Class specific rheumatoid factors in rheumatoid arthritis: response to chrysotherapy and relationship to disease activity

IgG rheumatoid factors (RF) may play an important role in the pathogenesis of rheumatoid arthritis (RA). Our study investigates the relationship between class specific RF levels measured by radioimmunoassay and disease activity in patients with RA undergoing chrysotherapy. Nineteen patients were treated with 20 mg disodium aurothiomalate weekly for 6 months. Rheumatoid disease activity was assessed before and after 6 months' treatment and the level of IgG, IgA and IgM RF measured. There were significant falls in disease activity (p less than 0.005), IgA RF (p less than 0.005) IgG RF (p less than 0.005) and SCAT (p less than 0.025), but not IgM RF, over the 6 month treatment period. No correlation was found between absolute levels of IgA, IgG or IgM RF and disease activity before or after 6 months' therapy but there was a highly significant linear correlation between reduction in IgG RF levels and fall in disease activity (r = 0.642, p less than 0.005) with treatment.     

Serum immune complexes containing IgA appear to predict erosive arthritis in a longitudinal study in rheumatoid arthritis.

Fifty seven patients with rheumatoid arthritis (RA) were studied longitudinally, and the presence of rheumatoid factor (RF) and various types of immune complexes (IC) was correlated with joint activity and the presence of extra-articular features (EAF). In a cross sectional study it was found that the levels of circulating IC and RF correlated significantly with joint disease activity and the presence of EAF. Longitudinally, levels of IC measured by the C1q binding activity and IC containing IgG and IgM correlated significantly with fluctuations in joint disease activity, whereas IC containing IgG and IgA correlated with the occurrence of EAF. RF and IC levels, however, did not predict the clinical course of the disease. IC containing C3 and C4 were found infrequently and were only present in patients with active rheumatoid vasculitis (RV). The continuous presence of these IC appeared to be linked to the recurrence of vasculitis, irrespective of treatment. Significantly more erosions of hands and feet were found after one year follow up in those RA patients who presented early (disease duration less than one year) who initially had a raised serum IgA IC level (r = 0.72; p less than 0.005).     

Prospective study of early rheumatoid arthritis. I. Prognostic value of IgA rheumatoid factor.

Thirty-three patients with early arthritis, 28 of whom developed classical/definite rheumatoid arthritis (RA), were followed up for two to four years. Rheumatoid factor (RF) levels of the IgM, IgA, and IgG isotypes were measured in serum and synovial fluid by an ELISA technique developed in our laboratory. All seven patients who presented with raised IgA RF developed erosions of their hands and wrists. This was significantly different from the remaining 26. By contrast none of the five patients who presented with isolated elevation of IgM RF developed erosive disease. The patients with raised IgA RF needed significantly more treatment with 'specific' drugs than the remaining 26. It is suggested that the detection of IgA RF in early RA indicates poor prognosis, justifying a more aggressive treatment at an early stage.     

Prevalence of IgM, IgA and IgG rheumatoid factors in juvenile rheumatoid arthritis

Using an enzyme immunoassay, sera from 50 children with juvenile rheumatoid arthritis (JRA) and 39 controls were tested for IgM, IgA and IgG rheumatoid factors (RF). RF of the IgM and IgA isotypes were present in 11 (22%) patients, but in only one control (p = 0.008). IgG RF was present in the sera of 2 (4%) patients and in none of the controls (p = 0.21). Of the 22 patients with IgM RF or IgA RF, only 3 sera (14%) contained RF of both isotypes. IgM RF was more common in patients with polyarticular disease, while IgA RF was more common in patients with pauciarticular disease. These results indicate that IgM and IgA RF are present in a significant minority of JRA patients and suggest that there is independent expression of the respective RF isotypes.     

Rheumatoid factors in rheumatoid arthritis and vasculitis

Summary To study the occurrence of rheumatoid factors (RF) in relation to the activity of rheumatoid arthritis and the occurrence of vasculitis, RF of IgM, IgA, and IgG classes were measured in sera from 35 patients with definite or classic rheumatoid arthritis (RA) using ELISA. For 26 patients, the RF levels were studied longitudinally and compared with changes in the articular index. Although IgM RF was occasionally found in patients without RA, IgA and/or IgG RF were almost exclusively associated with RA. The titers of IgM, IgA, and IgG RF were significantly higher in sera from patients with clinically diagnosed rheumatoid vasculitis than in sera from patients without vasculitis. No significant correlation between changes in the articular index and changes in titer of any class-specific RF could be found for the group of RA patients as a whole. However, in individual patients, increases or decreases in IgM and IgG RF titer were significantly correlated with an increase or decrease in the articular index.     

Effects of rheumatoid factor isotypes on disease activity and severity in patients with rheumatoid arthritis: a comparative study

The value of rheumatoid factor (RF) isotypes for assessing rheumatoid arthritis (RA) remains debatable. In this study, we have examined the relationships between RF isotypes and disease activity and severity in RA patients. Sixty-two patients with RA, 48 women and 14 men, were studied. RF was measured by nephelometry (RF–N) and IgG–, IgA–, and IgM–RF isotypes were measured using enzyme-linked immunosorbent assay. Serum C-reactive protein and erythrocyte sedimentation rate were also determined. The patients were classified according to disease activity, joint damage, functional status, and presence of pulmonary involvement, rheumatoid nodule, and secondary Sjögren’s syndrome. Although the patients with active disease had significantly higher IgA–RF and IgM–RF levels compared to inactive patients, IgA–RF and IgM–RF were not found to be independently associated with disease activity in multivariate analysis. In patients with severe joint damage, IgA–RF and RF–N were significantly higher than those of the other patients. Multiple regression analysis showed that IgA–RF was the unique variable independently associated to severe joint damage. The patients with class III and IV functional index had significantly higher IgM–RF, IgA–RF, and RF–N levels compared to the patients with class I and II functional index; however, RFs were not significantly associated with functional status in multivariate analysis. IgA–RF and IgM–RF were significantly associated with pulmonary involvement and rheumatoid nodule, respectively. No significant associations were found between RF isotypes and secondary Sjögren’s syndrome. Our results suggest that the clinical usefulness of IgA and IgM isotypes is better than RF–N. Elevated IgA–RF may be a marker of erosive disease. The usefulness of RF isotypes for monitoring disease activity or functional status appears to be limited.     

ELISA determined IgM, IgG and IgA rheumatoid factors in rheumatoid arthritis and in other connective tissue diseases

We used an adaptation of an enzyme-linked immunoadsorbent assay (ELISA) to determine serum levels of IgM, IgG and IgA rheumatoid factors (RF) in 50 patients with classic or definite rheumatoid arthritis (RA) according to the ARA criteria, balanced for positive or negative-routine Latex-RF reaction. A control group of 50 young normal subjects and a reference group of 44 patients with other connective tissue diseases (OCTD) were also studied. We confirmed the high sensibility of the method, together with its good specificity and reproducibility. For the IgM RF a very significant correlation was found between ELISA results and Latex-RF titration (p less than 0.001). Many Latex-RF negative RA patients had high ELISA levels of IgM RF, suggesting that this assay reveals, at least in part, hidden or non-agglutinating IgM RF. Among the OCTD group only some SLE cases, mainly Latex-RF positive, had enhanced IgM RF on ELISA. Considered quantitatively, IgG RF did not play a significant diagnostic role for RA (p greater than 0.05), because they were also found, with widely dispersed values, in normal subjects, and because the mean increase in RA patients was relatively small. Interestingly, IgA RF were above the normal range in many RA patients, both Latex-RF positive or negative. The mean values differed significantly from those of controls (p less than 0.005), and a correlation was observed between IgA RF levels and IgA containing immune-complexes. Normal IgA RF values were observed in SLE patients, even if Latex-RF positive, suggesting that their increase in RA patients is not the mere expression of a polyclonal B cell activation.     

Rheumatoid factors in psoriatic arthropathy and in Waaler-Rose negative rheumatoid arthritis

Summary Serum levels of IgG, IgA and IgM rheumatoid factor (IgG RF, IgA RF and IgM RF) were determined by means of the diffusion-in-gel enzyme-linked immunosorbent assay (DIG-ELISA) in 42 Waaler-Rose negative patients with psoriatic arthropathy (PsA) type 1 (arthritis with involvement of distal interphalangeal joints) and type 3 (polyarthritis of rheumatoid type) according to the criteria of Moll and Wright as well as in 53 patients with Waaler-Rose negative rheumatoid arthritis (RA). Elevated levels of RF were found in 22% of patients with PsA type 3 and 45% of patients with Waaler-Rose negative RA. In contrast, none of the patients with PsA type 1 had detectable amounts of RF. It is suggested that the presence of IgG, IgA or IgM RF in patients having psoriasis in conjunction with inflammatory polyarthritis indicates the RA nature of the joint disease and should be considered as exclusion criterion for the diagnosis of PsA.     

Prognostic laboratory markers of joint damage in rheumatoid arthritis

OBJECTIVE: To investigate whether determination of a set of laboratory markers at baseline provides prognostic information on joint damage in hands and feet in rheumatoid arthritis. METHODS: 183 patients with early rheumatoid arthritis included in a prospective study were examined. Radiographic changes in hands and feet at 5 and 10 years after inclusion were evaluated (Larsen). The markers analysed were: erythrocyte sedimentation rate (ESR); HLA-DRB alleles typed by restriction fragment length polymorphism; and C reactive protein, cartilage oligomeric matrix protein (COMP), rheumatoid factor (RF) (IgG, IgA, and IgM subtypes), antibodies against cyclic citrullinated peptide (anti-CCP), and antibodies against interleukin 1alpha (anti-IL1alpha), analysed by immunoassays. Multiple linear regression with backward elimination was used to determine the prognostic value of the variables. RESULTS: 117/176 patients were positive for IgG RF, 138/176 for IgA RF, 139/176 for IgM RF, 140/176 for anti-CCP, and 40/182 for anti-IL1alpha. After five years, ESR, the presence of IgA RF, serum COMP, and the presence of anti-CCP were significantly associated with more severe joint damage, and the presence of anti-IL1alpha with less severe joint damage. Baseline C reactive protein and anti-CCP predicted radiographic outcome after 10 years. A stronger prediction was obtained by combining the prognostic factors. CONCLUSIONS: Early determination of anti-CCP, IgA RF, anti-IL-1alpha, ESR, C reactive protein, and COMP predicted the development of joint damage in hands and feet in this cohort. A combination of these measures reflecting different aspects of the disease process should be useful for evaluating prognosis in individual patients with early rheumatoid arthritis.     

Population study of the importance of rheumatoid factor isotypes in adults.

Blood samples collected from 13,858 randomly selected subjects participating in a health survey in Iceland from 1974 to 1983 were tested for rheumatoid factor. Samples that were positive in a sensitive RF screening test were analysed further by the Rose-Waaler technique and an isotype specific enzyme linked immunosorbent assay (ELISA). In 1987 the 173 available participants who were RF positive and 156 matched RF negative controls were evaluated clinically for rheumatoid diseases. RF levels and isotype patterns were more persistent in the patients with rheumatoid arthritis (RA) than in RF positive subjects who did not have overt RA. The prevalence of RA was only 19% in the participants who were RF positive in 1987. Forty per cent of the participants who had a persistent (four to 13 years) increase of IgA RF combined with either IgM or IgG RF were diagnosed as having RA. A positive correlation was found between RF levels and various manifestations of RA. This association was stronger for the IgA and IgG RF isotypes than for IgM RF. Excluding RF positivity as a diagnostic parameter, RA was diagnosed in 33 of the participants and 20 (61%) of these patients had increased levels of IgM and IgA RF. Patients with RA with bone erosions in their hands had higher levels of IgA RF than patients without erosions, but an association was not found between bone erosions and other RF isotypes. None of the RF negative participants who were symptom free when the original blood sample was taken developed RA during the four to 13 year follow up period. In contrast, five symptom free RF positive participants developed RA during this period. These five patients had all had increased levels of at least two RF isotypes before the onset of their symptoms. It is concluded that the IgA and IgG RF isotypes have a closer association with the clinical parameters of RA than IgM RF. Furthermore, increases in RF can precede clinical manifestations of RA and this applies in particular to the IgA and IgG RF isotypes.     

Correlation between rheumatoid factor and IL-6 activity in synovial fluids from patients with rheumatoid arthritis

Synovial fluids (SF) and sera (S) from patients with rheumatoid arthritis (RA) were examined for IgM, IgM-rheumatoid factor (IgM-RF), albumin and interleukin-6 (IL-6) activity. The quotient of SF/S IgM-RF was elevated compared with that of SF/S albumin in 7 patients with seropositive RA, although the quotient of SF/S IgM was lower than that of SF/S albumin. SF IL-6 activity was much higher than serum IL-6 activity in all the 7 RA patients. In synovial fluids from 22 seropositive RA patients, SF IL-6 activity was significantly correlated with the SF IgM-RF, IgG-RF and IgA- less than RF, but not with SF IgM, IgG or IgA. Moreover, SF IgM-RF as well as SF IL-6 activity was significantly correlated with the Westergren erythrocyte sedimentation rate (ESR) or the Lansbury articular index. These results indicate that IL-6 and RF might be produced within the rheumatoid joints as a result of abnormal immune system activation, which is associated with the disease activity of RA. Three of the 4 seronegative RA patients, however, showed high SF IL-6 without detectable levels of SF IgM-RF, indicating that IL-6 alone is not sufficient for IgM-RF production.     

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.     

Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow up study.

Serum rheumatoid factors (RF) were measured yearly in 135 women with rheumatoid arthritis by the Waaler-Rose and latex fixation tests and IgM, IgA, and IgG RF were measured by enzyme linked immunosorbent assays (ELISAs). The patients were followed up from an early phase of the disease for a mean duration of six years. Patients with a persistently positive RF test, irrespective of the type of test used, had more radiological abnormalities, more disease activity, worse functional ability, more extra-articular manifestations, and needed more treatment with second line drugs than patients with persistently negative or variably positive and negative test results during the follow up. Increased RF levels, especially a high level of IgA RF within three years of the onset of symptoms, was prognostic for a more severe disease outcome six years after the onset of symptoms.     

Relationship of serum IgG rheumatoid factor to IgM rheumatoid factor and disease activity in rheumatoid arthritis

Rheumatoid factors (RF) constitute the major autoantibodies in rheumatoid arthritis (RA). RF are directed against IgG Fc, are polyclonal, and are predominantly of the IgG and IgM classes. RF may participate in both synovial and extraarticular inflammation in RA, although the precise roles of serum IgG and IgM RF are unclear. The purpose of our study was to correlate serum IgG RF with serum IgM RF levels measured by radioimmunoassay and with clinical disease activity in 42 prospectively evaluated seropositive RA patients. IgM RF correlated with IgG RF levels and articular disease activity. IgG RF correlated with IgM RF but not with articular disease activity when adjusted for IgM RF.     

IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF detected by ELISA in rheumatoid arthritis.

One hundred patients with rheumatoid arthritis (RA), of whom 73 were seropositive by latex or Waaler-Rose (WR) assays, or both, 100 healthy subjects, and 102 diseased controls (22 patients with systemic lupus erythematosus (SLE) and 80 with bronchial asthma) were evaluated for the presence of IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF by an enzyme linked immunosorbent assay (ELISA). Ninety two per cent, 65%, 68%, and 66% of the patients with RA were found to be positive for IgM, IgA, IgE, and IgG respectively. A positive correlation existed between the levels of IgM RF and IgA RF on the one hand and disease activity on the other, and the levels of IgM RF and IgA RF correlated with the levels of circulating immune complexes as measured by a C1q binding assay. The presence of extra-articular features also correlated positively with the levels of IgA RF and IgE RF. Five out of six patients with Sjögren''s syndrome had very high levels of IgA RF. Of 47 patients typed for HLA-DR, DR1 and DR2 were significantly more frequent in those with the highest levels of IgM RF. Conversely, DR3 was associated with low levels or absence of IgA RF and IgE RF. These results suggest that immune response genes may regulate the level of different RF isotypes. The frequencies of IgM, IgA, IgE, and IgG RF were 59%, 36%, 9%, and 27% respectively in SLE and 25%, 2.5%, 70%, and 59% in bronchial asthma.     

Low mannose binding lectin predicts poor prognosis in patients with early rheumatoid arthritis. A prospective study

OBJECTIVE: To determine whether low mannose binding lectin (MBL) is associated with poor prognosis in rheumatoid arthritis (RA) and whether patients with RA have increased frequency of MBL deficiency. METHODS: Patients with recent onset symmetric polyarthritis (< 1 year, median 3 mo) were recruited if they had not been treated longer than 2 weeks with disease modifying drugs. They were reevaluated after 6 months and their disease activity and progression were correlated with their MBL concentration, rheumatoid factor (RF) isotypes, and C-reactive protein (CRP). Sixty-three female patients with advanced RA were also analyzed. RESULTS: Sixty-five patients with early arthritis fulfilled American College of Rheumatology criteria for RA and 52 were followed for 6 months or longer. Low MBL was associated with raised RF, IgA RF in particular (p = 0.02). and also with a combined elevation of IgM and IgA RF (p = 0.035). Patients with low MBL (lowest 25th percentile) showed less improvement after 6 months of treatment than patients in the highest MBL quartile. This applied to the Thompson joint score (p = 0.03) and grip strength (p = 0.004). Low MBL was also significantly associated with radiological joint erosions at recruitment and at 6 month followup (p = 0.039); and the group with advanced RA also showed a significant association between low MBL concentration and radiological damage (p = 0.036). However. neither patient group had increased frequency of MBL deficiency compared to healthy controls. CONCLUSION: Low MBL predicts poor prognosis in patients with early RA.     

IgA related disorders in rheumatoid arthritis

Serum monomeric and polymeric IgA, IgA rheumatoid factor (IgA-RF) and IgA containing circulating immune complexes (IgA-CIC) were studied in 192 patients with rheumatoid arthritis (RA) to explore the relationships among IgA related abnormalities and to investigate their potential associations with disease activity, immunoregulatory disorders and effect of treatments. Total serum IgA and polymeric IgA (p-IgA) levels were elevated in 23 and 11% of patients with RA, respectively. Their respective mean concentrations in serum were significantly elevated compared to normal values (p less than 0.001 and p less than 0.004). A preferential increase in polymeric rather than monomeric IgA was observed. IgA-RF, detected by a solid phase ELISA, was found in 71% and was associated with decreased grip strength (p less than 0.005), active disease (p less than 0.05), increased p-IgA level (p less than 0.001), elevated p-IgA:total IgA ratio (p less than 0.05), the presence of IgA-CIC (p less than 0.005) and IgM-RF (p less than 0.005). Complement fixing IgA-CIC were detected in 40% of patients by IgA specific conglutinin and anti-C3 binding solid phase ELISA. High molecular weight IgA species precipitated by 2.5% polyethylene glycol from RA sera positive for IgA-CIC were shown to be IgA-RF complexed to IgG. Taken together, our results suggest that IgA-RF are essentially polymeric in nature and circulate as IgA-RF-IgG immune complexes. Although the presence of IgA-CIC was not associated with disease activity, IgA-CIC activated C3 and thus are potentially pathogenic.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isotypes of rheumatoid factors in rheumatoid arthritis and chronic liver diseases

We studied isotype-specific rheumatoid factors (RFs) to clarify their significance in rheumatoid arthritis (RA) and to verify the difference in RF isotypes between RA and chronic liver diseases (CLD). Isotype-specific RFs in RA and in CLD were measured by enzyme-linked immunosorbent assay (ELISA). Most sera (n = 51, 94.1%) from RA patients contained some kind of RF isotypes (92.1% for IgM RF, 76.4% for IgG RF, and 43.1% for IgA RF), and seronegative RA by ELISA was seen in only 11.8% (n = 6). The most characteristic combination of RF isotypes in active RA was IgG, IgA, and IgM. This combination of RF isotypes changed to IgG plus IgM, according to the diminution of RA activity; then, we found only IgM RF in inactive RA. The titers of each RF isotype also decreased in parallel with the activity of RA. IgA RF seemed to be the most sensitive factor for evaluating the activity of RA. In CLD, almost the same high frequency (n = 49, 89.8% for IgM RF, 59.2% for IgG RF), with the same titer levels seen in RA, was observed. On the other hand, IgA RF was significantly lower in frequency (n = 9, 18.4%) and in titer, compared with the finding in RA. Surprisingly, even in CLD, true seronegativity by ELISA was also found in very few patients (n = 4, 8.1%). In CLD, positive RFs detected by agglutination assay were seen more often in chronic hepatitis than in liver cirrhosis. In RA patients, significant associations of IgA RF and the serum concentration of IgA, and IgG RF and the serum concentration of IgG, were observed. On the other hand, in CLD patients, significant associations of IgG RF and the serum IgG concentration, and of IgM RF and the serum IgM concentration, were observed. These results indicated that IgA RF in active RA is the most characteristic RF isotype distinguishing it from other nonrheumatic diseases, as well as from inactive RA. RF isotypes reflected the background polyclonal B-cell activation in different manners in both diseases. In CLD, RF isotypes seemed to be disease-related immunological disorders reflecting disease progression. Received: February 17, 2000 / Accepted: July 5, 2001     

The relation of radiographic changes to serum acute-phase proteins and rheumatoid factor in 200 patients with rheumatoid arthritis

Radiographic parameters in 200 patients with rheumatoid arthritis (RA) were correlated with laboratory parameters, including hemoglobin (Hb), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), orosomucoid (OROS), immunoglobulin G (IgG), IgM, IgA, and rheumatoid factor (RF). CRP, OROS, and Hb showed a significant association with the severity and progress of radiographic parameters. ESR and WARO showed a significant association with the severity of radiographic parameters in late RA only. IgG, IgM, and IgA did not show any significant correlation with radiographic parameters.     

Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis

OBJECTIVES: Smokers have an increased incidence of rheumatoid factor (RF) and rheumatoid arthritis (RA) and one report has also indicated that smoking may also adversely influence the severity of RA. METHODS: Sixty-three women with advanced RA answered a structured questionnaire that included detailed information about their smoking history. The women were also evaluated clinically and radiologically. RESULTS: Heavy smoking (>/= 20 pack-yr) was associated with rheumatoid nodules (P: = 0.01), a higher HAQ score (P: = 0.002) and a lower grip strength (P: = 0.01). Smoking was also associated with more radiological joint damage (P: = 0.02). A positive correlation was observed between smoking and RF levels, in particular IgA RF and a combined elevation of IgM and IgA RF. CONCLUSIONS: Smoking has an adverse effect on disease progression in patients with RA. An association was also observed between smoking and those RF types that predispose to RA and have the highest diagnostic specificity for this disease.