IgM RF Research Articles

Positive anti-citrullinated protein antibody status and small joint arthritis are consistent predictors of chronic disease in patients with very early arthritis: results from the NOR-VEAC cohort

IntroductionThe current 1987 American College of Rheumatology (ACR) classification criteria for rheumatoid arthritis (RA) have proven less useful in early arthritis. The objective of this study was to identify and compare predictors of three relevant outcomes of chronic arthritis in a cohort of very early arthritis patients.MethodsThe Norwegian Very Early Arthritis Cohort (NOR-VEAC) includes adult patients with at least one swollen joint of ≤16 weeks' duration. Patients are followed for 2 years with comprehensive clinical and laboratory examinations. Logistic regression analyses were performed to determine independent predictors of three outcomes: persistent synovitis, prescription of disease-modifying anti-rheumatic drugs (DMARDs), and established clinical RA diagnosis within one year.ResultsOf 384 patients eligible for one year follow-up (56.3% females, mean (SD) age 45.8 (14.7) years, median (IQR) duration of arthritis 31 (10-62) days), 14.4% were anti-CCP2 positive, and 11.2% were IgM RF positive. 98 patients (25.5%) had persistent synovitis, 106 (27.6%) had received DMARD treatment during follow-up, while 68 (17.7%) were diagnosed with RA. Consistent independent predictors across all three outcomes were positive anti-citrullinated protein antibody (ACPA) status (odds ratio (OR) 3.2, 5.6 and 19.3), respectively, and small joint arthritis (proximal interphalangeal joint (PIP), metacarpo-phalangeal joint (MCP), and/or metatarso-phalangeal joint (MTP) joint swelling) (OR 1.9, 3.5, and 3.5, respectively).ConclusionsPositive ACPA status and small joint arthritis were consistent predictors of three relevant outcomes of chronic arthritis in very early arthritis patients. This consistency supports DMARD prescription as a valid surrogate endpoint for chronic arthritis. Importantly, this surrogate is used in ongoing efforts to develop new diagnostic criteria for early RA.

Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in leprosy patients with articular involvement

The objective of the present research was to evaluate the usefulness of anti-cyclic citrullinated peptide (anti-CCP) antibodies and the IgM rheumatoid factor (IgM RF) test for the differential diagnosis of leprosy with articular involvement and rheumatoid arthritis (RA). Anti-CCP antibodies and IgM RF were measured in the sera of 158 leprosy patients (76 with and 82 without articular involvement), 69 RA patients and 89 healthy controls. Leprosy diagnosis was performed according to Ridley and Jopling classification criteria and clinical and demographic characteristics of leprosy patients were collected by a standard questionnaire. Leprosy patients with any concomitant rheumatic disease were excluded. Serum samples were obtained from all participants and frozen at -20 degrees C. Measurement of anti-CCP antibodies and IgM RF were performed by ELISA, using a commercial second-generation kit, and the latex agglutination test, respectively. Anti-CCP antibodies and IgM RF were detected in low frequencies (2.6 and 1.3%, respectively) in leprosy patients and were not associated with articular involvement. Among healthy individuals both anti-CCP antibodies and IgM RF were each detected in 3.4% of the subjects. In contrast, in the RA group, anti-CCP antibodies were present in 81.2% and IgM RF in 62.3%. In the present study, both anti-CCP antibodies and IgM RF showed good positive predictive value for RA, helping to discriminate between RA and leprosy patients with articular involvement. However, anti-CCP antibodies were more specific for RA diagnosis in the population under study.

Anti-cyclic citrullinated peptide: its prevalence and clinical significance in a South African cohort with juvenile idiopathic arthritis

Results Records of 52 patients (54% males, 46% females) were reviewed. The mean (SD) age and follow-up period were 10.69 (3.81) and 2.3 (1.7) years, respectively. The majority of the children (83%) were Black. The subtypes of JIA were as follows: systemic 21%, polyarticular 50%, oligoarticular 19%, enthesitis-related arthritis 2%, psoriatic 2% and other 6%. Anti-CCP antibodies were present in the sera of 8 of 28 patients tested (29%). They were detected exclusively in patients with the polyarticular subtype of JIA. IgM RF was positive in 14 (29.17%) of the total cohort, but not exclusively in patients with the polyarticular subtype of JIA. The overall concordance between the 2 tests was fair (Kappa statistic = 0.39).

Diagnostic value and clinical significance of antibodies against a modified citrullinated vimentin (anti-MCV) in patients with early juvenile arthritis

Patients and methods: 85 pts were included in the study (M/F = 36/49) in the age of 1,5–16 years (mean 8.7 ± 4.9 years). Systemic JA – 10 pts (11.8%), poly – 37 (43.5%), oligo-38 (44.7%). Duration of disease was < 6 months. We studied also 54 pts with early RA, 28 pts with undifferentiated arthritis (UA) and 14 healthy children. Anti-MCV was measured in serum by enzyme-linked immunosorbent assay (ELISA) using the cut off value of 25 U/ml. IgM RF and hsCRP-by laser-nephelometry assay on BN-100 analyser.

Significance of Serum TRACP in Rheumatoid Arthritis

Human serum contains two related isoforms of TRACP: TRACP 5a and TRACP 5b. Serum TRACP 5a protein is increased in about one third of rheumatoid arthritis (RA) sera. This study was undertaken to examine the significance of serum TRACP isoforms 5a and 5b as disease markers of inflammation and bone destruction in RA. One hundred eighteen patients were recruited including 50 with RA (25 with nodules), 26 with osteoarthritis (OA), and 42 with other rheumatic diseases. Twenty-six healthy adults served as controls. Serum TRACP 5a activity, TRACP 5a protein, and TRACP 5b activity were determined by in-house immunoassays. C-reactive protein (CRP) was determined by in-house immunoassay using commercial antibodies and CRP. Other commercial markers included bone-specific alkaline phosphatase (BALP), C-telopeptides of type-I collagen (ICTP), cartilage glycoprotein-39 (YKL-40), and IgM rheumatoid factors (IgM-RF). Mean TRACP 5a protein was significantly elevated only in RA compared with healthy controls and other disease groups. TRACP 5a protein correlated significantly only with IgM-RF in RA. Among RA patients, mean TRACP 5a protein and IgM RF were significantly higher in nodule formers. In contrast, TRACP 5b activity was slightly elevated in RA and correlated with BALP, ICTP, and YKL-40 but not with IgM-RF or CRP. Mean TRACP 5b activity was no different in RA patients with or without nodules. TRACP isoforms could be useful disease markers in RA; TRACP 5a protein may be a measure of systemic inflammatory macrophage burden and disease severity. TRACP 5b activity is a marker for osteoclast number and perhaps local or systemic bone destruction.

IL-2 enhances polyclonal IgM but not IgM-rheumatoid factor synthesis by activated human peripheral blood B cells.

IgM-rheumatoid factor (RF) is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). Several cytokines are known to regulate immunoglobulin synthesis. In this study the effects of IL-2 on polyclonal IgM and IgM RF synthesis were compared. Cytokines were added to peripheral blood B cells from normal subjects and patients with RA after activation by Staphylococcus aureus Cowan 1 (SAC). The addition of IL-2, but not IL-4 or IL-6, resulted in significant enhancement of IgM synthesis in cultures from both healthy subjects and patients with RA. Similar degrees of enhancement were seen in both peripheral blood mononuclear cell and highly purified B cell cultures. IgM-RF was synthesized after activation in cultures from healthy subjects and spontaneously in cultures from RA patients. In contrast to polyclonal IgM synthesis, IL-2 failed to augment IgM-RF synthesis in cell cultures from either healthy subjects or RA patients. This study demonstrates different effects of IL-2 on IgM and IgM-RF synthesis.

Contribution of PTPN22 1858T, TNFRII 196R and HLA-shared epitope alleles with rheumatoid factor and anti-citrullinated protein antibodies to very early rheumatoid arthritis diagnosis

To evaluate the predictive value of TNFRII 196R, PTPN22 1858T and HLA-shared epitope (SE) alleles, RFs and anti-citrullinated protein antibodies (ACPAs) for RA diagnosis in a cohort of patients with very early arthritis. We followed up 284 patients who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for <6 months. At 2 yrs, patients were classified as having RA or non-RA rheumatic diseases according to the ACR criteria. Patients were genotyped with respect to TNFRII 196M/R and PTPN22 1858C/T polymorphisms and HLA-SE. The presence of IgA, IgG and IgM RF isotypes and ACPA was sought in sera collected at disease onset. HLA-SE alleles alone, concomitant presence of TNFRII 196R and PTPN22 1858T alleles, IgA, IgG and IgM RF alone and ACPA were found to be significantly associated with RA diagnosis. Using logistic regression analysis, the concomitant presence of RF and ACPA at disease onset was the best association to predict RA diagnosis. In patients (n = 34) who did not fulfil the ACR criteria for RA at inclusion but who progressed to ACR positivity, the study of the genetic risk markers did not contribute to predict RA diagnosis at 2 yrs. PTPN22 1858T, TNFRII 196R and HLA-SE alleles do not improve the predictive value of RF and ACPA for RA diagnosis in our cohort, and do not contribute to an earlier diagnosis in undifferentiated patients initially negative for RF and ACPA.

The Diagnostic Value of Anti-Cyclic Citrullinated Peptide Antibodies (anti-CCP) in Patients with Rheumatoid Arthritis

The Diagnostic Value of Anti-Cyclic Citrullinated Peptide Antibodies (anti-CCP) in Patients with Rheumatoid ArthritisA cross-sectional study was carried out to analyze the prevalence of anti-CCP antibodies and IgM RF in the sera of 160 randomly selected patients from the Rheumatology Department: 60 with RA, 50 with other rheumatic diseases (non-RA), 50 healthy controls (HC). The mean age of the group was 50.06+/-11.9 years. There were 141 females (88.1%) and 19 males (11.9%). RA patients fulfilled the revised ACR criteria. The mean duration of the disease was 82.4 months. Anti-CCP ELISA kit and IgM RF Latex test were used. The mean anti-CCP values were as follows: RA 60.4+/-57.6, non-RA 2.1+/-3.6, HC 1.3 +/-0.4 U/mL. Respectively, the mean values of IgM RF were: RA 515.8+/-525, non-RA 102+/-294, HC 15+/-57.5. Forty out of 60 (66.6%) RA patients were anti-CCP positive. Forty one out of 60 (68.3%) RA patients were positive for IgM RF. As expected, anti-CCP showed comparable sensitivity (66.8% vs. 68.3%) and higher specificity (98% vs. 87%) than IgM RF, at optimal cut-off values. The presence of either anti-CCP or IgM RF increased the testing sensitivity for the diagnosis of RA to 76.6%. AUC was greater for anti-CCP than for IgM RF (0.92 vs. 0.82).

Comparison of Three Anti-CCP Antibody Tests and Rheumatoid Factor in RA and Control Patients

It was the aim of this study to compare the diagnostic properties of two second generation anti-CCP antibodies assays (Quanta Lite CCP, Inova and EliA CCP, Phadia) with an assay containing a new antigen mixture (Quanta Lite CCP 3, Inova) and RF IgM. Sera from 86 RA patients and 90 control patients with other diseases, such as infections, connective tissue diseases, or other rheumatic diseases, were analysed using the four different methods. Specificity (84.4%) and PPV (80.3%) were lowest for RF IgM and highest for EliA CCP (specificity 97.8%, PPV 96.7%), the other values being close to those of EliA CCP. Sensitivity was highest for Quanta Lite CCP (73.3%). Efficiency was highest for Quanta Lite CCP (84.1%) at the lower cut off followed by EliA CCP at both cut offs (83.0%). The discrimination between RA sera (mean value 407.67 U/ml) and control sera (4.54 U/ml) and the relative risk (23.34) were best for EliA CCP. The results of this study reveal that there was no advantage of the anti-CCP antibodies assay applying a new antigen mixture (Quanta Lite CCP 3 ELISA) compared to two second generation anti-CCP antibodies assays (Quanta Lite CCP ELISA and EliA CCP).

A comparison of the frequency of antibodies to cyclic citrullinated peptides using a third generation anti-CCP assay (CCP3) in systemic sclerosis, primary biliary cirrhosis and rheumatoid arthritis

The objective was to investigate the frequency of anti-cyclic citrullinated peptides (CCP) antibodies in systemic sclerosis (SSc) and primary biliary cirrhosis (PBC), utilizing a new "third generation" anti-CCP ELISA (anti-CCP3) kit and a conventional anti-CCP2 assay. Patients with PBC, SSc, RA, and normal controls were included in the study. Serum samples were screened for autoantibodies by indirect immunofluorescence (IIF), antibodies to CCP by a second- and third-generation ELISA, antibodies to "scleroderma" antigens (CENP B, Scl-70, PM/Scl and fibrillarin-Scl-34) by a line immunoassay (LIA), and IgM RF by ELISA. The frequency of anti-CCP2 antibodies in SSc and PBC samples was 14.8% (11/74) and 6.2% (5/80), respectively, and the frequency of anti-CCP3 antibodies in SSc was 13.5% (10/74) and in PBC was 3.7% (3/80). By comparison, in the RA group the frequency of anti-CCP3 and anti-CCP2 antibodies was 79.1% (38/48) and 77% (37/48), respectively. Anti-CCP3 ELISA had a sensitivity, specificity, and positive and negative likelihood ratios (LR) of 79% (95% confidence interval [CI] = 64-89%), 93% (95% CI = 88-96%), 11.8 (95% CI = 6.8-20.3), and 0.22 (95% CI = 0.12-0.38), respectively. By comparison, the anti-CCP2 assay had a sensitivity, specificity, and positive and negative LRs of 77% (95% CI = 62-87), 90% (95% CI = 85-94), 8.3 (95% CI = 5.2-13.2), and 0.25 (95% CI = 0.15-0.42), respectively. In patients with SSc, there was an association of anti-CCP2 antibodies with the presence of arthritis, but there was no association of anti-CCP2 or anti-CCP3 with anti-CENP B, anti-Scl 70, or RF. This study confirmed the high specificity and sensitivity of both anti-CCP assays for the diagnosis of RA. The presence of anti-CCP antibodies in SSc was only correlated with the presence of arthritis.

Comparison of Anti-mutated Citrullinated Vimentin with Anti-cyclic Citrullinated Peptide and Rheumatoid Factors for the Diagnostic Value of Rheumatoid Arthritis

Objective: Serologic support is important for the diagnosis of rheumatoid arthritis (RA). Anti-cyclic citrullinated peptide (anti-CCP) has relatively low sensitivity despite of high specificity for the diagnosis of RA. Anti-mutated citrullinated vimentin (anti-MCV) is an indirect solid phase enzyme immunoassay for the quantitative measeurement of IgG class autoantibodies against MCV, a novel serologic marker for an aid in the diagnosis of RA. We investigated a diagnostic value of anti-MCV in comparison with those of anti-CCP, and rheumatoid factors (IgM, IgG, and IgA RFs) in RA patients. Methods: Cohorts of 48 patients with RA and 50 patients with osteoarthritis (OA) were enrolled. All patients underwent standard examinations, including anti-MCV, anti-CCP, IgM RF, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). We measured IgG RF and IgA RF titers in 21 RA and 50 OA patients. The sensitivities and specificities of anti-MCV, anti-CCP, RFs were determined. Correlations with these markers, ESR and CRP were analyzed.

P47 Comparative analysis of anti cyclic citrullinated peptide antibodies and rheumatoid factor (IgM RF isotype) in rheumatoid arthritis (RA) patients

P47 Comparative analysis of anti cyclic citrullinated peptide antibodies and rheumatoid factor (IgM RF isotype) in rheumatoid arthritis (RA) patients

Serial determination of cyclic citrullinated peptide autoantibodies predicted five-year radiological outcomes in a prospective cohort of patients with early rheumatoid arthritis

The objective of this study was to evaluate the potential of serially determined anti-cyclic citrullinated peptide (CCP) antibodies for predicting structural joint damage in patients with early rheumatoid arthritis (RA), compared to a single baseline determination. Ninety-nine RA patients with disease durations of less than one year and no history of disease-modifying antirheumatic drug therapy were followed prospectively for at least five years. Anti-CCP2 concentrations were measured using a second-generation ELISA. Sharp scores as modified by van der Heijde were determined on hand and foot radiographs. Anti-CCP2 antibodies were detected in 55.5% of patients at baseline and 63.6% at any time during the first three years. Presence of anti-CCP2 at any time during the first three years was associated with radiographic damage at baseline (odds ratio (OR), 3.66; 95% confidence interval (95% CI) 0.99–13.54) and with five year progression of the total Sharp score (OR, 3.17; 95% CI, 1.3–7.7), erosion score (OR, 5.3; 95% CI, 1.4–19.2) and joint space narrowing score (OR, 2.8; 95% CI, 1.15–6.8). The presence of anti-CCP2 or IgM RF at baseline did not predict these outcomes. Patients with negative anti-CCP2 tests throughout follow-up had less radiographic progression than patients with increasing anti-CCP2 concentrations; they did not differ from patients with decreasing anti-CCP2 antibody levels. HLADRB1* typing showed that progression of the mean modified Sharp score was not correlated with the presence of the shared epitope alleles. In conclusion, serially determined anti-CCP2 antibodies during the first three years of follow-up performs better than baseline determination for predicting radiographic progression in patients with early RA.

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.

Autoantibodies and self-reported health complaints in relatives of systemic lupus erythematosus patients: a community based approach

First-degree relatives (FDRs) and spouses to a population-derived cohort of lupus patients were investigated for the occurrence of selected autoantibodies and self-reported health complaints. A healthy reference population was included. The lupus population consisted of 103 index cases. A total of 275/375 available relatives accepted to enter the study. Two hundred and twenty-six/315 (72%) were FDRs and 49/60 (82%) were spouses. Serum was analysed for ANA using indirect immunofluorescence on Hep-2 cells at the following dilutions: 1:40, 1:80 and 1:160 and in addition sera were tested for anti-dsDNA, IgM RF, ACA (IgM, IgG), anti-beta2GPI (IgM, IgG) and antibodies to prothrombin. ANA positivity occurred more frequently in FDRs compared with spouses and controls at serum dilution 1:160 (10 versus 0% and 2.5%, respectively, P = 0.04 and P < 0.01), 1:80 (24 versus 4% and 5%, respectively, P = 0.003 and P < 0.001) and 1:40 (31 versus 10% and 10%, respectively, P = 0.006 and P < 0.0001). ANA positivity in FDRs occurred randomly, irrespective of family relationship. Fifty-three/184 versus 2/32 FDRs to patients with definite SLE (D-SLE) and incomplete SLE (I-SLE), respectively, tested ANA positive at 1:80 (P < 0.05). FDRs with ANA titer at 80 were affiliated to lupus probands with high SLICC scores (P < 0.05). Self-reported health complaints, cardiovascular/thromboembolic events in particular, were more frequent among FDRs than in spouses. The population-based approach adopted in the present study supports previous clinic-based evidence of an increased propensity for autoantibody occurrence in relatives to SLE patients. In FDRs, present ANA positivity was associated with increased prevalence of health complaints and ANA positivity in FDRs was related to the criterial burden and cumulated damage in corresponding lupus probands. The low ANA frequency among spouses of SLE patients argues against a significant autoantibody triggering effect of shared environment in adult life.

High prevalence of autoantibodies among Danish centenarians.

The aim of this study was to investigate the prevalence of organ and nonorgan specific autoantibodies in relation to disability and comorbidity in an unselected population of centenarians. A population-based survey of all persons living in Denmark who celebrated their 100th birthday during the period 1 April 1995 to 31 May 1996, a total of 276 persons, was undertaken. Participants underwent an interview, a physical examination and blood sampling. Organ specific autoantibodies (Tg-ab, TPO-ab, PCA-ab) and nonorgan specific autoantibodies (ANA, IgM RF, IgA RF, MPO-ab, c-ANCA, p-ANCA, oxLDL-ab, IgM ACA, IgG ACA, PR3-ANCA, histone-ab, SSA-ab, SSB-ab, Mit-ab) were measured, and comorbidity and disability (Katz Index of ADL) were registered. In all, 207 (75.0%) of 276 eligible subjects participated, and 148 agreed to blood tests. A large majority (79.3%) had at least one autoantibody detected. Organ specific autoantibodies were present in 32.1% of the centenarians. The high level of autoantibodies did not reflect an equally high level of overt autoimmune disease. While nonorgan specific autoantibodies were equally represented in less-disabled/disabled subjects as well as in subjects with low/high comorbidity, significantly fewer subjects with organ specific autoantibodies were found among less-disabled subjects or subjects with low comorbidity. Autoantibodies (both nonorgan and organ specific) are common in an unselected population of centenarians of today, but do not reflect an equally high level of overt autoimmune disease. Non-organ specific autoantibodies are evenly distributed irrespective of the level of disability or comorbidity, suggesting underlying, undiagnosed pathological processes which may be part of the processes involved in frailty.

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.

Rheumatoid Factor Specificity of a VH3-Encoded Antibody Is Dependent on the Heavy Chain CDR3 Region and Is Independent of Protein A Binding

Rheumatoid factors (RF) recognize conformational determinants located within the Fc portion of IgG. By analyzing a panel of monoclonal rheumatoid arthritis (RA)-derived RFs, we previously demonstrated that the somatically generated light chain complementarity-determining region 3 (CDR3) contributes to RF specificity. We have now generated a panel of heavy chain mutants of the B'20 Ab, a high affinity RA-derived IgM RF. B'20 also binds avidly to protein A and weakly to ssDNA and tetanus toxoid. B9601, a RF negative Ab that is highly homologous to B'20 but does not bind any of the Ags tested, and RC1, a low affinity polyreactive RF, were used to generate heavy chain mutants with framework (FR) and CDR switches. The mutated heavy chains were cotransfected into a myeloma cell line with the germline counterpart of the B'20 light chain, and the expressed Ig tested for antigenic specificity. We show that both RF specificity and polyreactivity of B'20 is dependent on its unique heavy chain CDR3 region. Replacement with a B9601 CDR3 shortened to the same length as the B'20 CDR3, and with only 5 amino acid differences, did not restore Fc binding. Conversely, absence of protein A binding of B9601 is due to the presence of a serine residue at position 82a in the B9601 heavy chain FR3 region. Together, our data suggest that Ig gene recombination events can generate B cells with autoantibody specificities in the preimmune repertoire. Abnormal release, activation, expansion, or mutation of such cells might all contribute to the generation of a high titer RF response in patients with RA.

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.

Analysis of the Molecular Basis of Synovial Rheumatoid Factors in Rheumatoid Arthritis

The objective of this study was to better understand the molecular basis of IgM rheumatoid factor in rheumatoid arthritis (RA). We recently generated 10 different monoclonal IgM RF (mRF) molecules isolated from the synovium of a single patient with RA. The heavy (H) and light chain (L) variable region (V) genes of these 10 mRFs were cloned and sequenced. Six mRFs used kappa light chains and 4 mRFs used lambda light chains. Of particular interest, 8 of 10 heavy chains used the JH4 joining region gene, and all five VH4 heavy chains used the DK4 diversity region gene with the JH4. Four of the VH4 clones used the same germline gene, likely representing a novel but closely related germline gene to VH4.18, and may be clonally related because of the extensive homology in their heavy chain sequence. Two VH4 clones shared the same light chain gene, VκIIIb kv325 (99% homology) and the same JK4 joining region gene, while three VH4 clones used two different light chain genes, an uncommon Vκ4 and a Vλ4 gene, respectively. In this RA patient, there was recurrent utilization of VH4-DK4-21/10-JH4 genes and a recurring association with gene elements Vκ3 and Vλ4. Recurring usage of Vκ3 (kv325) and Vλ4 (lv418) gene elements may result from a light chain editing process whereby immature autoreactive B cells encountering self-antigen attempt, and often succeed, in altering their specificities through secondary Ig light chain gene rearrangement. Moreover, the oligoclonality of these RFs suggest clonal relatedness secondary to an antigen-driven response.