IgA Rheumatoid Factor Research Articles

Disease activity and joint damage progression in early rheumatoid arthritis: relation to IgG, IgA, and IgM rheumatoid factor.

The clinical and biochemical correlations with joint damage progression over two years in a consecutive group of 68 patients with rheumatoid arthritis with disease duration of less than two years are reported. Joint damage was assessed with Larsen's severity scale and a measure of change in progression rate constructed. Initial haemoglobin concentration, Ritchie index, and Waaler-Rose titre in combination accounted for one third of the variance in joint damage progression. Rheumatoid factor (RF) concentrations were followed with enzyme linked immunosorbent assays (ELISAs) for IgG RF, IgA RF, and IgM RF. The RF concentrations, except IgG RF, decreased with time; significant correlations between RFs and disease activity were few and barely clinically useful. After two years IgG RF correlated significantly with a radiological score if early non-erosive changes were omitted. All RFs tended to correlate better with this radiological score at all three observation points. Analyses of the change in progression rate indicated a time delay between development of radiographic changes and increase of IgG RF. These results suggest an indirect relation between RFs and joint damage. Clinical and biochemical improvements in early RA occur despite joint damage progression, and conventional markers have insufficient predictive value.

Suppression of rheumatoid factor production by methotrexate in patients with rheumatoid arthritis: Evidence for differential influences of therapy and clinical status on IgM and IgA rheumatoid factor expression

Suppression of rheumatoid factor (RF) production in rheumatoid arthritis (RA) has been variably attributed to the use of remittive agents per se or to clinical improvement associated with their use. There have been conflicting reports with regard to the influence of methotrexate (MTX) on serum RF levels in RA. We determined IgM-RF and IgA-RF levels in paired serum samples (obtained at study entry and completion) from RA patients enrolled in multicenter trials with the Cooperative Systematic Studies of Rheumatic Diseases program. After exclusion of the 14 IgM-RF-negative sera, there were samples from 30 MTX-treated patients and 52 placebo-treated patients. Changes in IgM-RF and IgA-RF levels were weakly associated with each other. Significant decreases in IgM-RF levels were observed in the MTX-treated patients, but not in the placebo group. These changes were most significant in the MTX-treated patients who improved clinically. There were significant decreases in IgA-RF levels at study completion among MTX-treated patients who had improved clinically and those who had not improved clinically, but not in the placebo group. The contributions of clinical improvement and MTX treatment to changes in serum IgM-RF and IgA-RF levels were examined using a logistic regression model. Changes in IgM-RF were strongly related to MTX treatment and, to a lesser extent, to clinical improvement; changes in IgA-RF were related only to MTX treatment. These results indicate that MTX treatment per se decreases both IgM-RF and IgA-RF levels, whereas clinical improvement correlates with decreased IgM-RF levels only.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphocyte infiltration and the synthesis of IgM and IgA rheumatoid factors by rheumatoid synovial membrane

IgM and IgA rheumatoid factor (RF) synthesis by synovial membrane mononuclear cells was measured in 14 patients with rheumatoid arthritis (RA). The results were compared with blood mononuclear cell cultures and correlated with the intensity of lymphocyte infiltration of the synovium. IgM RF was produced by all synovial cultures compared with 56% of blood cultures; IgA RF was produced by 86% of synovial cultures and by 21% of blood cultures. A correlation was observed between synovial IgM RF synthesis, but not IgA RF synthesis, and the intensity of T cell and B cell infiltration of the synovial membrane.

Subcorneal pustular dermatosis associated with rheumatoid arthritis and raised IgA: simultaneous remission of skin and joint involvements with dapsone treatment.

A 44 year old white woman with rheumatoid arthritis for 19 years developed subcorneal pustular dermatosis. She had increased polyclonal IgA and IgA rheumatoid factor. After 4 months' treatment with dapsone 100 mg daily the patient had neither skin lesions nor active joint disease.

High prevalence of iga rheumatoid factor in severe polyarticular‐onset juvenile rheumatoid arthritis, but not in systemic‐onset or pauciarticular‐onset disease

The presence of IgA rheumatoid factor (IgA-RF) has been correlated with severe joint disease in adult rheumatoid arthritis (RA), but IgA-RF has not been reported in juvenile rheumatoid arthritis (JRA). In the present study, IgA-RF was assayed by an enzyme-linked immunosorbent assay and was found in the sera of 14 of 24 children (58%) with active polyarticular JRA. The presence of IgA-RF correlated with the degree of functional disability. In contrast, IgA-RF was not found in the sera of systemic-onset disease patients, regardless of the degree of dysfunction. IgA-RF was detected in only 1 patient with pauciarticular disease, despite the fact that several patients in this group had severe disease. The presence of IgA-RF in polyarticular JRA did not correlate with serum IgA levels, but did correlate with the presence and the level of serum IgM-RF. Thus, the presence of IgA-RF appears to be specific for polyarticular JRA, and shows a correlation with severe disease in this group.

IgG and IgA Subclass Distribution of Total Immunoglobulin and Rheumatoid Factors in Rheumatoid Tissue Plasma Cells

The subclass distribution of IgG and IgA plasma cells, and in IgG and IgA rheumatoid factor (RF) producing cells was studied in sections of synovial tissue from seropositive RA and various types of seronegative arthritis, including ankylosing spondylitis, psoriatic arthritis, and Reiter's syndrome. The study was performed with immunofluorescence technique and monoclonal IgG and IgA subclass specific antibodies. IgG RF producing cells were identified by their ability to bind and activate factors both in the early (C3) and late (C5b-9) part of the complement cascade. IgA RF cells were identified by double staining experiments with heat-aggregated IgG and monoclonal antibodies to IgA subclasses. In 23 tissues tested for total IgG, IgG1 cells were usually predominant, while the frequency of IgG3 cells was usually higher than that of IgG2. In 19 tissues also tested for IgA, both IgA subclasses were present in all tissues. IgA1 plasma cells were always predominant, with a mean ratio of IgA1 to IgA2 cells of approximately 10. In the 13 tissues tested for RF-producing cells, the highest frequency of IgG RF cells was found among the IgG3 cells, followed by IgG1 and IgG2. IgA RF cells were found in only one case, all cells being IgA1.

The rheumatic poison: a survey of some published investigations of the immunopathogenesis of Henoch-Sch�nlein purpura

Laboratory studies of the pathophysiology of Henoch-Schönlein purpura (HSP) have become more numerous in recent years with the recognition of the disease's links with the mucosal immune system in general and IgA nephropathy in particular. There are weak genetic associations with C4 null phenotypes and with HLA B35 and DR4. Studies of plasma proteins in HSP patients show an increased IgA concentration, activation of the alternative pathway of complement and consumption of factor XIII. High molecular weight (polymeric) IgA has been detected in affected individuals, which some investigators have called "immune complexes". Many patients synthesise an IgA rheumatoid factor in the acute phase, but other autoantibodies are largely absent. In vitro studies of lymphocytes from HSP patients have demonstrated an increased number of IgA-bearing and secreting B-cells, with altered T-cell regulation of antibody synthesis. While these observations point to immune dysregulation--primarily of IgA production--as a consistent feature of acute HSP, there is as yet insufficient information available to allow a consistent theory of pathogenesis to be formulated.

Measurement of Rheumatoid Factor Isotypes in the Clinical Laboratory

In this study we assessed the clinical utility of measuring all major rheumatoid factor (RF) isotypes (IgG, IgA, and IgM) in the diagnostic immunology laboratory using an enzyme-linked immunoassay (ELISA). An improved method for IgG-RF was tested which employed a commercially available monoclonal anti-human IgG Fd antibody and did not require pepsin digestion of samples. We detected elevated levels of all three RF isotypes in a population of hospitalized rheumatoid arthritis patients (n = 109). We demonstrated a significant association between IgM and IgA RF which occurred in 36% of our subjects, while less than 6% had IgM + IgG RF or IgG + IgA RF. A comparison of the IgM ELISA with the Rheumaton revealed a statistically significant correlation (r = 0.65, p = 0.001). In addition, the two methodologies were equivalent in sensitivity (ELISA: 76%, Rheumaton: 78%). However, the ELISA procedure was more time consuming, costly, and required greater technical expertise. The following clinical and laboratory findings were significantly associated with RF isotypes: IgG RF and the presence of rheumatoid nodules (p = 0.03), elevated erythrocyte sedimentation rate (ESR) and IgG RF (p = 0.007), and elevated ESR and IgM RF (p = 0.0009). Our ELISA methodology did not provide significant advantages over existing techniques to justify its use as part of the routine laboratory assessment of rheumatoid factor.

Circulating IgA- and IgM-rheumatoid factors in patients with primary Sjögren syndrome. Correlation to extraglandular manifestations.

IgM- and IgA-rheumatoid factors (RF) were determined by ELISA technique in 40 consecutive patients with primary Sjögren syndrome (primary SS), all fulfilling the Copenhagen diagnostic criteria. Increased concentrations of IgM-RF were found in 25 patients (63%) (median concentration: 85 IU/ml, range 11-302 IU/ml). Increased concentrations of IgA-RF were found in 22 of the patients (55%) (median concentration: 100 AU/ml, range 25-255 AU/ml). The levels of IgM- and IgA-RF were closely correlated (r = 0.82, p less than 0.001). IgM-RF (p = 0.037), but not IgA-RF (p = 0.17), was significantly correlated to the presence of antinuclear antibodies (ANA). In contrast, IgA-RF (p = 0.002), but not IgM RF (p = 0.068), was significantly correlated to the presence of hypergammaglobulinemia. The most common extraglandular manifestations were: arthralgia/synovitis (60%), myalgia/myositis (28%), Raynaud's phenomenon (20%) and pulmonary manifestations (15%). Concentrations of both IgM-RF (r = 0.43, p less than 0.01) and IgA-RF (r = 0.57, p less than 0.001) were correlated to the number of extraglandular manifestations present in each patient.

Composition of IgA-Containing Circulating Immune Complexes in IgA Nephropathy

Macromolecular IgA is found with a relatively high frequency in the sera of patients with IgA nephropathy (IgAN). This macromolecular IgA consists of polymeric IgA, IgA-containing immune complexes, or both. The presence of polymeric IgA antibodies reflects a recent IgA response. Vaccination data in patients with IgAN suggest that these patients respond more vigorously with their mucosal immune system than do controls. The association of exacerbations with upper respiratory tract infections suggests that the immunogenic stimuli probably are of microbial origin and are presented to mucosal surfaces. Analysis by sucrose density ultracentrifugation has shown that the macromolecular IgA may contain IgG, IgA rheumatoid factor, and C3. The search for the antigen or antigens specifically responsible for IgAN has been unsuccessful. Although IgG and IgA rheumatoid factor may contribute, they do not account for the pathogenesis of the disease in all patients. Alternative mechanisms have to be assumed for patients who do not have detectable levels of IgA-containing immune complexes. They could have polymeric IgA or IgA-containing immune complexes intermittently, as has been shown in children with relapsing IgAN. The binding of circulating IgA antibodies to antigens present in the mesangium can lead to the local formation of deposits in the absence of circulating IgA complexes.

The Role of Polymeric IgA in Complement-Mediated Solubilization of IgG and IgA Immune Complexes

Sera from patients with IgA nephropathy (IgAN) have a reduced capacity to solubilize immune complexes. The in vitro complement-mediated solubilization of immune complexes containing IgG (bovine serum albumin [BSA]-anti-BSA) or IgA (DNP29-BSA-anti-DNP) was decreased, despite normal serum levels of complement. The close correlation between low values for complement-mediated solubilization and high serum levels of polymeric IgA and/or IgA rheumatoid factor indicates that these macromolecules interfere with the process. These findings suggest that polymeric IgA produced during stimulation of mucosae specifically interferes with immune complex solubilization. Further studies are necessary to elucidate the mechanisms. The decreased complement-mediated solubilization in patients with IgAN could be responsible for persistently high levels of immune complexes containing IgA or IgG in the circulation and their continual deposition in the mesangium.

Immunoglobulin-Antiimmunoglobulin Interactions and Immune Complexes in IgA Nephropathy

IgA nephropathy (IgAN) is characterized by mesangial co-deposition of IgA and C3. Elevated levels of circulating immune complexes containing these components in significant numbers of patients have been found in several studies; IgAN is therefore assumed by many investigators to be an immune complex-mediated disease. Our studies have shown that IgG is often co-complexed with IgA within circulating immune complexes, and we have begun to examine the potential mechanisms for these observations. In this regard, elevated levels of IgA rheumatoid factor and of IgG anti-IgA antibodies were found in some patients. Nevertheless, we were unable to correlate levels of circulating immune complexes with any clinical index of disease. Furthermore, many individuals with the acquired immune deficiency syndrome (AIDS) also have elevated levels of circulating immune complexes containing IgG and IgA, IgA rheumatoid factor, and IgG anti-IgA antibodies, although these patients apparently do not have mesangial IgA deposits. Therefore, the role of circulating IgA-containing immune complexes in the pathogenesis of IgAN requires further evaluation.

Treatment of primary Sjögren's syndrome with hydroxychloroquine

Sjögren's syndrome is an autoimmune disease characterized by lymphocytic infiltration of the salivary/lacrimal glands, autoantibody production, and polyclonal hyperglobulinemia. In view of the efficacy and relative safety of hydroxychloroquine in other autoimmune disorders, the potential benefit of hydroxychloroquine (200 mg per day for 12 months) in 10 patients with Sjögren's syndrome was evaluated. Changes in levels of total immunoglobulin, antibody against Sjögren's syndrome-associated antigen B, rheumatoid factor, and in vitro production of immunoglobulin in the serum were evaluated. For comparison, 10 patients matched according to age and sex, who did not receive hydroxychloroquine were studied. In the hydroxychloroquine-treated group, the following observations were made: (1) significantly decreased total immunoglobulin G (IgG) and IgA levels with little change in IgM levels; (2) significant decrease in IgA-rheumatoid factor with a smaller decrease in IgM-rheumatoid factor; (3) decreased IgG anti-Sjögren's syndrome-associated antigen B autoantibody; and (4) decreased erythrocyte sedimentation rate and increased hemoglobin level. Further, a specific idiotype present on their rheumatoid factor (defined by monoclonal antibody 17-109) was significantly decreased, with disappearance of detectable circulating paraprotein in two hydroxychloroquine-treated patients. Finally, rheumatoid factor production in vitro by lymphocytes from hydroxychloroquine-treated patients using a T cell-dependent mitogen was significantly decreased. These results suggest that hydroxychloroquine modulates lymphoproliferation in patients with Sjögren's syndrome and may prevent progression to extraglandular sites of neoplastic transformation.

ASSOCIATION BETWEEN VILLOUS ATROPHY IN RHEUMATOID ARTHRITIS AND A RHEUMATOID FACTOR AND GLIADIN-SPECIFIC IgG

93 patients with rheumatoid arthritis (RA) were examined for histological or other evidence of gut abnormalities. 44 had raised levels of IgG to gliadin, and of these 38 (86%) were also positive for IgA rheumatoid factor (RF). 24 patients (15 with raised levels of IgA RF and wheat protein IgG [AB + ] and 9 with normal levels of both antibodies [AB - ]) underwent jejunal biopsy. 6 of the AB + and 1 of the AB - patients had villous atrophy. The AB + group had lower villous surface/volume ratio and small intestinal lactase concentrations than did the AB- group or age-matched controls. There was no significant difference between the two groups of RA patients in disease severity or treatment regimen. The findings suggest that the gut may play a more important part in the immunopathogenesis of some cases of RA than in others, and that the former may be identified by raised levels of IgA RF and wheat protein IgG.

Occurrence of polymeric IgA1 rheumatoid factor in the acquired immune deficiency syndrome.

The sera of 34 acquired immune deficiency syndrome (AIDS) patients and 20 healthy male homosexuals were examined for the presence of elevated levels of IgA and IgM rheumatoid factor (RF) and compared with results obtained with sera from 23 healthy laboratory volunteers. IgA RF levels were elevated (greater than 3 standard deviation units) in 9 of 34 (26%) patients with AIDS as compared to the panel of laboratory controls. Levels of IgM RF did not differ significantly in the AIDS patients and in the controls. There were no differences in levels of either IgA RF or IgM RF when the homosexual controls were compared with the laboratory volunteers. Sucrose-gradient ultracentrifugation experiments and assays using monoclonal reagents specific for IgA subclasses indicated that the IgA RF was predominantly of the polymeric configuration and restricted to the IgA1 subclass, respectively. Polyethylene glycol (PEG) precipitates of serum enriched for circulating immune complexes (CIC) were also assayed for the presence of IgA RF and IgM RF. Although levels of IgA RF in serum and in PEG precipitates did not correlate with levels of IgA- or IgA/IgG-containing CIC in AIDS patients, levels of IgA RF in both serum and CIC-enriched material were significantly elevated in the AIDS population when compared with the control panel. In contrast, levels of IgM RF in both serum and CIC-enriched material were low and not significantly different from those in healthy controls. These results indicate that both IgA-containing CIC and IgA RF occur in many AIDS patients and raise the possibility that IgA RF may contribute significantly to the formation of immune complexes in this disease.

Polymeric IgA and IgA rheumatoid factor decrease the capacity of serum to solubilize circulating immune complexes in patients with primary IgA nephropathy.

Abstract Primary IgA nephropathy (IgAN) is characterized by the presence of immune complexes (IC), high levels of polymeric IgA (pIgA), and IgA rheumatoid factor (RF) in the blood. The impaired capacity of serum to solubilize IC in the presence of normal values of C hemolytic activity as well as high serum levels of C3, C4, and properdin factor B have led us to analyze whether pIgA and IgA RF from patients with IgAN where capable of inhibiting the capacity of normal human serum to solubilize immune precipitates (BSA-anti-BSA) preformed at equivalence. The results showed a significant reduced mean capacity of serum from patients with IgAN to solubilize "in vitro" immune precipitates (p less than 0.001) and significant high mean levels of pIgA (p less than 0.001) and IgA RF (p less than 0.005) in the blood. Increasing amounts of pIgA inhibited solubilization of IC in the fluid phase, and inhibitory activity was also shown by the IgA RF. There were inverse correlations between pIgA and the capacity of serum to solubilize IC (r = -0.36; p less than 0.05), and between IgA RF and the complement-mediated solubilization (r = -0.57; p less than 0.001). It is suggested that pIgA and IgA RF may be responsible for the impaired complement-mediated solubilization of serum and the persistence of insoluble nephritogenic IC in the blood of patients with primary IgAN.

Class-specific rheumatoid factors, DR antigens, and amyloidosis in patients with rheumatoid arthritis.

Class-specific rheumatoid factors (RFs) were measured by enzyme immunoassay in 59 patients with rheumatoid arthritis complicated by systemic amyloidosis (RA+A), 47 patients with rheumatoid arthritis without amyloid (RA), 106 patients with other rheumatic diseases (juvenile rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome), and 55 blood donors. The patients with RA+A were characterised by a high prevalence of RF negativity; the IgM RF concentration was raised in only 18 of the 59 patients (31%, p less than 0.001 v RA), the IgG RF concentration in 20 of 59 (34%, p less than 0.001 v RA), and the IgA RF concentration in 24 of 59 (41%, p less than 0.001 v RA). A higher prevalence of HLA-DR4 (p less than 0.001) and a lower prevalence of DR2 (p less than 0.05) were found among 48 tested patients with RA+A when compared with a control panel consisting of 500 blood donors. No significant differences in the prevalence of DR1-DR7 or B27 antigens were observed, however, between patients with RA with or without amyloid.

IgA rheumatoid factor as predictor of disease activity.

IgA rheumatoid factor (RF) was shown to occur in rheumatoid arthritis (RA) sera in 1963, but for almost 20 years thereafter this RF isotype received little attention. Solid-phase immunoassays, esp. ELISA, are now widely used for the detection of serum IgA RF which may be raised in RA, primary Sjögren's syndrome, systemic lupus erythematosus (SLE) and several other diseases. Over the past four years the following observations on IgA RF have been published: While IgM RF levels showed positive correlation with age, IgA RF levels did not. Gold therapy reduced IgA RF levels but the relationship to clinical improvement was not clear. In longitudinal studies, changes in overall disease activity, Ritchie articular index, grip strength and ESR showed a closer association with IgA RF than with IgM RF. Five groups have reported an association between IgA RF and the severity of erosive arthritis. In early RA, IgA RF may be a more specific predictor of disease severity than IgM RF or IgG RF. Further work is needed on the occurrence and biology of IgA RF, but measuring this isotype alone would improve the clinical specificity of routine RF tests.

IgA and IgM rheumatoid factors as markers of later erosive changes in rheumatoid arthritis (RA).

Stored samples from within the first year of disease of 119 patients with rheumatoid arthritis (RA) enrolled in a long-running prospective study have been studied for the presence of IgM and IgA rheumatoid factors (RF), using agglutination of rabbit IgG-coated red blood cells to detect IgMRF and an ELISA technique using rabbit IgG coated on the microtitre plates and labelled F(aB)2 fragment of goat anti-IgA. Outcome measures at a mean follow-up of 10.1 years (range 3-20) included the Steinbrocker functional grade and grading of erosive changes on hand and feet Xrays using a modification of Lawrence's method. Both IgA and IgG levels at presentation correlated significantly with outcome measured by erosive changes and functional grade at a mean of 10 years and with the time of first appearance of erosions. In patients who are IgMRF negative early in the disease, IgARF positivity indicates a greater chance of developing both erosions and impaired function than when both tests are negative. IgARF positivity seems to precede IgMRF.

Relation between bone erosions and rheumatoid factor IgA and IgM isotypes in recent onset rheumatoid arthritis.

In this prospective study 58 patients with early rheumatoid arthritis were followed up for two years with six-monthly assessments including rheumatoid factors (RF) of IgA and IgM subtypes. Initial and mean serum levels of IgA-RFs were raised in patients with an erosive disease course in comparison to non erosive disease. The cases with initially increased serum levels of RFs of both isotypes developed more eroded joints in their hands and feet during the study period than the rest of the patients. None of the differences, however, were statistically significant. Of the tested parameters only clinical rheumatoid activity (Mallya-index) was significantly related to the number of eroded joints during the follow-up. We conclude that serum IgA-type RFs are raised in erosive RA, but the determination of RFs of any kind cannot be used to prognosticate erosiveness.