IgM-RF Levels Research Articles

Anti-cyclic citrullinated peptide autoantibodies in IgM rheumatoid factor-positive patients

Background Antibodies to citrullinated proteins have been described in patients with RA and these appear to be the most specific markers of the disease. The objective of this study was to analyse the improvement in diagnostic accuracy of anti-cyclic citrullinated peptide autoantibodies and IgA rheumatoid factor in patients with clinical suspicion of RA and who were IgM rheumatoid factor-positive. Anti-CCP antibodies were measured with three different second-generation enzyme immunoassays. Methods We chose 133 serum samples with IgM RF levels greater than 20 IU/mL sent to our Laboratory from Specialized Care Units. Subsequently, patients were classified according to their clinical records. Eighty-seven had rheumatoid arthritis and 46 had other diseases. In all samples anti-CCP and IgA RF were measured by the corresponding ELISAs. Results Comparison of the three anti-CCP second-generation ELISAs revealed differences between them. Likewise, clinical performances in terms of sensitivity, specificity, and positive and negative likelihood ratios were different. In patients with IgM RF higher than 20 IU/mL, anti-CCP antibodies increased the clinical efficiency of IgM RF and offered better performance as compared with IgA RF. Conclusions The use of anti-CCP antibodies affords good clinical efficiency and modifies the pre-test probability of the occurrence of RA in patients with IgM rheumatoid factor higher than 20 IU/mL.

Rheumatoid factor isotypes and anti-agalactosyl IgG antibodies in systemic sclerosis

Rheumatoid factor isotypes and anti-agalactosyl IgG antibodies (anti-AG IgG) have been reported to be detected and correlated with the disease activity in some collagen diseases. To study the frequency and the clinical significance of IgM, IgG and IgA rheumatoid factor (IgM-RF, IgG-RF and IgA-RF) and anti-AG IgG in patients with systemic sclerosis (SSc). Seventy-nine serum samples from patients with SSc were examined by specific enzyme-linked immunosorbent assays. The levels of IgM-, IgG-, IgA-RF and anti-AG IgG were significantly higher in SSc patients than in normal healthy controls. The levels of IgM- and IgA-RF were significantly higher in patients with diffuse cutaneous SSc than in those with limited cutaneous SSc. IgM-, IgG- and IgA-RF and anti-AG IgG were significantly elevated in 39%, 32%, 23% and 35% of 79 SSc patients, respectively. The prevalence of pulmonary fibrosis, oesophageal involvement and cutaneous telangectasias in patients with elevated IgA-RF levels was significantly higher than in those with normal levels. The incidence of pitting scars of digits in those with elevated IgG-RF levels and the incidence of contracture of phalanges in those with elevated IgM-RF levels were significantly higher than in those with normal levels. The frequency of increased erythrocyte sedimentation rate in patients with elevated IgG-RF and the frequency of increased C-reactive protein in those with elevated IgM-RF were significantly greater than in those with normal levels. IgM-, IgG-, IgA-RF and anti-AG IgG can be serum indicators of specific clinical manifestations in SSc patients.

Rheumatoid arthritis is already expensive during the first year of the disease (the Swedish TIRA project).

To calculate direct and indirect costs in early rheumatoid arthritis (RA) and to characterize patients generating high and low costs respectively. Two hundred and ninety-seven patients with recent-onset (< or = 12 months) RA were recruited. Clinical/laboratory data and 'health assessment questionnaire' (HAQ) were registered at inclusion and after 3, 6 and 12 months. After 6 and 12 months, the patients completed a questionnaire concerning health-care utilization and days lost from work. A cut-off point for direct costs was set at 34,000 Swedish kronor (euro3675) defining one-third of the patients as a high-cost group and two-thirds as low-cost group. Indirect costs were calculated for patients aged <65 yr. Two hundred and eleven patients completed the HAQ on both occasions. Indirect costs exceeded direct costs by a factor of 2.3. Sixty three per cent experienced work disability during the first year and were identified as the 'high-indirect-cost group'. Indirect costs accounted for >70% of total costs. Direct costs included ambulatory health care (76%), hospitalization (12%) and medication (9%). Men aged > or = 65 yr had low costs compared with younger men and women of all ages. In multiple logistic regression tests, HAQ, high levels of IgM rheumatoid factor (IgM RF) and poor hand function increased the odds of entering the high-direct-cost group, and poor hand function and pain increased the odds of entering the high-indirect-cost group. Substantial costs were incurred during the first year after diagnosis of early RA, mainly due to work disability. Indirect costs were two to three times higher than direct costs. High levels of IgM RF, high HAQ score, poor hand function and pain increased the odds of entering high-cost groups.

The genetic control of rheumatoid factor production in a rat model of rheumatoid arthritis.

To investigate the genetic regulation of rheumatoid factor (RF) in a rat model of rheumatoid arthritis, in order to gain understanding of the enigmatic role of RF in the disease. IgM-RF and IgG-RF, as well as total levels of immunoglobulins of different subclasses, were measured in sera from rats with pristane-induced arthritis (PIA). The major gene regions were identified by linkage analysis of genetically segregating crosses. The production of RF was found to correlate with development of arthritis and to be higher in females than in males. Surprisingly, the relatively arthritis-resistant E3 strain had higher levels of RF than the arthritis-susceptible DA strain. In an (E3 x DA)F(2) cohort a major locus controlling the levels of IgM-RF in serum was identified on chromosome 11 (Rf1) and another on chromosome 16 (Rf3), and these were not related to arthritis susceptibility. However, the Rf2 locus on chromosome 4 controlled IgG-RF levels, IgG2a levels, and chronic arthritis in males (Pia5). Some previously defined arthritis loci (Pia4, Pia6, Pia7, and Pia8) were found to also control immunoglobulin levels in serum. RFs are produced in the rat PIA model and correlate with development of arthritis. Gene regions controlling RF and serum immunoglobulin levels were identified, of which some cosegregated with arthritis. This suggests a new focus of study to elucidate the role of RF in the pathogenesis of arthritis.

Increased mucosal synthesis of rheumatoid factor (RF) in coeliac disease.

Increased serum levels of RF have been reported in patients with gluten sensitivity. The objective of this study was to investigate the in vivo secretion of different isotypes of RF in the small bowel in coeliac disease. Nineteen patients were investigated by perfusion of a defined jejunal segment, and the jejunal perfusion fluid was analysed for the presence of IgA and IgM anti-Fc (IgG). Five of the patients studied had serum IgA deficiency. Patients with partial/subtotal villous atrophy but no IgA deficiency (n = 7) had a four-fold increase of IgM-RF (P < 0.001) and a three-fold increase of IgA-RF (P < 0.001) compared with healthy controls (n = 29). Patients with normal jejunal mucosa but no IgA deficiency (n = 7) had similar IgA-RF and IgM-RF concentrations to healthy controls. Patients with serum IgA deficiency had no IgA-RF detectable in jejunal fluid but the highest IgM-RF concentrations, in particular in active disease. The coeliac patients had serum levels of IgA-RF and IgM-RF within the reference ranges. Jejunal fluid levels of IgA-RF and IgA-anti-gliadin antibodies were significantly correlated (P < 0.001). The data indicate that enhanced jejunal mucosal production of RF occurs above all in active coeliac disease. The findings suggest that the immune response to gluten induces a mucosal RF synthesis.

Relationship of interleukin-12 and interleukin-13 imbalance with class-specific rheumatoid factors and anticardiolipin antibodies in systemic lupus erythematosus.

The aim of the study was to evaluate whether the imbalance between IL-12 and IL-13 serum levels, reflecting Th1/Th2 activity, is related to class-specific circulating rheumatoid factors (RF) and anticardiolipin (aCL) antibodies in SLE. Using ELISA we measured serum IL-12, IL-13, RF and aCL antibodies in 73 SLE patients and 20 healthy controls. The determination of IL-12/IL-13 ratio showed that IL-12 levels were above (group A), equal to (group B) or below (group C) IL-13 levels in 71.2%, 15.1% and 13.7% of SLE patients, respectively. IgM-RF levels were significantly higher in group C than in groups A ( P < 0.002) and B ( P < 0.019). Group C had also higher IgM-aCL levels than group A ( P < 0.04). No relationship between IL-12/IL-13 ratio and clinical or other laboratory parameters was found. It was concluded that the increased levels of both IgM-RF and IgM-aCL in patients with prevalent Th2 activity suggest that the predominance of Th2 over Th1 could drive autoantibody production in SLE patients.

Class specific rheumatoid factors and antiphospholipid syndrome in systemic lupus erythematosus.

The relationship of rheumatoid factors (RF) with antiphospholipid syndrome (aPLS) and anticardiolipin antibodies (aCL) has rarely been investigated in systemic lupus erythematosus (SLE). We found IgM-RF, IgG-RF, IgA-RF, IgM-aCL, IgG-aCL, IgA-aCL, respectively, in 35.4%, 35.4%, 33.8%, 23.1%, 23.1%, 20.0% of 65 SLE patients. Class specific RFs were negatively associated (P<0.05) with IgG-aCL. The frequency of definite or probable aPLS according to Alarcon-Segovia classification criteria was significantly (P<0.05) different (8.7% vs 30.9%) in patients with or without IgG-RF. Among the other clinical features of SLE, we found that patients with IgG-RF, compared to patients lacking this autoantibody, showed a lower frequency (P<0.05) of serositis (21.7% vs 52.4%) and hematologic (52. 2% vs 80.9%) disorders. The levels of IgG-RF and IgM-RF negatively correlated with the number of ARA criteria (P<0.05) but not with the indices of diseases activity or damage. Our study shows that in SLE the presence of RFs are not markers of severity of the disease, but the negative association between IgG-RF and IgG-aCL suggests a distinct role of these autoantibodies in the pathology of SLE, whereas the presence of IgG isotype may identify a subset of SLE patients having a lower risk to develop some clinical manifestations such as aPLS.

Correlation of Serum IgA Rheumatoid Factor Levels with Disease Severity in Rheumatoid Arthritis

In the present study, the IgA rheumatoid factor (IgA RF) was assayed by ELISA in 114 sera of patients with active RA. IgA RF was found in the sera of 38 (33.3%) patients. A total of 56 disease variables were studied, differences in variables between IgA RF positive and negative patients were analyzed. The presence of IgA RF was found to be associated with a rapid progressive course, RA activity, onset of extra-articular manifestations (especially systemic rheumatoid vasculitis), high IgM RF titres, circulating immune complexes, cryoglobulins, and C-reactive protein levels. There was no statistically significant difference in serum IgA levels between IgA RF seropositive and seronegative patients. The presence of IgA RF showed a positive correlation with the level of IgM RF. The results of this study showed that the determination of IgA RF has a practical use in the establishment of the severe course of RA with systemic damages.

Quantitative Assessment of Clinical Disease Status in Primary Sjögren's Syndrome

Quantitative and qualitative assessment of the clinical disease manifestations in 41 primary Sjögren's syndrome (pSS) patients was performed according to a new classification model. Frequencies of subgrouped disease manifestations were as follows: 1) surface exocrine disease: 100%, 2) internal organ exocrine disease: 63%, 3) monoclonal B lymphocyte disease: 5%, 4) inflammatory vascular disease: 71%, 5) non-inflammatory vascular disease: 59%, 6) mediator induced disease: 98%. Summary scores for severity of surface exocrine disease correlated to the summary scores of all other disease manifestations (p = 0.02), to the summary scores of internal organ exocrine disease (p = 0.003), and to the summary scores of mediator induced disease (p = 0.03). Blood leucocyte counts showed significant negative correlations to levels of plasma IgG, serum IgA-RF, IgM-RF, anti-SSA/SSB antibodies, IL-6, and IL-lRa. We conclude that the model made detailed analysis of the clinical presentation of pSS possible, and thus may assist in elucidating important pathobiological aspect of the disease.

Inflammatory and immunological parameters of disease activity in rheumatoid arthritis patients treated with minocycline

The objective of this study was to analyze the anti-inflammatory effect of minocycline in rheumatoid arthritis. Serum samples of 65 RA patients who completed a 26-week randomized double-blind trial of minocycline (100 mg twice a day) versus placebo were studied. In this trial some clinical parameters and in particular the acute phase response decreased significantly in the minocycline-treated group. Serum levels of albumin and interleukin-6 (IL-6) were compared with CRP levels in order to study the acute phase response. Furthermore, rheumatoid factor (RF) and total immunoglobulin isotypes as well as serum levels of soluble interleukin-2 receptor (sIL2-2R) were determined in order to study immunological parameters of the disease. Immunoglobulins and cytokines were measured by ELISA. Serum levels of albumin remained stable, whereas serum CRP levels decreased both in the minocycline- and in the placebo-treated group. Serum levels of IL-6 decreased in the minocycline-treated group only and this decrease was positively correlated with the decrease in CRP levels. Minocycline significantly decreased serum IgM-RF, IgA-RF, total IgM and total IgA levels. In addition the ratio of IgM-RF/total IgM decreased in the minocycline-treated group. No such changes were observed in the placebo-treated group. The anti-inflammatory effect of minocycline in RA patients may be due to the reduction in the synthesis of IL-6 and rheumatoid factor.

The levels of memory (CD45RA-, RO+) CD4+ and CD8+ peripheral blood T-lymphocytes correlate with IgM rheumatoid factors in rheumatoid arthritis.

We investigated whether, in rheumatoid arthritis (RA), the CD45 isoform expression of peripheral blood T-lymphocytes (T-PBL) is related to auto-immune processes (e.g. IgM rheumatoid factors) and to clinical manifestations. By three-colour flow cytometry, we quantified three subsets of CD4+ or CD8+ T-PBL: "naive" CD45RA+,RO-, "transient" CD45RA+,RO+, and "memory" CD45RA-,RO+ cells, in 102 patients with RA and in 41 age- and sex-matched controls. The serum levels of rheumatoid factors (RF) were determined--besides conventional agglutination tests--by ELISA (IgM-RF). Extensive clinical examination was performed at the time of blood sampling. In RA, age, sex and drug therapy did not constitute major influences on the CD45RA/RO patterns. In "healthy" men, higher age significantly' correlated with fewer naive and more memory CD4+ T-PBL (P < 0.01). In RA, distinct correlations between the T-PBL subsets, autoimmune and clinical manifestations became obvious when patients with low and high levels of RF against human IgG Fc fragments, as determined by ELISA, were analysed separately. RA patients with high IgM-RF had elevated proportions of CD45RO+ T-PBL (P < 0.05), that correlated with clinical parameters of disease activity (tender joint count, Ritchie index, P < 0.05) and outcome (Health Assessment Questionnaire, Larsen radiographic scores, P < 0.05). The proportions of memory CD4+ and CD8+ T-PBL correlated strongly (P < 0.001) with the IgM-RF levels. Within 1 year, only three of 34 patients (disease duration of 5-9 years) showed seroconversion from low to high levels of IgM-RF (and positive agglutination tests); this was paralleled by reductions in naive and increases in transient T-PBL (P < 0.02). Thus, in RA, the proportions of memory CD4+ and CD8+ T-PBL correlate with the level of IgM-RF and, together with transient T-PBL, with clinical parameters of disease activity and outcome.

IgM, IgA, and IgG rheumatoid factors in early rheumatoid arthritis predictive of radiological progression?

The significance of IgM, IgA and IgG rheumatoid factors (RF) for the prediction of radiological progression, and as process variables during follow-up, was evaluated in a three-year prospective study of 149 patients with early rheumatoid arthritis (symptoms < 1 year at study entry). The occurrence of IgA-RF and IgG-RF at study entry without simultaneous occurrence of IgM-RF, and the seroconversion from RF-negative at entry to RF-positive during follow-up appeared to be unusual. A significant correlation was found between each of the RF-isotype levels at entry and radiological progression after three years. However, no significant prognostic value of IgA-RF and IgG-RF could be demonstrated if analysed in combination with IgM-RF, initial disease activity (as measured by C-reactive protein level), initial radiologic score, HLA-DR4 and HLA-DR2. Although IgM-RF levels generally reflected the course of disease activity and did so better than IgA-RF and IgG-RF levels, their clinical significance as process variables appeared to be limited compared to C-reactive protein.

Comparison of microheterogeneity of alpha-1-acid-glycoprotein in serum and synovial fluid from rheumatoid arthritis patients

Microheterogeneity of alpha-1-acid glycoprotein was studied using affinity immunoelectrophoresis with concanavalin A as a ligand in the samples of serum and synovial fluid obtained at the same time from 22 patients with rheumatoid arthritis. Individuals with intercurrent infection or other illnesses were excluded from the study. The results were expressed as reactivity coefficient (RC). Disease activity was evaluated by Mallya-Mace Activity Score, Lansbury Joint Index and laboratory tests. In most of the studied samples the glycosylation pattern was similar, composed of a nonreactive variant and 2 reactive (the first and the second) with Con A variants. In seven samples of synovial fluid an extra third peak representative of the strongly reactive one with Con A fraction was observed. It was the cause of the remarkable elevation of AGP-RC. Moreover, the level of IgM and IgA RF was higher in the synovial fluid derived from these patients--with the presence of the third peak in AFF-EP with Con A--than in those without the considered fraction.

Serum Concentration of Hyaluronan, IgM and IgA Rheumatoid Factors in a Population Based Study of Juvenile Chronic Arthritis

Increased serum levels of hyaluronan (HA) have been found in patients with liver diseases, psoriasis, malignancies as well as in rheumatoid arthritis and osteoarthritis. In the two latter groups serum HA levels may reflect the extent of synovial involvement and inflammation, rather than only unspecific information. This study was performed to elucidate the value of measuring HA in children with juvenile chronic arthritis (JCA) and to study its relation to class specific rheumatoid factors (IgM Rf and IgA Rf). HA was analysed in sera from 271 patients with JCA and 130 controls using a radiometric assay and IgM Rf and IgA Rf were analysed using an enzyme immunoassay. The results were analysed in relation to JCA subgroup, disease activity and functional outcome. In patients and controls higher levels of HA were found in young children than in older. Raised levels of HA and IgM Rf were mainly found in children with polyarticular disease. Impaired functional outcome was related to raised HA levels. No correlation was found between HA levels and IgM Rf or IgA Rf. Measurement of HA levels in JCA is of no diagnostic value because of low sensitivity. Quantification of HA may, however, have prognostic value in a subgroup of patients belonging to the polyarticular subgroup.

Associations of IgA and IgA-rheumatoid factor with disease features in patients with rheumatoid arthritis.

In previous studies we have shown that levels of IgM-rheumatoid factor (RF) in plasma and peripheral blood mononuclear cell supernatants are correlated with disease activity and response to second-line therapy in patients with rheumatoid arthritis (RA). The present studies were designed to examine whether IgA-RF levels are also correlated with clinical features of this disease. Two groups of RA patients were studied. Group I consisted of 87 patients in whom extensive clinical data had been collected. Group II included nine patients beginning treatment with gold or methotrexate who were studied during the first year of therapy. Measurement of IgM, IgA, IgM-RF and IgA-RF in culture supernatants and plasma was done by an ELISA method. These data were examined for correlations with clinical and laboratory features. Levels of IgA-RF in supernatants and plasma were found not to be correlated with disease features in the cross-sectional analysis of Group I patients, while IgM-RF and total IgA levels did show significant clinical correlation. Treatment of Group II patients with gold or methotrexate was associated with significant decreases in plasma levels of total IgA and IgM-RF as well as a small but statistically significant decrease in plasma IgA-RF. Plasma levels of total IgM were not altered during therapy. These findings suggest that production of IgA but not IgA-RF is correlated with disease status in patients with RA.

Lymphoproliferation in primary Sjögren's syndrome. Evidence of selective expansion of a B cell subset characterized by the expression of cross-reactive idiotypes.

To evaluate the possibility that lymphoproliferation in primary Sjögren's syndrome (SS) arises within a subset of B cells. A panel of monoclonal antibodies (MAb) specific for rheumatoid factor (RF)-associated cross-reactive idiotypes (CRI) and anti-V kappa and anti-VH subgroup antibodies were used to define the clonality of B lymphocytes undergoing neoplastic transformation in 5 patients with primary SS. Anti-CRI antibodies were also used to study longitudinal variations in serum paraprotein levels and in vitro regulation of IgM and IgM-RF production by peripheral blood lymphocytes. The levels of CRI, IgM, and IgM-RF were quantitated in serum and culture supernatants by enzyme-linked immunosorbent assay. Heavy and light chain isotypes and VH subgroups of the paraproteins were determined by immunoelectrophoresis, immunofixation, and Western blotting. Paraproteins from all patients expressed an epitope associated with V kappa IIIb sub-subgroup of light chains. Three of the paraproteins were cryoglobulins with RF activity, all of which expressed the V kappa IIIb-associated CRI (detected by MAb 17-109) and the VHI-associated CRI (detected by MAb G6 and G8). None of the paraproteins expressed the VHIII-associated CRI (detected by MAb B6 and D12). The CRI were consistently expressed over a period of 5-6 years. The anti-CRI and anti-subgroup antibodies substantially inhibited spontaneous production of IgM-RF and IgM by peripheral blood B lymphocytes from 3 of the SS patients. These results suggest that lymphoproliferation in primary SS is highly selective, and that the anti-CRI antibodies can be used as an aid to early diagnosis as well as for monitoring and modulating the lymphoproliferative process in primary SS.

One year treatment with low dose methotrexate in rheumatoid arthritis: Effect on class specific rheumatoid factors

We evaluated the effect of a one-year treatment of low dose methotrexate (MTX) on class specific rheumatoid factors in 27 patients with rheumatoid arthritis (RA). Enzyme-linked immunosorbent assay (ELISA) showed after 6 and 12 months a significant reduction of IgM-RF, IgA-RF and IgG-RF levels from the baseline values. During MTX treatment, changes of each RF isotype were not correlated with any other isotype and its corresponding immunoglobulin changes. Moreover, immunological changes were not related to the improvement of clinical parameters. Our results showed that low dose MTX can specifically affect levels of RF isotypes, which are involved in the immune pathogenesis of RA.

Serum rheumatoid factors in spinal cord injury patients.

The rheumatoid factor (RF) levels of IgM-RF and IgG-RF types in sera from patients with spinal cord injuries (SCI) and osteochondrosis were investigated by ELISA. According to the findings in the late stages of the disease, SCI patients showed 46% seropositiveness for IgG-RF and 40% for IgM-RF. Patients with fresh central nervous system (CNS) injuries were 12% and 14% seropositive, respectively. Patients with osteochondrosis exhibited 33% seropositiveness for IgG-RF. The determination of serum RF enables us to identify the systemic body lesion in the SCI late stages as a rheumatoid disease. These data support the conclusion that RF determination is a reliable serological indicator of the severity of a patient's traumatic disease.

Changes in levels of IgM RF and alpha 2 PAG correlate with increased disease activity in rheumatoid arthritis during the puerperium.

In this prospective study of 24 pregnant patients with rheumatoid arthritis, quiescent disease activity in 21 patients (88%) during gestation was followed by more active disease in the puerperium in 19 patients (79%). Increased disease activity was reflected in a deterioration in manual dexterity and this was found to correlate with a post-partum rise in IgM rheumatoid factor (IgM RF) (r = 0.86) and a post-partum decline in pregnancy associated alpha-2 glycoprotein (PAG) (r = 0.44). The increase in IgM RF also correlated with increased disease activity measured by a visual analogue scale (r = 0.44). Changes in IgA RF were not observed. These results suggest that PAG and IgM RF could contribute to the modulation and pathogenesis of rheumatoid arthritis during pregnancy.

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.