New diagnostic tests for rheumatoid arthritis

Rheumatoid factor(RF) is one item in the classification criteria for rheumatoid arthritis(RA), with a tolerable sensitivity of 69.3% for RA but low specificity against other rheumatic diseases(76.4%). Anti-agalactosyl IgG antibody(CARF) showed a slightly higher sensitivity(72.0%) but the specificity was even lower(67.9%). Anti-cyclic citrullinated peptide antibody(anti-CCP), a new diagnostic test for RA, demonstrated higher sensitivity(76.0%) and specificity(91.5%), and the ROC analysis revealed the marked superiority of anti-CCP to other markers(i.e. RF, CARF, and IgG-RF). Matrix metalloproteinase-3 (MMP-3) showed a significantly positive correlation with CRP, suggesting it might be more useful for evaluation of RA activity and prediction of the prognosis of joint destruction. On the contrary, two combination assays, "MMP-3 or CARF" and "MMP-3 or anti-CCP", showed the highest sensitivity(86.7%) for RA. Similarly, in early RA the sensitivities of CARF, MMP-3 and anti-CCP were lower than in RA(66.7%, 66.7% and 58.3%, respectively), but the sensitivities of combination assays "MMP-3 or CARF" and "MMP-3 or anti-CCP" were 91.7% and 83.3%, respectively. Thus, we concluded that these combination assays are useful in the diagnosis of RA and detection of early RA.     

New biomarkers for rheumatoid arthritis

Rheumatoid factor (RF) has been commonly used as a biomarker of rheumatoid arthritis (RA). It is important to diagnose RA early and to prevent joint destruction before irreversible damage occurs. For this purpose, several new biomarkers, such as anti-cyclic citrullinated peptide antibody (anti-CCP) and matrix metalloproteinase-3 (MMP-3), have become available for both the diagnosis and prognosis of RA. RF showed a tolerable sensitivity of 68.5% for RA, but low specificity of 77.1% for patients with other rheumatic diseases. Anti-agalactosyl IgG antibodies (CARF) showed a slightly higher sensitivity of 73.9%, but specificity as low as that for RF. In contrast, anti-CCP demonstrated high sensitivity of 76.1% and marked specificity of 92.4% for patients with other rheumatic diseases. Anti-CCP was significantly superior to other biomarkers on receiver-operating characteristic curve (ROC) analysis. Moreover, meta-analysis revealed that the pooled sensitivity and specificity were 67% and 95% for anti-CCP, and 69% and 85% for RF, respectively, and that anti-CCP was more specific than RF for diagnosing RA. On the other hand, MMP-3 has been suggested to be a prognostic biomarker as well as an evaluative biomarker for RA. We next examined if the diagnostic accuracy of early RA is improved by combining these biomarkers. The specificity of RF was not as high as anti-CCP but rose to 92% when combined with MMP-3. Thus, we concluded that anti-CCP is superior to other biomarkers in terms of diagnostic accuracy, and that these combined assays are useful in the early diagnosis of RA.     

Topics on immunological tests for rheumatoid arthritis

To prevent joint destruction, it is important to diagnose RA early and to speculate the prognosis. Several new laboratory tests have been developed for this purpose. In addition to rheumatoid factor (RF), IgG-RF, anti-agalactosyl IgG antibodies (CARF), and matrix metalloproteinase 3 (MMP-3) have become available as diagnostic tests for RA. Among them, anti-cyclic citrullinated peptide antibodies (anti-CCP antibodies) have the sensitivity and specificity of 81.0% and 92.4%, respectively, which are superior to other laboratory tests by ROC analysis. Moreover, the specificity of anti-CCP antibodies to diagnose early RA was much higher than that of RF, although the sensitivity of CARF was slightly high compared with that of RF. In contrast, MMP-3 is thought to be an evaluative test for the activity of RA because a significant correlation was found between MMP-3 and CRP, but MMP-3 has a possibility as a prognostic test to know the joint damage of RA. We have shown that the progression of joint damage (Sharp score) was faster in MMP-3-positive patients than negative patients. Anti-CCP antibodies was also reported to associate with the progression of joint damage and may be used also as a prognostic test. We next examined how efficiently was the diagnosis of RA made by combining these laboratory tests. Although anti-CCP antibodies are highly specific to RA, the specificity of RF was not so high but became up to 92% when combined with MMP-3. In order to diagnose RA efficiently, we may firstly examine RF, next MMP-3 if RF is positive, and anti-CCP antibodies if RF is negative.     

Usefulness of anti-cyclic citrullinated peptide antibodies (anti-CCP) for the diagnosis of rheumatoid arthritis

Rheumatoid factor (RF) has been commonly used as a marker of rheumatoid arthritis (RA). RF can be detected in 60-80% of RA patients, but the specificity is low against other rheumatic diseases patients. We evaluated the diagnostic accuracy of anti-cyclic citrullinated peptide antibody (anti-CCP), a new diagnostic test for RA. Anti-CCP demonstrated higher sensitivity (81.0%) and specificity (92.4%). By the receiver operating characteristic (ROC) curve analysis, anti-CCP was superior to other markers (ie. RF, CARF, IgG-RF, and MMP-3). In early RA patients (RA patients who had had disease symptoms for < 2 years), sensitivity was 68.8%. Positivities of anti-CCP in RA patients became higher as the advance of stage defined by the Steinbrocker classification. We concluded that anti-CCP is a very valuable tool for the diagnosis of RA. Moreover, anti-CCP is a useful for finding RA of recent onset.     

The diagnostic utility of anti-cyclic citrullinated peptide antibodies, matrix metalloproteinase-3, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein in patients with erosive and non-erosive rheumatoid arthritis

OBJECTIVE: To compare the diagnostic utility of laboratory variables, including matrix metalloproteinase-3 (MMP-3), anticyclic citrullinated peptide (CCP) antibodies, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in patients with erosive and non-erosive rheumatoid arthritis (RA). METHODS: We assembled a training set, consisting of 60 patients with RA, all fulfilling the revised criteria of the American College of Rheumatology. A commercial enzyme linked immunosorbent assay (ELISA) was used both to test for anti-CCP antibodies (second generation ELISA kit) and MMP; RF were detected by latex-enhanced immunonephelometric assay. CRP was measured by latex turbidimetric immunoassay. RESULTS: The levels of anti-CCP antibody titers and ESR were significantly higher in patients with erosive disease than those in non-erosive RA patients (p < 0.001 and 0.0341) respectively. Moreover, a higher frequency of elevated titers of anti-CCP antibodies was found in RA patients with erosions compared to patients with non-erosive RA (78.3% vs. 43.2% respectively). The ROC curves of anti-CCP passed closer to the upper left corner than those other markers and area under the curve (AUC) of anti-CCP was significantly larger than AUC of other markers (0.755 for anti-CCP, 0.660 for ESR, 0.611 for CRP, 0.577 for RF, and 0.484 for MMP-3 female). A positive predictive value was higher for anti-CCP antibodies in comparison to other markers. We did not find significant statistical correlation between anti-CCP antibody titers and inflammatory markers such as ESR or CRP. However, we confirmed the correlation of elevated titers of anti-CCP antibodies and RF in both groups of patients whereas the degree of correlation was more significant in non-erosive patients. CONCLUSION: The results of our study suggest that the presence of elevated anti-CCP antibody titers have better diagnostic performance than MMP-3, RF, CRP and ESR in patients with erosive RA.     

Rheumatoid factor is a marker of disease severity in Korean rheumatoid arthritis

Serum rheumatoid factor (RF) is important in the diagnosis and prognosis of rheumatoid arthritis (RA). The purpose of this study is to compare the clinical characteristics and treatment patterns of RA according to the presence of RF in Korean patients. A retrospective analysis was performed on the records of 109 patients who were followed for at least 2 years, among 230 RA patients who visited at the rheumatology clinic in Ajou University Hospital and who fulfilled the 1987 revised American College of Rheumatology criteria for RA. Sixty-four patients were RF positive (58.7%) and 91 patients were female (83.5%). There was no significant difference in demographic characteristics, joint involvements, or percentage of morning stiffness between seropositive and seronegative groups. Antinuclear antibody was detected more frequently in the seropositive group (p < 0.05). At initial diagnosis, the seropositive group had higher white blood cell and platelet counts than the seronegative group (p < 0.01). However, the difference was disappeared at the last follow-up. Inflammatory markers such as ESR and CRP were also higher at diagnosis in the seropositive group (p < 0.01). These inflammatory markers were still greater than the seronegative group at the last follow-up (p < 0.01). There was no significant difference in the use of disease modifying antirheumatic drug (DMARD) and steroid dosage between groups. However, DMARD combination therapy was more commonly used in the seropositive group (p < 0.05), especially triple DMARD combination. These results suggest that disease activity is more severe in the seropositive than the seronegative group, and more aggressive treatments are needed in the seropositive group.     

Novel autoantibody markers for early and seronegative rheumatoid arthritis

Approximately one-third of rheumatoid arthritis (RA) patients are seronegative for the 2 serological RA markers, rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (ACCP). Moreover, the sensitivities of both markers are lower in the diagnostically important early disease phase. The aim of this study was to identify additional autoantibody markers for early RA and for RF-negative, ACCP-negative (seronegative) RA.We screened an RA synovium cDNA phage display library with autoantibodies in plasma from 10 early (symptoms of maximum 1 year) and 10 seronegative (RF-negative, ACCP-negative) RA patients with validation in 72 additional RA patients and 121 controls (38 healthy controls, 43 patients with other inflammatory rheumatic diseases, 20 osteoarthritis patients and 20 subjects with mechanical joint complaints). Fourteen novel autoantibodies were identified that showed a 54% sensitivity and 90% specificity for RA. For 11 of these autoantibodies, an exclusive presence was demonstrated in RA patients (100% specificity, 37% sensitivity) as compared to controls. All early RA patients were positive for at least one of the identified autoantibodies and antibody-positivity was associated with a shorter disease duration (P = 0.0087). 52% of RA patients who initially tested negative for RF and ACCP, tested positive for at least one of the 14 novel autoantibodies, resulting in a 19% increase in sensitivity compared to current serological testing. Moreover, 5 identified autoantibodies were detected more frequently in seronegative RA patients, indicating that these autoantibodies constitute novel candidate markers for this RA subtype. We demonstrated that the targets of 3 of these 5 autoantibodies had an increased expression in RA synovial tissue compared to control synovial tissue, pointing towards a biological rationale for these auto antibody targets in RA.In conclusion, we identified novel candidate autoantibody markers for RA that can be detected in early and seronegative RA patients indicating the potential added value for RA diagnostics.     

New diagnostic and evaluative tests for rheumatoid arthritis

To prevent joint destruction, it is important to diagnose RA early and to consider the prognosis. For this purpose, several new laboratory tests, such as IgG-RF, anti-agalactosyl IgG antibodies (CARF), and matrix metalloproteinase-3 (MMP-3), have become available for diagnosing RA. RF has a tolerable sensitivity of 68.5% for RA, but low specificity of 77.1%, and also 76.0% for patients with other rheumatic diseases and chronic inflammatory disease, respectively. CARF showed slightly higher sensitivity but low specificity for other rheumatic diseases and chronic inflammatory patients. In contrast, anti-cyclic citrullinated peptide antibody (anti-CCP), a new diagnostic test for RA, demonstrated significantly high specificity for other rheumatic diseases, and also for chronic inflammatory disease patients. Anti-CCP was superior to other laboratory tests by ROC analysis. Moreover, both CARF and anti-CCP had higher sensitivity of 66.7%, 61.5%, respectively, for the diagnosis of early RA than RF. On the other hand, MMP-3 is thought to be not only an evaluative test for the activity of RA because of its significant correlation with CRP, but also has potential as a prognostic test to identify joint damage from RA. Anti-CCP was also reported to associate with the progression of joint damage and may be also used as a prognostic test. We next examined the efficiency of RA diagnosis made by combining these laboratory tests. The specificity of RF was not as high as anti-CCP but reached 92% when combined with MMP-3. Thus, it is concluded that anti-CCP is superior to other laboratory tests in sensitivity and specificity, and that these combination assays are useful in the early diagnosis of RA.     

Diagnostic performances of anti-cyclic citrullinated peptides antibody and antifilaggrin antibody in Korean patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown etiology. We studied the diagnostic performances of anti-cyclic citrullinated peptides antibody (anti-CCP) assay and recombinant anti-citrullinated filaggrin antibody (AFA) assay by enzyme linked immunosorbent assay (ELISA) in patients with RA in Korea. Diagnostic performances of the anti-CCP assay and AFA assay were compared with that of rheumatoid factor (RF) latex fixation test. RF, anti-CCP, and AFA assays were performed in 324 RA patients, 251 control patients, and 286 healthy subjects. The optimal cut off values of each assay were determined at the maximal point of area under the curve by receiver-operator characteristics (ROC) curve. Sensitivity (72.8%) and specificity (92.0%) of anti-CCP were better than those of AFA (70.3%, 70.5%), respectively. The diagnostic performance of RF showed a sensitivity of 80.6% and a specificity of 78.5%. Anti-CCP and AFA showed positivity in 23.8% and 17.3% of seronegative RA patients, respectively. In conclusion, we consider that anti-CCP could be very useful serological assay for the diagnosis of RA, because anti-CCP revealed higher diagnostic specificity than RF and AFA at the optimal cut off values and could be performed by easy, convenient ELISA method.     

Idiotypic network: possible explanation of seronegativity in a patient with rheumatoid arthritis

In order to explain long term seronegativity in certain patients with rheumatoid arthritis (RA), we looked for the presence of anti-idiotypic antibodies against rheumatoid factors (RFs). From a patient's serum with classical but seronegative RA, we isolated a low quantity of the IgG fraction which partially recognized polyclonal RF idiotypes. The purified Fab'2 anti-idiotypic antibodies were able to inhibit up to 48% of in vitro RF production by pokeweed mitogen stimulated lymphocytes from a patient's peripheral blood with seropositive RA. The two main conclusions of this study are: (1) this single patient with seronegative RA has serum antibodies directed against RF idiotypes and (2) these anti-idiotypic antibodies could be implicated in the generation of seronegativity.     

New immunoserological tests and pathogenesis for rheumatoid arthritis

In 1987, the ACR (American College of rheumatology) guidelines for classification of RA were published and the JCR (Japan College of rheumatology) classification of early diagnosis for RA was established in 1994. The determination of rheumatoid factor (RF) was included in both the above classification standards. However, Ig-M type of RF has problems in specificity and sensitivity. Recent progress in various RA studies has revealed the molecular mechanism of RA and new therapy and laboratory tests (ie. CA-RF, MMP-3) have been developed. Thus, determination changes in various diagnostic markers such as MMP-3, and inflammatory cytokines (ie. IL-1beta, IL-2, IL-6, IL-8, IL-18) are important for treatment of RA patients.     

Raising rheumatoid factor cutoff helps distinguish rheumatoid arthritis

The presence of rheumatoid factor (RF) is one of the clinical criteria for the diagnosis of rheumatoid arthritis (RA). The cutoff point of RF assays is usually based on a reference level obtained from normal subjects in the same population as the patients. We evaluated 63 rheumatoid arthritis (RA), 25 other arthritis patients and 110 blood donors. Their rheumatoid factors (RF) ranged from < 9.9 to 2,264, < 9.9 to 262, and < 9.9 to 66 mIU/ml, respectively. The sensitivity at different cutoff points of 15, 20, and 25 mIU/ml was 92.1%, 90.5%, and 88.9%, respectively. The specificity at the same cutoff points was 81.5%, 84.4%, and 85.2%, respectively. Having minimally sacrificed the sensitivity, we recommend using a higher RF cutoff to increase specificity.     

Occurrence of two germline-related rheumatoid factor idiotypes in rheumatoid arthritis and in non-rheumatoid seropositive individuals.

Human rheumatoid factor (RF) paraproteins express two distinct light chain cross-reactive idiotypes defined by the monoclonal antibodies 17.109 and 6B6.6. These germline gene-related cross-reactive idiotypes are both carried on VK3 light chains and are each present on about one-third of IgM RF paraproteins. We assessed the degree to which these idiotypes are represented in polyclonal RFs. We used rheumatoid arthritis (RA) and non-RA RF-positive sera selected from a large cross-sectional population study (the Mini-Finland Health Survey), and sera from a community-based follow-up study of recent-onset RA patients from Heinola, Finland. In the Mini-Finland Health Survey, elevated levels of the 17.109 RF idiotype were seen in sera of 13% of the RA and 19% of the non-RA group; 6B6.6 RF was seen in 26% of the RA and 28% of the non-RA group. In sera of the Heinola follow-up study, 17.109 RF was seen in 12% initially, but in only 3% at 8 years. Similarly, 6B6.6 RF was detected in 25% initially, but in only 7% at 8 years. Ten sera positive for RF prior to the onset of clinical RA were identified from individuals of a second large population study from Finland (North Karelia project); two of these sera exhibited the 6B6.6 idiotype; none exhibited the 17.109 idiotype. The data are consistent with the concept that these germline gene-related cross-reactive RF idiotypes occur frequently in the polyclonal RF of non-RA as well as RA sera, and that in RA the idiotypes may sometimes be reduced or lost as a consequence of somatic diversification of the RF through somatic mutation, usage of new germline genes, or both.     

抗环瓜氨酸肽抗体、葡萄糖6-磷酸异构酶及类风湿因子的检测及对类风湿关节炎的诊断价值

目的为寻找敏感性高、特异性强的诊断类风湿关节炎(RA)的实验指标,选择抗环瓜氨酸肽(CCP)抗体、葡萄糖6-磷酸异构酶(GPI)和类风湿因子(RF)并探讨对RA的诊断价值。方法抗CCP抗体和GPI试验采用酶联免疫吸附(ELISA)法,RF用胶乳凝集法,检测了125例RA患者(RA组)、56例其他风湿性疾病患者(对照组)和36例健康体检者(正常组)血清中上述3者的浓度。结果抗CCP抗体、GPI及RF,在RA组分别是:(83.6±45.9)RU/ml、(2.8±2.3)μg/ml和(320.4±208.6)IU/ml;在对照组分别是:(36.2±15.3)RU/ml、(0.19±0.06)μg/ml和(36.3±12.5)IU/ml;在正常组分别是:(19.2±8.6)RU/ml、(0.16±0.08)μg/ml和(19.2±6.5)IU/ml。在RA组中,3者的敏感度分别是64.8%、73.6%和69.6%,特异性分别是92.0%、72.8%和74.4%。结论 RA患者血清抗CCP抗体、GPI和RF显著高于其他疾病患者(P<0.01)。抗CCP抗体和GPI有可能成为诊断RA的新指标、RA的血清标志物,对提高诊断RA的敏感性和特异性,具有良好的临床研究和推广价值。     

Association of rheumatoid factor with complement activation in rheumatoid arthritis and other diseases.

Rheumatoid factor (RF) is a complement activating autoantibody. In rheumatoid arthritis (RA) the rate of catabolism of complement is closely related to the titre of RF. Therefore, we have examined whether these relationships are unique to RA or will be found in non-RA disorders in which RF may be found in the circulation. We studied patients with subacute bacterial endocarditis, leprosy, tuberculosis, and a variety of other rheumatic and vasculitic disorders. We found that in all the disorders examined the RF had a complement activating potential which was equivalent to that of the RF of RA patients. Furthermore in vivo activation of complement, as exhibited by the appearance of C3 degradation products, was significantly related to higher titres of haemolytically active RF in non-RA as well as the RA group. In these respects, therefore, the RF in RA and non-RA patients is indistinguishable. A possible survival value for RF is discussed.     

Immunologic laboratory testing in clinical practice for rheumatoid arthritis

The recent clinical practices for rheumatoid arthritis have changed greatly. First, biologic agents such as tumor necrosis factor blocker have been developed as well as disease-modifying antirheumatic drugs, with great efficacy in intractable RA. On the other hand, the importance of early effective therapeutic intervention has been recognized since early treatment prevents the progression of joint damage. However, early diagnosis of RA is not so easy because of the lack of appropriate diagnostic criteria. New laboratory tests have appeared for the diagnosis and prognostic prediction of RA. Among them, anticyclic citrullinated peptide antibodies (anti-CCP), which bind epitopes containing citrulline, seem to be attracting the most attention. Although rheumatoid factor (RF) is the only serologic marker among the seven classification criteria of the American College of Rheumatology (ACR) for RA, variability of the RF assay within laboratories and/or between laboratories, and quality assurance has not been established. We must address the standardization of RF assay as soon as possible.     

Allotype-dependent stimulation of peripheral blood and synovial lymphocytes by IgG3 in rheumatoid arthritis.

The immunopathologic process of rheumatoid arthritis (RA) is primarily expressed in the synovium where rheumatoid factor (RF) synthesis is concentrated. We hypothesized that RF synthesized by rheumatoid synovial cells (RSC) may be driven via a T cell-mediated immune response developed against IgG3 epitopes. To identify and characterize specific RSC RF epitopes and T cell antigens, two 28 amino acid peptides homologous with the C-terminus of IgG1 (P1) and IgG3 [G3m(5)] (P3) were synthesized and used in RF-binding studies and lymphocyte proliferation assays. Our results indicate that (i) the C-terminus of the CH3 domain contains epitopes for IgG3-reactive RSC RF; (ii) IgG3-reactive RSC RF binds primarily to IgG3 [G3m(5)]; (iii) P3 stimulated proliferation of T lymphocytes from both RA peripheral blood and RSC; and (iv) RF production was enhanced by P3 in selected RA cell cultures. These observations suggest that the C-terminus of IgG3 allotype G3m(5) may be important in T cell activation and RF production in RA.     

Human monoclonal rheumatoid factors: incidence of cross-reactions with tissue components and correlation with VH gene usage.

Human monoclonal antibodies with rheumatoid factor (RF) activity, derived from lymphocytes from the synovial tissue of rheumatoid arthritis (RA) patients and the peripheral blood of healthy individuals were examined for cross-reactivity with tissue and cellular antigens. The majority of IgM RF from RA patients (68%) showed reactivity with at least one component, and were frequently multispecific. A very significantly smaller proportion (28%) of the RF derived from healthy individuals demonstrated reactivities against tissue/cellular antigens (P = 0.004). RF from RA patients most commonly reacted with gastric glands (61%), nuclei (50%) and smooth muscle (50%), whereas RF from healthy donors most commonly reacted with gastric glands (20%), smooth muscle (16%), endothelium (16%) and glomeruli (16%). The most striking difference between the two groups was the reactivity with nuclear components, demonstrated by 50% of the RA RF, but by none of the healthy donor RF. As the two groups of antibodies share the same specificity for IgG Fc, but show differences in variable region segment usage, we investigated the relationship between VH gene usage and tissue/cell cross-reactivity using these antibodies and anti-blood group antibodies. Antibodies using VH3 or VH4 gene segments showed a very significantly greater frequency of tissue/cell reactions than those using VH1 (P = 0.0095 and 0.0004 respectively).     

IgG rheumatoid factors and anti-nuclear antibodies in rheumatoid vasculitis.

We studied the distribution and characteristics of circulating rheumatoid factors (RF) and anti-nuclear antibodies (ANA) in 30 rheumatoid arthritis (RA) patients who had polyarthritis alone (group I), 28 RA patients with polyarthritis and extra-articular disease (group II), 28 RA patients with systemic vasculitis (group III) and 60 healthy matched controls. IgG RF occurred more frequently and in higher serum titres in group III (100%) than RA patients in group I (40%), or in group II (18%) or in normal controls (5.8%). The serum titre of IgM RF was higher in vasculitis patients than in other RA patients. ANA were found in 74% of all RA patients and although the frequency did not differ in the three patient groups, the serum titre was significantly higher in the vasculitis group. Antibodies to extractable nuclear antigen were found only in group III (18.7%). Antibodies to histones were also more prevalent in group III than in the other RA groups. The serological abnormalities in rheumatoid vasculitis differed quantitatively as well as qualitatively from other RA patients.     

IgA rheumatoid factor and IgG dietary protein antibodies are associated in rheumatoid arthritis

This study sought to determine whether patients with rheumatoid arthritis (RA) were immunologically sensitised to dietary protein (DP). Using an enzyme linked immunosorbent assay (ELISA), antibodies to milk and wheat proteins were measured in 93 unselected out-patients with classical or definite RA. Of these 93, 53 had raised levels of IgG antibodies to one or both dietary proteins (DP). In the DP antibody positive group, 48 patients (90%) also had raised levels of IgA rheumatoid factor (measured by ELISA) while only 7 (17%) of the 40 DP antibody negative patients had detectable IgA RF; P less than 0.02. There was no association between IgM rheumatoid factor and dietary protein antibodies. These results demonstrate that in RA, raised levels of IgA RF are associated with an increased IgG response to antigens which enter the body through the gastrointestinal tract. A breakdown in gastrointestinal tolerance to dietary antigens may play a role in the immunopathogenesis of RA in these patients who might therefore benefit from dietary manipulation.