High Rheumatoid Factor Research Articles

Aortic Valve Rheumatoid Nodules Producing Clinical Aortic Regurgitation and A Review of the Literature

The majority of cardiac involvement in rheumatoid arthritis (RA) is an incidental finding at postmortem, as less than 3% of patients with RA have clinical cardiac signs or symptoms. Most cardiac involvement in RA involves the pericardium and has been known since Charcot first described an RA patient with pericarditis in 1881. Cardiac involvement takes two different forms: non-specific inflammatory changes and specific granuloma formation. Specific rheumatoid nodules in the heart are an infrequent complication of RA. This is the first case report of a surgically excised heart valve with rheumatoid nodules. A 74-year-old RA patient with a high seropositive rheumatoid factor presented with severe aortic regurgitation and underwent a valve replacement. The native aortic valve showed significant stenosis with multiple, classic rheumatoid nodules. Cardiovas Pathol 1999;8: 333–338

A Rheumatoid Factor Specific Mimotope Identified by a Peptide Display Library

We screened a 10 amino acid peptide display library in filamentous phage with B'20, a monoclonal high affinity IgM rheumatoid factor (RF) expressing the Vk111a-dependent 4C9 idiotype. Using direct and indirect selection techniques, 12 B'20 reactive peptides were identified, 9 of which belonged to one of two motifs. Binding of B'20 to phage-bearing peptides was inhibited by both IgG and 4C9 antiidiotype. Synthetic peptides corresponding to the two motifs inhibited the Fc binding of a low avidity IgA B'20 construct. Purified IgM from 6/8 RF-positive RA patients and 8/11 monoclonal RFs with Vk111-encoded light chains bound to the phage, whereas none of the four monoclonal RFs with Vk1 or Vk11 encoded light chains bound. Phage binding appeared to be RF specific. Three 4C9 positive/RF negative cell lines from RA patients did not bind to phage nor did three B'20 mutants that had lost RF specificity, whereas two mutants that retained RF specificity also retained phage binding. We propose that there is a common epitope(s) recognized by Vk11 I encoded RFs that is mimicked by the structure of these peptides. Such mimotopes might be exploited to design novel agents that interfere with autoantibody binding.

Early aggressive DMARD therapy: The key to slowing disease progression in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation, joint destruction, progressive disability, and premature death. Patients at risk for poor prognoses can be identified by a variety of prognostic indicators. These include sociodemographic factors (e.g., older age, female sex), clinical indicators (e.g., higher joint counts), laboratory variables (e.g., higher erythrocyte sedimentation rate, high rheumatoid factor titer), and radiographic indicators (e.g., the presence of bone erosions). Patients with a poor prognosis, as evidenced by the presence of one or more indicators of poor outcome, should be treated promptly and aggressively with disease-modifying antirheumatic drugs (DMARDs) or combination DMARD therapy to limit or prevent further disease progression. Limiting the severity of RA with early and aggressive treatment is the best way to minimize the dire consequences of untreated or inadequately treated disease.

Pulmonary malignant B cell lymphoma found by autopsy in a patient with progressive systemic sclerosis associated with mutilans rheumatoid arthritis

The patient reported had progressive systemic sclerosis plus rheumatoid arthritis (RA) manifestations, demonstrating severe joint destruction similar to the mutilans variant of RA. She was also noted to have generalized and massive subcutaneous hydroxyapatite accumulation and a variety of autoimmune antibodies (anti-DNA,-ANA,-Scl-70 and high titer rheumatoid factor) was detected. Finally, malignant B cell lymphoma was found in her lungs at autopsy.

Pulmonary malignant B cell lymphoma found by autopsy in a patient with progressive systemic sclerosis associated with mutilans rheumatoid arthritis

The patient reported had progressive systemic sclerosis plus rheumatoid arthritis (RA) manifestations, demonstrating severe joint destruction similar to the mutilans variant of RA. She was also noted to have generalized and massive subcutaneous hydroxyapatite accumulation and a variety of autoimmune antibodies (anti-DNA,-ANA,-Scl-70 and high titer rheumatoid factor) was detected. Finally, malignant B cell lymphoma was found in her lungs at autopsy.

High affinity rheumatoid factor transgenic B cells are eliminated in normal mice.

Although systemic autoimmune diseases can be accompanied by multiple autoantibodies, certain specificities are dominant. Presumably, these specificities and their cognate Ags have properties that make them particularly amenable to autoimmune induction. Rheumatoid factors (RFs) are a dominant class of autoantibodies in rheumatoid arthritis and certain other autoimmune syndromes. To study the regulation of RFs in normal and autoimmune animals, we previously created a RF Ig transgenic model based on an RF isolated from an autoimmune MRL/lpr mouse. Using this model, called AM14, we were surprised to find that normal mice do not regulate disease-related RF B cells. This raised the question of whether RFs in general are not susceptible to tolerance induction, perhaps due to the unique properties of serum IgG and its FcRs. Alternatively, RFs can be tolerized, and the disease-related RFs are below the affinity threshold for such tolerance. To distinguish these possibilities, we generated a second RF transgenic model with the same specificity but much higher affinity than AM14. We found that, in contrast to AM14, high affinity RF B cells are subject to central tolerance, showing that there is not an absolute defect in RF B cell tolerance, but, rather, that RF B cell tolerance is affinity dependent even in normal animals. This is also the first model in which a disease-related specificity has been shown clearly to delete in a system in which Ag-positive and negative mice can be produced and compared.

Peripheral deletion of rheumatoid factor B cells after abortive activation by IgG.

Rheumatoid factor (RF) B cells proliferate during secondary immune responses to immune complexed antigen and antigen specific T cells, but higher affinity RFs are not detected except in patients with rheumatoid arthritis and other autoimmune diseases. Consequently, there must exist highly efficient mechanisms for inactivation of these higher-affinity RF B cell clones under normal circumstances. Exposure of transgenic mice expressing a human IgM RF to soluble human IgG in the absence of T cell help causes antigen specific B cell deletion in 2-3 days. The deletion is independent of the Fas/Fas ligand (FasL) pathway of apoptosis and is preceded by a phase of partial activation involving increase in cell size and expression of B7 and ICAM-1, and transient release of low levels of immunoglobulin. Complete B cell activation involving the formation of germinal centers and sustained high level RF secretion only occurs if T cell help is provided simultaneously. RF B cells exposed to tolerogen remain competent to secrete RF in vitro if provided with an appropriate antigenic stimulus and T cell help. Consequently, death of these cells is not preceded by anergy. Abortive activation/deletion of B cells by antigen in the absence of T cell-derived survival signals may represent the major mechanism for maintaining peripheral tolerance in B cells expressing higher affinity RF. The lack of anergy, and the potential for reactivation before death, provide a means for maintaining RF production under pathologic circumstances, such as may occur in the inflamed rheumatoid synovium.

Prognostic markers in rheumatoid arthritis and classification of antirheumatic therapies.

Rheumatoid arthritis is characterised by a generally poor outcome and high morbidity, and has a variable course. Identifying those patients most likely to have a poor prognosis is of key clinical significance. Disease outcome can be predicted from a variety of prognostic markers. Some of these are simple demographic features of the patients, and include age, disease duration, and gender. Others are more specific features of rheumatoid arthritis, including the presence of early erosive changes on plain radiographs, high rheumatoid factor titres, high levels of C-reactive protein, and high scores for disease activity. Although no single marker has adequate specificity or sensitivity to form the basis of clinical decisions, the presence of several is predictive of more severe disease. Thus, patients with early erosive damage who are seropositive for rheumatoid factor and have high levels of C-reactive protein are more likely to have a poor outcome. New markers and imaging techniques are likely to become the prognostic tools for the future. These include genetic markers, and a combination of magnetic resonance imaging and dual energy x-ray absorption scans for localised osteoporosis.

CILIORETINAL ARTERY OCCLUSION IN SICKLE CELL TRAIT AND RHEUMATOID ARTHRITIS

Background Although once thought to be a benign condition, retinal vascular occlusive disease and proliferative retinopathy can occur with sickle cell trait (hemoglobin AS) when additional systemic diseases or trauma are present. Methods The authors discuss the ophthalmologic evaluation and clinical course of a 49-year-old woman with sickle cell trait and rheumatoid arthritis who presented with a cilioretinal artery occlusion. Results The patient's laboratory evaluation showed both a high rheumatoid factor titer and a mild hypergammaglobulinemia, causing increased serum viscosity. The high level of sickle hemoglobin—42.3% (range in trait, 22%-46%)—increased serum viscosity, and lower cilioretinal artery perfusion pressure relative to the central retinal artery resulted in cilioretinal artery occlusion. Conclusions Isolated cilioretinal artery occlusions carry a good prognosis, and this patient recovered 20/20 visual acuity in the affected eye. The association between sickle cell trait and rheumatoid arthritis resulting in retinal vascular occlusive disease has not been reported previously. The presence of retinal vascular occlusion in sickle cell trait necessitates a medical evaluation for additional systemic diseases.

Improved immunoturbidimetric method for rheumatoid factor testing.

The performance of two immunoturbidimetric modifications for rheumatoid factor (RF) testing, which differ with respect to the means of complement inactivation (heat treatment and inactivation with polyvinyl sulphonate), were compared in serum samples from 87 patients with rheumatoid arthritis (RA) and from 403 healthy subjects. IgM-rheumatoid factor titres were also measured with an enzyme linked immunosorbent assay (ELISA). Both immunoturbidimetric tests gave positive reactions (rheumatoid factor > or = 20 IU/ml) in 74 out of the 87 (85%) RA sera. In cases with high RF concentrations the results after chemical inactivation tended to be slightly higher compared with heat inactivation. In healthy subjects rheumatoid factor was detected in 19/403 (4.7%) sera using heat inactivation and in 22/403 (5.5%) sera with chemical inactivation of complement. Interrun coefficient of variation in the chemical inactivation assay was 4.4%; with the heat inactivation method it was 8.1%. In the ELISA, a marginally better correlation was noted in the results obtained using chemical inactivation. Inactivation of complement by means of polyvinyl sulphonate offers the advantage of easier test performance and better reproducibility, and the results may reflect more accurately true rheumatoid factor concentrations.

Human rheumatoid B-1a (CD5+ B) cells make somatically hypermutated high affinity IgM rheumatoid factors.

To analyze the structure and formally ascertain the B-1a cellular origin of IgM rheumatoid factor (RF) autoantibodies, we generated 4 IgM RF mAb-producing cell lines using sorted (surface CD5+) B-1a cells from a patient with active rheumatoid arthritis. The RF mAb111, mAb112, mAb113, and mAb114 were monoreactive and displayed a relatively high affinity for human IgG Fc fragment (Kd, 3.1 x 10(-7) to 6.8 x 10(-7) M). The B-1a origin of the lymphocytes that gave rise to the IgM RF was confirmed by the expression of surface CD5 and specific CD5 mRNA by all mAb-producing cell lines. Analysis of the genes encoding the RF mAb VH and VL regions revealed that members of the VHI and VHIII families were utilized in conjunction with V kappa IIIa, V kappa IIIb, or V lambda I genes. JH3 and JH4 genes were each utilized twice. The H chain CDR3 sequences were divergent and variable in length. The RF mAb VH genes were identical or closely related to those expressed in the "restricted" fetal B cell repertoire and/or were JH-proximal. For instance, mAb111 VH gene likely constituted a mutated variant of the expressed fetal 20P3 which is the second most JH-proximal gene (125 kb from JH). In addition, the expressed VH and VL genes were among those that have been found to encode other RF, different autoantibodies, high affinity antibodies induced by exogenous Ag, and natural autoantibodies in the adult and neonatal B cell repertoires. When compared with those of known germline genes, the expressed V gene sequences displayed a number of differences. By cloning and sequencing DNA from PMN of the same patient whose B lymphocytes were used for the mAb generation, we showed that such differences resulted from somatic hypermutation in the RF mAb112 VH gene. The germline gene (112GL) that presumably gave rise to the RF mAb112 VH segment was identical to the expressed fetal 51P1 gene. The distribution and the high replacement to silent mutation ratio of the nucleotide mutations in RF mAb112 VH segment were highly consistent with their selection by Ag. RF mAb113 was clonally related to RF mAb112, as shown by the utilization of the same sets of VHI-D-JH4 and V kappa IIIb-J kappa 4 genes, displaying identical junctional sequences, and the presence of two identical replacement and one silent mutations.(ABSTRACT TRUNCATED AT 400 WORDS)

Survey of methods for measuring human anti-mouse antibodies

Human anti-mouse antibodies (HAMA) methods were surveyed using a panel of 17 serum and two plasma specimens which were circulated to ten laboratories for analysis. The panel included HAMA-negative and HAMA-positive specimens (from patients given a variety of mouse monoclonal antibodies) and a specimen with a high rheumatoid factor titer. The participating laboratories used a diverse range of methods to determine HAMA and all three of the commercially available quantitative methods for HAMA were represented. The survey revealed significant differences in HAMA results among the different laboratories.

Characterization of monoclonal IgG antibodies produced by hybridomas derived from rheumatoid synovial cells

IgM rheumatoid factors (RF) are the predominant autoantibody found in rheumatoid arthritis. They are polyclonal, fix complement, and are directed against epitopes in the Fc portion of IgG. One hypothesis regarding the induction and persistence of RF production in rheumatoid arthritis is that the Fc of IgG is somehow altered, rendering it antigenic. In this study, to better understand the derivation and pathogenicity of RF in rheumatoid arthritis, monoclonal IgG (mIgG) constitutively secreting hybridomas were established by fusing rheumatoid synovial mononuclear cells (RSC) from patients with a mouse/human heteromyeloma cell line, F3B6. To clarify the primary structure of IgG Fc constant regions produced locally by RSC, we amplified the cDNA corresponding to the CH2 and CH3 domains of an IgG1-, IgG2-, and an IgG3-producing hybridoma derived from RSC. The amplified DNA segments were cloned in M13 vectors and sequenced. Interestingly, very few differences in the nucleotide sequences were observed, and the deduced amino acid sequences were identical, except for the allotype, with those encoded by the human germline genes GEA and CL. Thus, the primary structure of the IgG1, IgG2, and IgG3 Fc regions produced by RSC were not altered when compared with those encoded by the unmutated human germline gene. These results suggest that factors other than altered IgG induce and sustain high avidity RF production in rheumatoid arthritis.

Expression of the major rheumatoid factor cross-reactive idiotype in pediatric patients with systemic lupus erythematosus

Rheumatoid factor cross-reactive idiotype (RF-CRI) is expressed in high concentrations in the sera of some patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). To determine if RF-CRI is specifically expressed in rheumatic disease or if it is secondary to polyclonal B-cell activation, we examined sera of 23 children with SLE, 16 adolescents with infectious mononucleosis (IM), and age-matched pediatric controls for RF-CRI expression. Concentrations of RF-CRI in serum, determined by an inhibition ELISA, were 24 ± 17 μg/ml (mean ± SD) in 25 normal children, 31 ± 17 in 16 young adults with IM, and were significantly increased, 70 ± 80 μg/ml, in the 23 children with SLE ( p < 0.036). Eleven of 23 SLE patients had serum RF-CRI greater than the mean ± 2 SD for normal children. Ten of 23 SLE sera contained IgM rheumatoid factor (RF) activity. One patient with IM had a borderline elevated RF-CRI level, and 5 IM patients had RF in their sera. The serum IgM concentrations in sera were: SLE (192 ± 93 mg/dl) and IM (234 ± 77 mg/dl) sera. These levels were significantly elevated compared to controls (132 ± 44 mg/dl), p < 0.031 for SLE and p < 0.001 for IM, suggesting that polyclonal activation of B cells was present in SLE and IM patient groups. Increased expression of RF-CRI in the SLE patients correlated directly with high titer anti-DNA antibody values ( r = 0.3965, p < 0.05) and RF activity when human IgG ( r = 0.5026, p < 0.05) was used as the RF binding substrate and inversely with serum C3 levels ( r = 0.3925, p < 0.05). RF-CRI expression did not correlate with RF that bound rabbit ( r = 0.3123, p < 0.05). Increased serum RF-CRI expression is not a result of polyclonal B-cell activation. RF-CRI may be selectively up-regulated in patients with SLE.

Evaluation of a Commercial Anti-Delta EIA Kit for Detection of Antibodies to Hepatitis Delta Virus

Anti-hepatitis delta virus (anti-HDV) antibodies were measured by solid phase IgG and IgM capture radioimmunoassays (RIA) as well as by a competitive binding enzyme immunoassay (EIA) in both acute and chronic HDV infections. EIA anti-delta test measures total delta antibody without discriminating IgM from IgG anti-delta. Low titer IgG antibodies were detected by both techniques with equal sensitivity. High titer IgG antibodies reached the end point sooner with EIA than with RIA (10(-3) versus greater than 10(-6)). When IgM anti-HDV was present without accompanying IgG anti-HDV, EIA failed to identify the antibody. Presence of high titer rheumatoid factor in the serum and lipemic samples produced false-positive results by EIA. Usage of undiluted serum samples for EIA probably exaggerates the factors contributing to false-positive reaction.

Rheumatoid factor production and polyclonal non-antiviral antibody responses elicited by infection with common mouse viruses

Rheumatoid factor (RF) production and antibody responses directed against antigens unrelated to infectious agents were measured in the serum of 129/Sv mice infected with various viruses. Some of these viruses induced a polyclonal B lymphocyte activation reflected by the presence of serum antibodies reacting in ELISA with dinitrophenylated albumin and with transferrin, but failed significantly to trigger the production of RF capable of agglutinating IgG2a-coated latex particles. In contrast, high RF serum levels were detected only in mice infected with an intestinal agent which was not able to induce other non-antiviral antibody responses. This observation indicates that the strong RF production previously reported in 129/Sv mice is a phenomenon specifically elicited by infection with this particular intestinal agent that cannot be explained by mere polyclonal B lymphocyte activation similar to that induced by common viruses.

Leg ulcers in rheumatoid arthritis

A retrospective study over an eight-year period of 33 episodes of leg ulceration in 26 patients with rheumatoid arthritis requiring inpatient management is reported. the aetiology of the ulcers was found to be multifactorial. The most common factors were venous insufficiency (45.5%), trauma or pressure (45.5%) and arterial insufficiency (36.4%). Vasculitis (18.2%) and Felty's syndrome (12.1%) were less frequent causes, and pyoderma gangrenosum was rare. Most patients had seropositive erosive disease with high rheumatoid factor titres and significant functional impairment; over half were on maintenance corticosteroids. Colonisation of the ulcers by organisms, predominantly Staphylococcus aureus, was common (69.7%). Skin grafting was required in 63.3%, but the rate of complete take was only 42.9% despite multiple attempts. Hospitalisation was prolonged (mean 47.9 days) and the recurrence rate requiring further hospitalisation was 26.9%. The diagnosis of vasculitis and the limited role of biopsy in establishing its presence are discussed.

An IgG subclass imbalance in connective tissue disease.

A group of 16 patients with a disproportionate polyclonal increase in their serum IgG1, resulting in raised concentrations of total IgG immunoglobulin, has been discovered. The other IgG subclasses in these patients are either normal or slightly reduced, resulting in an IgG1:IgG2 ratio of at least 10:1. Most cases are marked by the presence of anti-extractable nuclear antigen (anti-ENA) antibodies and high titres of rheumatoid factor and antinuclear antibody. All but one patient has a connective tissue disease, nearly twice the prevalence found in similarly hypergammaglobulinaemic patients without this IgG subclass imbalance. Among patients with systemic lupus erythematosus (SLE), those with the IgG1 disorder have a higher prevalence of high titre rheumatoid factor and antinuclear antibody, but a lower prevalence of anti-double-stranded DNA (anti-dsDNA) antibodies above 30 U/ml. It is suggested that this immunoglobulin abnormality may reflect a unique immunoregulatory dysfunction in these patients.

Acute rheumatoid factor positive (IgM) polyarthritis associated with a klebsiella pneumonitis

The authors report a case of a patient suffering from acute polyarthritis with a high rheumatoid factor titre, associated with a Klebsiella pneumonitis. A polyclonal B lymphocyte activation or a possible cross reaction between rheumatoid factor and an antigen related to Klebsiella may explain the elevated production of rheumatoid factor observed.

Immunoglobulin Class and Subclass Profile of the Ro/SS-A Autoantibody Response

We have developed an enzyme-linked immunosorbent assay (ELISA) for autoantibody to Ro/SS-A antigen (anti-Ro/SS-A) in order to more fully characterize the autoimmune response that occurs to this antigen in patients with subacute cutaneous lupus erythematosus (SCLE). The microtiter plate-immobilized, biochemically purified Ro/SS-A antigen reacted with anti-Ro/SS-A antibody, but not with other closely related specificities (anti-La/SS-B, anti-SM, anti-U1-RNP) or normal sera. The optimal pH of antigen-antibody reaction in this ELISA was 7.2. The binding of sera containing anti-Ro/SS-A was inhibited 80% by preincubation with the same amount of Ro/SS-A antigen used for coating the plate. Although 11 of the 14 (79%) SCLE sera studied had precipitating anti-Ro/SS-A antibody by immunodiffusion, 13 (93%) sera had abnormally elevated IgG, IgA, or IgM ELISA binding levels. A good correlation between IgG anti-Ro/SS-A ELISA binding levels and immunodiffusion titers was observed (r - 0.8588, p less than or equal to 0.001) suggesting that IgG is the major anti-Ro/SS-A antibody class detected by double immunodiffusion, Sera with a combination of high rheumatoid factor levels (latex 3+ or higher) and high anti-Ro/SS-A titers (1:8 or higher in immunodiffusion) tended to give an abnormally high IgM anti-Ro/SS-A ELISA binding levels. After rheumatoid factor activity was removed by absorption with heat-aggregated human IgG, a 50% decrease in IgM anti-Ro/SS-A ELISA binding was noted. On the other hand, absorption of rheumatoid factor-negative sera that contained high IgM anti-Ro/SS-A binding activity did not significantly decrease ELISA binding levels. Prednisone and 6-azathioprine reduced the level of IgG anti-Ro/SS-A autoantibody in sera of treated SCLE patients by 50%. The IgG subclass profile of anti-Ro/SS-A autoantibody was analyzed by using mouse monoclonal antibodies specific for the 4 human IgG subclasses. Of anti-Ro/SS-A positive SCLE sera, 91% had predominantly IgG1 subclass autoantibody. The coexistence of IgM and IgG anti-Ro/SS-A autoantibody and the predominance of the IgG1 subclass is compatible with the possibility that this autoantibody response is under T-cell control. The predominance of IgG1 in the autoimmune response to Ro/SS-A antigen in SCLE patients is consistent with the hypothesis that antibody dependent cell mediated cytotoxicity could be an important immunologic effector mechanism in this disorder.