this was significantly less than the production observed with seropositive RA MNL (13 of 20; 37.5 ng/10⁶ cells). In contrast, IgM production in response to PWM was significantly less in both the seronegative (999.7 ng/10⁶ cells) and seropositive RA groups (471.7 ng/10⁶ cells) than in the control group (2,678 ng/10⁶ cells). IgM RF constituted a significantly higher proportion of total IgM synthesized by seropositive RA MNL (10.7%) than either seronegative RA MNL (2.5%) or control MNL (1.2%). Differences in IgM RF production in vitro could not be explained by HLA—DR4 status. Hidden RF was not detected in seronegative MNL supernatants. The results indicate clear differences in the pattern of in vitro release of IgM and IgM RF by MNL from seronegative RA patients as compared to either seropositive RA MNL or control MNL. The similarity of seronegative RA MNL to control MNL with regard to in vitro expression of IgM RF suggests that regulatory mechanisms governing RF synthesis are relatively intact in patients who have seronegative RA.     

Gold-induced immune complex nephritis in seronegative rheumatoid arthritis.

Proteinuria, with or without the nephrotic syndrome, developed in 8 patients with seronegative rheumatoid arthritis after the institution of gold therapy. Light microscope examination of renal biopsies showed normal findings in 7, and a focal increase in the mesangial matrix of one glomerulus in the eighth. In all patients immunofluorescence showed deposits of IgG and C3 along the glomerular basement membrane, indicative of immune complex nephritis. The renal biopsies of 5 patients were studied with the electron microscope and subepithelial deposits were detected in all. The Rose-Waaler test for the detection of IgM-rheumatoid factor (IgM-RF) was repeatedly negative in all patients. These results suggest that the development of gold nephropathy may be related to an absence of IgM-RF in serum.