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.     

用受试者工作曲线评价抗环瓜氨酸肽抗体对诊断类风湿关节炎的价值

目的评价抗环瓜氨酸肽抗体(抗CCP抗体)在类风湿关节炎(RA)诊断中的价值。方法收集110例RA患者,与38例其他疾病患者以及36名正常人作为对照,应用受试者工作曲线(re-ceiveroperativecharacteristiccurve,ROC)分析软件评价抗CCP抗体在RA诊断中的价值,在ROC曲线上制定抗CCP抗体与类风湿因子(RF)各亚型在诊断RA中的最佳临界点。用四格表计算系列试验的特异度,进行统计学检验。用SPSS软件比较抗CCP抗体与RF各亚型之间的相关性。结果在诊断RA中,抗CCP抗体的ROC曲线下的面积(AUCROC)明显大于RF(IgA、IgM、IgG)AUCROC(P<0.01),抗CCP抗体联合任何一个RF亚型的系列试验的特异度高达100%。抗CCP抗体和RF(IgA、IgM、IgG)经Spearman相关分析,呈正相关。结论抗CCP抗体对RA有较高的诊断价值;诊断RA的系列试验中,含抗CCP抗体的系列试验的特异度高。     

Absence of cyclic citrullinated peptide antibody in nonarthritic patients with chronic hepatitis C infection

OBJECTIVE: The increased prevalence of rheumatoid factor (RF) in patients with chronic hepatitis C virus (HCV) infection markedly diminishes the diagnostic specificity of serum rheumatoid factor (RF) for rheumatoid arthritis (RA) in patients with HCV. Cyclic citrullinated peptide (CCP) antibody, a highly specific biomarker for RA in the general population, may have better diagnostic utility for RA in the HCV population. To investigate if CCP antibody retains its specificity for RA in HCV infection, we determined the prevalence of CCP antibodies and examined the relationship between RF production and CCP antibody levels in a population of nonarthritic patients with chronic HCV infection. METHODS: CCP antibody and IgM, IgG, and IgA RF isotypes were determined by ELISA in serum from nonarthritic patients with chronic HCV infection. RESULTS: In a series of 50 HCV patients, IgG-RF, IgM-RF, and IgA-RF were detectable in 52%, 26%, and 14%, respectively, with a total seropositivity rate of 54%. Marginally elevated CCP antibody was detected in a single patient (2%). By regression analysis, serum levels of CCP antibodies did not correlate with RF levels. CONCLUSION: In contrast to RF, CCP antibody is not increased in HCV infection. CCP antibody may have improved utility for the diagnosis of RA in this patient population.     

Levels of Rheumatoid Factor Isotypes, Metalloproteinase-3 and Tissue Inhibitor of Metalloproteinase-1 in Synovial Fluid from Various Arthritides

When synovial effusion is the only symptom, it is often difficult to make an exact diagnosis of the arthritic disease. To distinguish various types of arthritis with synovial effusion, we measured the levels of matrix metalloproteinase-3 (MMP-3, Stromelysin), tissue inhibitor of metalloproteinase-1 (TIMP-1) and rheumatoid factor (RF) isotypes in synovial fluid (SF) from patients with rheumatoid arthritis (RA), osteoarthritis (OA), pyogenic arthritis (PA), pseudogouty arthritis (PG), gouty arthritis (GA) and traumatic arthritis (TA). SF was aspirated from the knee joint or the ankle joint. Levels of IgG-, IgM- and IgA-RF isotypes were measured by ELISA. Levels of MMP-3 and TIMP-1 in SF were simultaneously determined by a one-step EIA system. Levels of IgG-RF, IgM-RF and MMP-3 in SF from RA patients were significantly higher than those in OA, PA, PG, GA and TA. However, IgA-RF in SF from RA patients, when compared with PA and GA, did not show a significantly increased level. In addition, TIMP-1 in SF from RA, when compared with PA and TA, also has not shown a significantly increased level. Therefore, in addition to analysing clinical data, measurements of IgG-RF, IgM-RF and MMP-3 in SF may contribute in distinguishing RA from other arthritic diseases. Received: 18 January 1999 / Accepted: 15 June 1999     

Rheumatoid factor isotypes in mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a connective tissue disorder that is often accompanied by various immunological abnormalities. In this study, we analyzed serum levels of rheumatoid factor (RF) isotypes in patients with MCTD and in normal controls to determine if any of these isotypes reflects the severity of the disease. IgM-RF, IgG-RF, and IgA-RF were positive in 48, 38, and 33% of the patients, respectively. The frequency of positive anti-SS-A antibody and decrease in white blood cell counts were significantly greater in patients with elevated IgA-RF levels than that in those with normal levels. These results suggest that the presence of RF isotypes can be regarded as one of the various immunological abnormalities of MCTD.     

Felty''s syndrome associated with high levels of IgA rheumatoid factor.

A 64-year-old woman with rheumatoid arthritis developed Felty's syndrome. Her serum contained large amounts of IgA rheumatoid factor (RF) but insignificant levels of IgM-RF and IgG-RF. It is postulated that the high levels of IgA-RF may have contributed to the neutropenia.     

IgA rheumatoid factor synthesis by dissociated synovial cells. Characterization and relationship to IgM rheumatoid factor synthesis

We examined patterns of IgA rheumatoid factor (RF) and IgM-RF synthesis by dissociated synovial cells obtained from 27 patients with seropositive rheumatoid arthritis. Synthesis of IgA-RF was observed in 19 of 34 synovial cell preparations from these patients and constituted a mean of 16% of the total IgA produced. IgA-RF expression correlated only weakly with IgM-RF production (r = 0.385) and could be dissociated from production of IgA-RF (and IgM-RF) exhibited by simultaneously obtained peripheral blood plasma cells. While wide variations were observed in the ratio of IgA-RF:IgM-RF produced by synovial B cells in the patient sample studied, remarkable consistency in the relationship of IgA-RF to IgM-RF synthesis was observed over time in different joints of the same patient. IgA-RF synthesized by dissociated synovial cells was predominantly of the IgA1 subclass and existed in both monomeric and polymeric forms. Our results are compatible with the view that local production of IgA-RF and IgM-RF are regulated independently of each other.     

Diagnostic impact of contemporary biomarker assays for rheumatoid arthritis

OBJECTIVE: The impetus towards early treatment for patients with rheumatoid arthritis (RA) requires more reliable disease markers than the non-specific immunoglobulin M (IgM) rheumatoid factor (RF). To determine the accuracy of newer biomarkers for RA testing for antibody against cyclic citrullinated peptides (anti-CCP Ab), IgA- and IgG-RF and cartilage oligomeric matrix protein (COMP) levels, measured by enzyme-linked immunosorbent assay (ELISA), were compared with IgM-RF isotyping. METHODS: Serum samples were investigated in patients with an established diagnosis of RA (n = 54), ankylosing spondylitis (AS) (n = 36), and non-inflammatory conditions (n = 18) (cohort A), and in 234 consecutive outpatients in a blinded fashion (cohort B). Non-parametric analysis of areas under the curve (AUC) of receiver operator characteristics were performed. RESULTS: The presence of anti-CCP Ab had the highest accuracy (96%) in distinguishing RA patients in cohort A and cohort B (accuracy 83%), and in both cohorts combined (accuracy 87%). This was related to the high specificity of anti-CCP Ab for RA (95-96%), even though IgM-RF was the most sensitive test (87-96%). Sensitivity (15-48%) and specificity (66-69%) of COMP as a marker for RA was low. Combining results of anti-CCP Ab and IgM-RF or any of the other assays did not increase the diagnostic accuracy for RA. CONCLUSION: The presence of anti-CCP Ab is the most accurate biomarker for RA in both selected and unselected cohorts, while the COMP assay is not very useful in RA diagnosis. Combining assays for anti-CCP Ab and IgM-RF or IgA-RF does not enhance RA diagnosis.     

IgM,IgA and IgG rheumatoid factors in patients with rheumatoid arthritis and normal donors

Summary IgM, IgA, and IgG Rheumatoid Factors (RF) were measured by ELISA assay in serum from 26 patients with definite rheumatoid arthritis (RA) and 11 normal controls. IgM-RF was assayed by ELISA, radioimmunoassay,and also by the standard latex fixation test in all sera from RA patients. In patients with RA quantitative amounts of IgM, IgA, and IgG-RF as estimated by ELISA were highly correlated. Significant correlations were found between a physician's rating of disease activity and IgG-RF (r=0.44; p<.02) and IgA-RF (r=0.38; p=.06 but not for IgM-RF as measured in any of the three assays.During the course of this work F.S. was supported by a NATO fellowship from the Consiglio Nazionale delle Ricerche, Roma, Italy.     

IgG and IgM rheumatoid factor synthesis in rheumatoid synovial membrane cell cultures

The detection of rheumatoid factors (RFs) in synovial membranes and fluids of patients with rheumatoid arthritis (RA) has suggested that local production of these antiimmunoglobulin autoantibodies may have a role in the pathogenesis of synovitis. To quantitate RF synthesis in the rheumatoid synovial membrane, 12 synovial specimens were obtained from patients with seropositive RA, 5 from patients with seronegative RA, and 6 from patients with other arthritides. Single cell suspensions were cultured, and supernatants were analyzed for IgG, IgM, IgG-RF, and IgM-RF by solid-phase radioimmunoassays. IgM-RF was detected in all of the 12 seropositive culture supernatants, and IgG-RF was detected in 8 of the 12. Addition of cycloheximide to the cultures resulted in a greater than or equal to 40% decreased in the amount of IgM-RF. A similar decrease in IgG-RF occurred in the 4 cultures in which the largest amounts of IgG-RF were detected. IgM-RF synthesis represented 7.3 +/- 0.7% (mean +/- SEM) of the total IgM produced, and IgG-RF represented 2.6 +/- 1.1% (mean +/- SEM) of the IgG synthesized in those cultures with detectable IgG-RF. Cultures of synovial membrane cells (SMC) from seronegative RA patients or patients with other arthritides did not contain detectable amounts of IgM-RF or IgG-RF. Selective synthesis of RF by seropositive synovium was suggested by the observation that the fractions of synthesized IgM with RF activity were greater in the SMC supernatants than in paired sera in all cases, and the fractions of IgG with RF activity were greater in the SMC supernatants of 3 of the 4 cases in which substantial amounts of IgG-RF were produced. Comparison of the percentages of newly synthesized IgM with RF activity in paired cultures of SMC and peripheral blood mononuclear cells similarly indicated selective synthesis of IgM-RF by the synovium. These results demonstrate active and selective synthesis of both IgG-RF and IgM-RF by seropositive SMC. However, RFs account for only a minor fraction of the total Ig produced.     

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.     

The occurrence of rheumatoid factor isotypes in early definite rheumatoid arthritis--no relationship with erosions or disease activity

Seventy-one patients with definite rheumatoid arthritis and disease duration less than 2 years were followed prospectively. At study entry 43 patients had IgG rheumatoid factor (RF), 59, IgA-RF and 64, IgM-RF as measured with an ELISA; 48 were Waaler-Rose positive. After 2 years, joint erosions were present in 51 patients and absent in 19. One patient has not been followed long enough. The calculated relative risks contributed by different RF to the presence of erosions were low. No significant correlations between markers of disease activity and RF levels initially were found. The clinical value of RF isotype determination seems limited.     

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

Summary 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 IgF-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.     

Rheumatoid factor and antibodies to cyclic citrullinated Peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis

OBJECTIVE: To study the diagnostic value of IgM rheumatoid factor (RF), IgA-RF, antibodies to cyclic citrullinated peptide (anti-CCP), and combinations of these antibodies, measured at baseline, to discriminate rheumatoid arthritis (RA) from undifferentiated polyarthritis (uPA) in patients with recent onset arthritis. METHODS: Patients with early arthritis with peripheral arthritis of 2 or more joints and symptom duration less than 3 years were clinically diagnosed as having RA or uPA by an experienced rheumatologist during the first year. Patients with bacterial, psoriatic, or crystal induced arthritis or spondyloarthropathy were excluded. Optimal cutoff values for serum IgM RF, IgA RF, and anti-CCP were deduced from receiver operating characteristics curves in order to predict the diagnosis of RA in early arthritis. RESULTS: A total of 379 patients (69% female, median age 57 yrs, range 17-86 yrs) were studied; 258 patients were clinically diagnosed as RA and 121 as uPA. Both IgM-RF > 40 IU/ml and anti-CCP > 50 AU/ml showed high specificity, but the sensitivity of these tests was low. In many RA patients the occurrence of IgM-RF and anti-CCP antibodies was independent. Thus the optimal criterion proved to be the combination of IgM-RF > 40 or anti-CCP > 50, which yielded sensitivity of 55.4% and specificity of 96.7%. CONCLUSION: The criterion IgM-RF > 40 or anti-CCP > 50 is able to predict the diagnosis of RA in early arthritis patients with high specificity and acceptable sensitivity. Anti-CCP testing combined with IgM-RF testing has additional value over IgM-RF testing alone in patients with early undifferentiated oligo and polyarthritis.     

The prevalence of rheumatoid factor isotypes and anti-cyclic citrullinated peptides in Malaysian rheumatoid arthritis patients

Aim: The purpose of this study is to compare the prevalence of rheumatoid factor (RF) isotypes and second generation anti‐cyclic citrullinated peptides (anti‐CCP) in Malaysian rheumatoid arthritis (RA) patients. Methods: In this cross‐sectional study, 147 established RA patients from three ethnic groups were recruited from a major rheumatology clinic in Malaysia. Enzyme‐linked immunosorbent assays (ELISA) for serum RF isotypes IgA, IgG and IgM as well as second‐generation anti‐CCP were performed and the prevalence of each auto‐antibody was compared in the three ethnic groups. Results: The anti‐CCP was the most prevalent auto‐antibody in each of the ethnic groups, followed closely by RF IgM and RF IgG. Rheumatoid factor IgA was the least prevalent across all three ethnic groups. The anti‐CCP–RF IgM combination provided the best test sensitivity. Seroprevalence of anti‐CCP was strongly associated with the presence of each of the RF isotypes. The seroprevalence of RF and anti‐CCP did not increase or decrease with advancing age, age at onset and disease duration. Conclusion: When used alone, anti‐CCP provides a diagnostic advantage over RF IgM on the basis of test sensitivity. Considering the high cost of the anti‐CCP assay, step‐wise serum testing with IgM RF followed by anti‐CCP may provide a more economically sensible option to optimize test sensitivity for RA.     

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)     

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.     

Rheumatoid factor isotypes and circulating immune complexes in rheumatoid arthritis

Solid phase enzyme immunoassays were here used to quantify rheumatoid factors (RF) of the IgM, IgG and IgA classes and the immune complexes (IK) by their ability to bind to C1q or conglutinin in both the serum and synovial fluid of patients with rheumatoid arthritis (RA). Elevated serum levels of any RF isotype could be found in all patients with seropositive RA (IgM: 63%, IgG: 87%, IgA: 90%). Seronegative patients with RA presented to a significantly lesser extent with elevated levels of all the RF isotypes tested (IgM: 0%, IgG: 40%, IgA: 32%). Synovial fluid RF levels were significantly higher in SPRA patients than in SNRA patients with the exception of IgG-RF. All of the RF classes in both RA groups, however, were elevated when compared to RF in the synovial fluid of patients with osteoarthrosis. Both C1q binding and conglutinin binding immune complexes were significantly higher in the synovial fluid than in the serum of RA patients. The erythrocyte sedimentation rate and plasma iron levels were correlated with the levels of C1q binding immune complexes (IC) in the synovial fluid; total iron binding capacity showed an inverse relationship to synovial fluid IgG-RF levels. A radiographic index was also correlated with IgG-RF levels in the synovial fluid. Extraarticular manifestations were significantly more frequent in patients with elevated serum levels of IgM-RF or conglutinin binding IC. These findings indicate that IgG-RF in the synovial fluid and the formation of IC determined by their ability to bind C1q seem to be closely related to clinical features of local disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis

OBJECTIVE: To study the effect of tobacco smoking and rheumatoid factor (RF) isotypes on disease activity and joint damage in early rheumatoid arthritis (RA). METHODS: One hundred early RA patients were followed prospectively for 2 yr. They were evaluated at recruitment and at 6 and 24 months. Sociodemographic information included smoking history, and radiographs of hands and feet were obtained. RF was monitored by IgM- and IgA-specific RF enzyme-linked immunosorbent assay and by agglutination, and serial measurements were also obtained for C-reactive protein. The influence of tobacco smoking and RF positivity on disease outcome was evaluated using multivariate analysis. Covariates for the regression analysis included sex, age, coffee consumption and IgA-RF positivity. RESULTS: A gradient of increase in disease activity was observed from never smokers to former smokers to current smokers during the 2 yr of observation, defined by number of swollen joints (SJC), tender joints (TJC) and visual analogue scale for pain (P<0.001, P=0.02 and P=0.005, respectively), but smoking status did not influence radiological progression. Ever smokers were more often IgA RF positive (P<0.05). IgA RF-positive patients had more active disease (SJC P=0.002, TJC P=0.01) and showed more radiological progression (P<0.0001) compared with IgA RF-negative patients. Of the RF-positive patients 22% had elevated IgM RF without IgA RF and these patients showed similar disease activity and radiological joint progression to the RF-negative patients. None of these associations were explained by possible confounders. CONCLUSION: Tobacco smoking has an adverse effect on patients with early RA and this is possibly immunologically mediated. IgM RF does not predict poorer prognosis in RA unless it is associated with a concomitant elevation of IgA RF.