The functional affinity of IgM rheumatoid factor is related to the disease duration in patients with rheumatoid arthritis

OBJECTIVE—To determine the relevance of the functional affinity of IgM rheumatoid factor (RF) to the clinical and serological characteristics of patients with rheumatoid arthritis.
METHODS—The functional affinity of IgM RF of 57 seropositive rheumatoid arthritis patients was evaluated by an enzyme linked immunosorbent assay based on the use of a chaotropic agent. The inhibition index was taken as an estimate of functional affinity. The patient group was divided into high functional affinity subgroup 1 (functional affinity < 0.5, n = 37) and low functional affinity subgroup 2 (functional affinity > 0.5, n = 20). The medical records of all patients were reviewed with a particular note of the disease activity and the articular damage score.
RESULTS—The disease duration was shorter (P < 0.01) in subgroup 1 patients [7.9 (SD 6.4) years] than in subgroup 2 patients [13.4 (11.29) years], so that Ritchie's, Lee's, and Steinbrocker's indices were lower in the former than in the latter (P < 0.01, 0.001, and 0.01, respectively). In contrast, erythrocyte sedimentation rates, C reactive protein concentrations, antinuclear antibody, and HLA DR4 prevalences were similar in the two subgroups.
CONCLUSIONS—Different forms of RF are present during progression of the disease.

     

IgG and IgM rheumatoid factors in rheumatoid arthritis. Quantitative response to penicillamine therapy and relationship to disease activity

Penicillamine treatment of patients with rheumatoid arthritis (RA) leads to falling titers of agglutinating IgM rheumatoid factor (RF), but its effect on IgG RF has not been described. Using specific solid phase radioimmunoassays, we have determined serial levels of IgM RF and IgG RF in 18 patients receiving penicillamine for 1 year, and correlated the results with the change in RA activity. Mean IgM RF levels fell to 76 +/- 10% (mean +/- SEM) after 3 months, and 30 +/- 5% of the pretreatment value after 1 year of penicillamine treatment. This decline was greater than that for total IgM (P less than 0.0001), indicating a selective reduction of RF. Patients receiving maintenance doses of 750 mg/day manifested more rapid and greater decreases than did those given 250 mg/day. In contrast, serial mean IgG RF levels did not change significantly, and actually increased in 6 of 18 cases. At onset, there was a significant correlation with erythrocyte sedimentation rate for both IgM RF (r = 0.535, P = 0.05) and IgG RF levels (r = 0.570, P = 0.02). But changes in RF concentration demonstrated no correlation with changes in either erythrocyte sedimentation rate or joint score over the 1-year period, suggesting that circulating IgM RF or IgG RF levels may be unrelated to the degree of RA activity.     

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.     

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

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

Functional affinity of IgM rheumatoid factor in patients with rheumatoid arthritis and other autoimmune diseases.

The functional affinity of IgM rheumatoid factors (RF) was measured in 31 patients with rheumatoid arthritis (RA), 24 with systemic lupus erythematosus (SLE), 13 with Sjögren''s syndrome (SS), and in 13 seropositive healthy individuals. The functional affinity of IgM RF from patients with RA was significantly lower than in the other clinical groups studied. In addition, there was a significant inverse correlation between functional affinity and titre of IgM RF in all the groups. These results suggest that the usual mechanisms of affinity based selective pressure (somatic diversification and antigen selection) may operate differently for autoantibodies to serum antigens such as IgG.     

Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis

The diagnostic value of measuring rheumatoid factor (RF) by agglutination or isotype-specific enzyme-linked immunosorbent assay (ELISA) was compared. The study included 70 patients with rheumatoid arthritis (RA) and 205 patients with various other rheumatic conditions. Of the RA patients, 74% were RF-positive by agglutination and 90% had one or more RF isotypes elevated by ELISA compared to 14% and 22%, respectively, of the other patients. Strikingly, 70% of the RF-positive RA patients had an elevation of two or more RF isotypes compared to only 16% of the other RF-positive patients (P<0.0001). Furthermore, a combined elevation of IgM and IgA RF was found in 52% of the RF-positive RA patients, but only in two (4%) of the other RF-positive patients (P<0.0001). It is concluded that a combined elevation of IgM and IgA RF is highly specific for RA and is very rarely found in rheumatic diseases other than RA. Isotype-specific RF assays are therefore diagnostically superior to agglutination tests. The detection of the RA-specific RF isotype pattern may be particularly helpful early in the course of RA even before the disease is fully differentiated. Received: 10 December 1997 / Accepted: 25 June 1998     

Complement activation by 19S IgM rheumatoid factor: relationship to disease activity in rheumatoid arthritis

19S IgM rheumatoid factor (RF) in rheumatoid arthritis (RA) are polyclonal autoantibodies directed against the Fc piece of IgG. Rheumatoid patients with RF tend to have aggressive synovitis, nodules, and extraarticular manifestations. Although RF titer does not correlate with disease activity, RF activates complement (C) by the classical pathway. Thus, we postulated that selective stimulation of cell clones producing efficient C activating RF molecules might be associated with disease flares, independent of changes in serum RF concentration. To address the question, 42 patients with RA were evaluated prospectively. Serum RF concentration was measured by radioimmunoassay (RIA) and C activating activity by hemolytic assay. We then calculated the mean hemolysis (MH) of sensitized sheep erythrocytes (SRC) produced/ml of RF serum (MH/ml) and MH/microgram of RF as an expression of RF C activating properties (CAP). The following observations were made: RF CAP varied among the patients studied; RF CAP varied over time in individual patients; RF CAP differences varied in both groups independently from RF concentration; RF CAP correlated with both systemic and articular disease activity; and total RF concentration correlated with articular findings and nodules but less well with systemic disease activity.     

Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis

OBJECTIVE: To determine the radiologic outcome in juvenile rheumatoid arthritis (JRA) and the relationship of radiologically detected joint damage to functional disability using multivariate analyses. METHODS: Selection criteria included a diagnosis of JRA made by 1977 American College of Rheumatology criteria, onset of arthritis > or = 5 years prior to study, current age > or = 8 years, a minimum grade 3 reading ability, and the availability of radiographs. Disability was measured by the Childhood Health Assessment Questionnaire (CHAQ) and Steinbrocker classifications. Radiographs taken within 2 years after onset (early) and the most recent radiographs (late) were examined by a single pediatric radiologist blinded to patients' identities, diagnoses, and outcomes. Multiple regression analyses were performed. RESULTS: On late radiographs the frequencies of joint space narrowing were 38, 14, 43, and 79%, respectively, among patients with systemic, pauciarticular, rheumatoid factor (RF) negative polyarticular, and RF positive polyarticular onset; erosions occurred in 63, 25, 39, and 75%, respectively. Early erosions were most frequent in patients with RF+ polyarticular onset, while both joint space narrowing and erosions occurred early in systemic onset. Radiologic signs of joint damage were most frequent at hips and wrists, while knees and ankles were relatively spared. Based on patients who had radiographs performed within one year of clinical study, 17.7% of the variation in CHAQ score was explained by joint space narrowing, 32.4% by pain, and 5% by a severe rating on physician's global estimate of disease activity. The odds of a Steinbrocker class > I were increased by joint space narrowing, pain, systemic onset, and active joint count. CONCLUSION: Differences in the frequencies and patterns of joint damage occur both among JRA onset subtypes and among individual joints. Radiographic damage, especially joint space narrowing, correlates with functional disability. However, pain is the major contributor to variation in CHAQ scores.     

Comparative specificities of serum and synovial cell 19S IgM rheumatoid factors in rheumatoid arthritis

Rheumatoid factor (RF) may play a role in sustaining the inflammatory events and tissue damage in rheumatoid arthritis (RA). However, many serum RF have greater specificity for rabbit IgG than for human IgG, thus raising questions about RF pathogenicity in RA. Serum RF also has specificity for human IgG subclasses 1, 2 and 4, but not for IgG3. The synovium is central to the pathology of RA; thus, RF made there may have greater pathogenicity than serum RF. We examined the specificity of 19S IgM RF in an RF plaque forming cell assay (RF-PFC) using RA synovial cells (RSC). We found that: (1) RSC produced greater numbers of RF-PFC/10(6) cells than did RA peripheral blood mononuclear cells (PBM); (2) RSC RF-PFC had greater specificity for human than for rabbit IgG compared to autologous serum RF; (3) RSC RF had significantly greater specificity for human IgG3 relative to autologous serum RF. In contrast, RSC RF and autologous serum RF had the same relative specificities for polyclonal human IgG, IgG1, IgG2, and IgG4. Thus, the specificity of much of the RF synthesized by RSC differed from serum RF. The potential pathogenic significance of these observations is discussed.     

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.     

可溶性CD147与类风湿关节炎动脉粥样硬化危险因素的相关性

目的 通过研究类风湿关节炎(RA)患者外周血中可溶性CD147(sCD147)的表达水平及其与血脂水平相关性的分析,探讨sCD147在RA动脉粥样硬化中的作用.方法 采用双抗体夹心ELISA方法分别检测RA、动脉粥样硬化性心脏病(CAHD)患者各36例及30名健康人血清中sCD147含量;测定RA患者病情活动度(DAS28),分析sCD147水平与其病情活动度的相关性;使用全自动生化分析仪测定RA患者血脂水平,分析患者血清中sCD147与血脂水平的相关性.结果 RA患者血清中sCD147分子水平显著高于冠心病患者及健康对照,且病情高度活动RA组的sCD147含量显著高于病情低度及中度活动组(P均＜0.05).总胆固醇(TC)升高组及甘油三酯(TG)升高组RA患者的TC、TG水平与其血清中aCD147含量呈正相关(r=84,P＜0.05;r=0.87,P＜0.05),而TC轻度升高及正常组或TG正常组患者的TC、TG水平则与其血清中sCD147含量无相关性(r=0.41,P=0.21;r=0.14,P=0.57;r=0.49,P=0.87).低密度脂蛋白胆固醇(LDL-C)升高及轻度升高组患者的LDL-C水平与其血清中sCD147含量呈正相关(r=0.86,P＜0.05;r=0.81.P＜0.05),LDL-C正常组两者则无相关性(r=0.78,P=0.22.RA患者高密度脂蛋白胆同醇(HDL-C)降低与否和其血清中sCD147水平无相关性(r=0.04,P=0.96;r=0.13,P=0.87.结论 RA患者体内sCD147分子可能参与了RA的发病,且与病情活动度有关.同时,其sCD147水平的升高还可能与其血清中血脂的异常有关.     

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.     

The relationship between vitamin D and disease activity and functional health status in rheumatoid arthritis

We aimed to establish the relationship between serum vitamin D levels and disease activity and health status in rheumatoid arthritis. Sixty-five patients with RA fulfilling ACR criteria for the classification of rheumatoid arthritis and forty healthy controls were included in this study. Disease activity was assessed according to the Disease Activity Score including 28 joint counts. C-reactive protein (CRP, mg/dl) was determined by the nephelometric method. Erythrocyte sedimentation rate (ESR, mm/h) was determined by the Westergren method. Rheumatoid factor (RF, IU/ml) was also determined by the nephelometric method, and RF > 20 IU/ml was defined as positive. 25-OH Vitamin D EIA Kit was used to measure serum 25-OH Vitamin D levels. We found that the mean of the 25-OH D vitamin levels of the patients with RA was not different than that of controls (P = 0.936). We divided patients with RA into three groups according to DAS28 as low activity group (group 1, n = 25), moderate activity group (group 2, n = 25), and high activity group (group 3, n = 15). 25-OH vitamin D levels of the patients in the high activity group (group 3) were found to be the lowest (P < 0.001), and the patients with moderate disease activity had lower levels than those in the mild group (P = 0.033). Serum 25-OH vitamin D levels were significantly negatively correlated with DAS28, CRP, and HAQ (respectively, r = −0.431, P = 0.000, r = −0.276, P = 0.026, and r = −0.267, P = 0.031). Serum vitamin D levels in patients with RA were similar those in the healthy controls, while it significantly decreases in accordance with the disease activity and decreasing functional capacity.     

Anti-cyclic citrullinated peptide antibodies,IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis

OBJECTIVES: To evaluate the association of anti-cyclic citrullinated peptide (anti-CCP) antibodies with immunoglobulin (Ig) M and IgA rheumatoid factors (RF) in discriminating between rheumatoid arthritis (RA) and other rheumatic diseases, and to determine, in a longitudinal study, whether clinical signs of disease severity are associated with the presence of these autoantibodies at the time of patient inclusion. METHODS: The presence of these three markers was determined in 196 patients with established RA, 239 non-RA controls with various rheumatic diseases (cross-sectional study) and in 27 patients with arthritis of less than 1 yr disease duration who were subsequently followed during about 8 yr (longitudinal study). At the time of follow-up, 21 of these 27 patients had RA. They were further evaluated and several clinical variables were recorded. RESULTS: The specificity was significantly increased (from 82-90% to 98% in the cross-sectional study) when the combination of anti-CCP antibodies with IgA RF or the combination of the three serological markers was used. An association was observed between the presence of the three autoantibodies and clinical signs of disease severity (functional disability, presence of erosions and absence of clinical remission). CONCLUSIONS: The presence either of anti-CCP antibodies and IgA RF or of the three markers appears to be useful in the diagnosis of RA. Their association with clinical signs of disease severity at the time of patient inclusion suggests their potential usefulness as markers for prognosis.     

IgE and IgE-rheumatoid factors in circulating immune complexes in rheumatoid arthritis.

The sera of 21 patients with rheumatoid arthritis (RA), 11 patients with systemic lupus erythematosus (SLE), and 20 healthy subjects were analysed for the presence of IgE in immune complex fractions. These fractions were isolated by polyethylene glycol precipitation and gel filtration. Thirteen sera from RA patients contained IgE immune complexes (IC) and 11 of these were from patients with extra-articular manifestations. One SLE and none of the control sera contained such material. The serum IgE level did not correlate with IgE content of the IC fractions. Higher mean serum IgE levels were found in RA patients with extra-articular complications than in controls or RA patients with joint disease only, but the differences did not reach statistical significance. IgE anti-rabbit IgG (IgE rheumatoid factors) could be demonstrated in some IgE positive IC fractions. Antibodies to IgE, in 2 instances characterised as belonging to IgG class, were also found in ICs. This suggests the presence of anti IgE complexes. It is suggested that IgE, including some with rheumatoid factor activity, is contained in complexes which may be involved in some extra-articular manifestations of RA.     

Tiopronine-induced reduction of rheumatoid factor functional affinity and asialylated IgG in patients with rheumatoid arthritis.

Serum and synovial fluid (SF) from 16 rheumatoid arthritis patients were evaluated before and after a 2-month treatment with tiopronine (TP). The levels of rheumatoid factor (RF) declined, as did the functional affinity of the remaining RF (p less than 0.01 in serum and p less than 0.05 in SF). Concomitant restoration of the sialylation of IgG was observed (p less than 0.05 in serum and SF). Following an initial increase, a significant reduction was observed in the level of soluble interleukin-2 receptors in serum (p less than 0.05) and SF (p less than 0.05) after treatment with TP.