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ID PMID Title PublicationDate abstract
8663901 Altered fatty acid, cholesterol and Na+/K+ ATPase activity in erythrocyte membrane of rheu 1996 May Rheumatoid arthritis (RA) is a chronic inflammatory disease whose cause remains obscure. Blood from 15 RA patients and controls was taken and their ghosts separated. The ghosts were analysed for cholesterol content, Na+/K+ ATPase activity and eicosapentaenoic acid. The cholesterol content in the ghosts of RA patients was significantly lower as compared with the set of controls. There was a major difference in the activity of Na+/K+ ATPase between the two groups with RA patients showing significantly elevated activity. The ghosts of the RA patients exhibited major abnormality in the polyunsaturated fatty acids of phospholipids with the level of eicosapentaenoic acid (omega-3, 20:5) being significantly reduced.
7797417 Reliability of three methods of radiologic assessment in patients with rheumatoid arthriti 1995 Mar RATIONALE AND OBJECTIVES: To assess the intraobserver reliability of three methods used frequently to evaluate joint destruction in rheumatoid arthritis: the Sharp method, the Larsen method, and the carpo:metacarpal ratio. METHODS: One observer analyzed twice within a 6-week interval 71 radiographs from patients with rheumatoid arthritis. Reliability was estimated by intraclass correlation coefficient (R) and by Altman-Bland graphical method. Correlations were examined by the Spearman's coefficient (r). RESULTS: The intraobserver reliability of each method appeared satisfactory with a good result for the Sharp method (R = 0.97). The correlation was strong (r > 0.80) between the results obtained by Sharp's and Larsen's methods and weaker between the results of the two former methods and the carpo: metacarpal ratio. CONCLUSIONS: Sharp's method should be used preferentially in studies evaluating the radiologic changes in rheumatoid arthritis over time, especially in clinical trials. The carpo:metacarpal ratio may be considered as a complementary method, when wrist destruction is of conceptual importance.
8782135 Presence of ED-A containing fibronectin in human articular cartilage from patients with os 1996 Jun OBJECTIVE: To determine whether normal (fetal and adult) and osteoarthritic (OA) and rheumatoid arthritic (RA) cartilage express a specific isoform of fibronectin, the extra domain A (ED-A) containing fibronectin (EDA+Fn). METHODS: Presence of fibronectin (EDA+Fn and native molecule) in cartilage matrix was studied using immunohistochemical assays with specific monoclonal antibodies. Fibronectins were identified by Western blots, in synovial fluids (SF) and cartilage extracts. RESULTS: EDA+Fn was either moderately present in the surface zone or undetectable in normal cartilage, while it was increased in OA cartilage surface. In one OA cartilage sample, EDA+Fn was localized in the matrix distant from the cartilage surface (patches of staining) and its presence was confirmed by immunoblotting. In RA cartilage EDA+Fn was present in the pericellular areas of the different layers. By Western blots, the presence of EDA+Fn was confirmed in OA SF (2/3) and RA SF (3/3) (with different patterns of fragmentation). CONCLUSION: EDA+Fn generally accumulates in the surface zone of OA cartilage, where it may play a role in extracellular matrix remodelling. Its presence was more abundant in SF and in cartilage from patients with RA.
7611036 Quantitative cerebral MR in rheumatoid arthritis. 1995 Apr PURPOSE: To determine the presence of hyperintense white matter lesions and atrophy reflecting cerebral vasculitis in rheumatoid arthritis. METHODS: Thirty-three patients with rheumatoid arthritis and 48 control subjects were examined with MR. Mean age was 45.1 years (range, 26 to 55 years) for the patients and 42.2 years (range, 25 to 55 years) in the control group. To determine atrophy we measured the area of corpus callosum, the cerebrum, and the cerebellum on midline sagittal sections. On transverse images, the ventricle-to-brain ratio, the bifrontal ratio, and the bicaudate ratio were selected as atrophy parameters. Area and signal intensity were measured for the biggest and the smallest lesions in both groups. RESULTS: Nine patients (27%) had hyperintense lesions compared with 15 (31%) of the control subjects. Mean numbers of hyperintense lesions were 1.3 in patients and 2.1 in control subjects. Mean area of the largest lesion in each patient was 27.4 mm2 for the patients and 29.8 mm2 in the control group. In patients with long disease duration (> 15 years) the mean ventricle-to-brain ratio was 0.09 compared with 0.08 in the control subjects. The midsagittal area of the cerebellum was 1349.8 mm2 in the patients with long disease duration and 1573.3 mm2 in the control group. No difference in number of hyperintense white matter lesions was detected between patients with long disease duration and the control subjects. Comparing the total group of patients with the control subjects, no significant differences in atrophy parameters or hyperintense white matter lesions were found. Also, there were no significant differences in relative signal intensity of the hyperintense lesions and corpus callosum between the two groups. We were not able to detect differences between treated versus untreated patients. CONCLUSION: This study indicates a tendency of more cerebral and cerebellar atrophy in patients with severe rheumatoid arthritis. The number and size of the white matter lesions were not significantly different in the two groups and do not support a higher frequency of even clinically silent infarcts caused by vasculitis in the patients with rheumatoid arthritis compared with control subjects.
8856817 Psychiatric aspects of rheumatology. 1996 Sep The rheumatic diseases pose significant and challenging problems for the consulting psychiatrist because of their multifaceted clinical features. Consideration must be given to the complexity of the social system in which the patient lives, the rheumatologist-patient relationship, the losses incurred by the illness, immunologic vulnerability to opportunistic infections, the effects of concurrent medical treatments (especially drug treatments), and any antecedent pathologic conditions. This article examines the clinical and treatment highlights of two representative rheumatologic diseases: rheumatoid arthritis and systemic lupus erythematosus.
7934491 Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis fact 1994 Oct 22 Tumour necrosis factor alpha (TNF alpha) is a critical inflammatory mediator in rheumatoid arthritis, and may therefore be a useful target for specific immunotherapy. In support of this hypothesis, we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a chimeric monoclonal antibody to TNF alpha (cA2). We now report the results of a four-centre, randomised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis. The primary endpoint of the study was the achievement at week 4 of a Paulus 20% response, an amalgam of six clinical, observational, and laboratory variables. Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time, compared with 11 of 25 patients treated with low-dose cA2 (p = 0.0083) and 19 of 24 patients treated with high-dose cA2 (p < 0.0001). Over half of the high-dose cA2 patients responded by the more stringent 50% Paulus criteria at this time (p = 0.0005). The magnitude of these responses was impressive, with maximum mean improvements in individual disease-activity assessments, such as tender or swollen-joint counts and in serum C-reactive protein, exceeding 60% for patients on high-dose treatment. There were two severe adverse events. 1 patient on 1 mg/kg cA2 developed pneumonia ("possibly" treatment-related) and 1 on 10 mg/kg had a fracture ("probably not" treatment-related). The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis.
8638438 Megakaryocyte-related interleukins in reactive thrombocytosis versus autonomous thrombocyt 1996 The primary thrombocytosis (thrombocythemia) associated with myeloproliferative disorders is believed to be due to autonomous platelet production. Secondary or reactive thrombocytosis can be observed in a number of clinical circumstances, and may be related to persistent overproduction of some thrombocytopoietic factors acting on megakaryocytes. Several cytokines, including IL-6, IL-1 and IL-4 have been shown to act alone or in concert, to affect various cellular stages of megakaryocytopoiesis in humans. The aim of this study is to assess the serum concentrations of these cytokines in myeloproliferative disorders (MPD) with thrombocythemia and in rheumatoid arthritis (RA) with marked reactive thrombocytosis. Twenty-two patients (14 men, 8 women) with MPD and thrombocythemia (platelet counts > 500 x 10(9)/1; range 507-996 x 10(9)/1), 33 RA patients (28 women, 5 men) with marked thrombocytosis (platelet counts > 500 x 10(9)/1; range 500-745 x 10(9)/ 1), 27 RA patients (24 women, 3 men) with normal platelet counts (range 168-399 x 10(9)/1) and 15 healthy volunteers (8 women, 7 men) with normal platelet counts (range 161-385 x 10(9)/1) enrolled in the study. Serum IL-1 alpha, IL-1 beta, IL-4 and IL-6 concentrations were measured in these four groups. Of the 22 patients with MPD, 10 had chronic myelogenous leukemia, 5 had polycythemia vera, 6 had essential thrombocytosis and 1 had osteomyelofibrosis. Serum interleukin concentrations in patients with MPD and thrombocythemia were either suppressed or similar to those of normal subjects, whereas IL-6, IL-1 beta and IL-4 levels were increased in RA patients with reactive thrombocytosis. We conclude that thrombocythemia associated with MPD is an autonomous phenomenon, and is not regulated by cytokines which affect megakaryocytopoiesis.
8162643 Cytokine concentrations in the synovial fluid and plasma of rheumatoid arthritis patients: 1994 Jan Cytokines are important protein mediators in inflammatory joint diseases. The synovial fluid and plasma concentrations of interleukin-1 alpha (IL-1 alpha), interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-alpha), interferon-alpha (IF-alpha) and interferon-gamma (IF-gamma) were measured by RIA and ELISA in 28 rheumatoid arthritis (RA) patients (5 males and 23 females). Ten patients with knee effusions due to other causes (osteoarthritis, psoriasis, gout, rheumatic fever, systemic lupus erythematosus) were also studied. Eight of the RA patients had erosive disease. The synovial fluid IL-1 alpha and IL-2 concentrations were higher in Group 1 (erosive) [IL-1 alpha: 524 pg/ml (SEM: 127), IL-2: 3.28 ng/ml (SEM: 1.0)] than in either Group 2 (non-erosive) [IL-1 alpha: 241 pg/ml (SEM: 24), IL-2: 1.93 ng/ml (SEM: 0.6)] or Group 3 (non-RA) [IL-1 alpha: 267 pg/ml (SEM: 58), IL-2: 0.35 ng/ml (SEM: 0.6)] (p < 0.003 and p < 0.06 respectively). Plasma IL-1 and IL-2 levels were higher in Group 1 [IL-1 alpha: 408 pg/ml (SEM: 107), IL-2: 4.20 ng/ml (SEM: 1.5)] than in Group 2 [IL-1 alpha 150 pg/ml (SEM: 15), IL-2: 2.58 ng/ml (SEM: 0.7)] or Group 3 [IL-1 alpha: 140 pg/ml (SEM: 11), IL-2: 1.93 ng/ml (SEM: 0.3)] (p < 0.01, p < 0.009 respectively). There were no differences in the IFN-alpha, IFN-gamma or TNF-alpha levels between groups. These findings suggest that plasma cytokines levels may reflect synovial levels and that IL-1 alpha may play a significant role in erosive joint disease.
8022742 Monoclonal antibody therapy in rheumatic disease. 1994 Mar 19 In rheumatic disease, monoclonal antibodies have been used for the treatment of refractory rheumatoid arthritis, systemic lupus erythematosus, unresponsive vasculitis and relapsing polychondritis. Our greatest experience has however been with rheumatoid arthritis. After molecular engineering, hybrid monoclonal antibodies constructed from animal sources become largely human, and thus well tolerated, and highly specific. They can be focused selectively to particular targets, but the problem is to identify the causative antibody. In rheumatoid arthritis, we do know a great deal about the pathogenesis of the disease and rational targets can be selected. The major histocompatibility complex class II molecules would theoretically be the most effective target, but no specific antigen has been identified. Total blockade of all class II molecules would probably result in unacceptable immunosuppression. Despite this handicap, anti-HLA-DR4 monoclonal antibodies have been used in humans in an attempt to generate an anti-idiotypic response against DR4. T lymphocytes are known to play a major role in the pathogenesis of rheumatoid arthritis, thus targeting their surface markers would be a reasonable approach to monoclonal antibody therapy. Trials have been conducted using antibodies against the surface markers CD7, CD5, CDw52 and CD4. Further work has centered on differentiation antigens. Preliminary evidence suggests anti-interleukin-2-receptor monoclonal antibodies may be effective in rheumatoid arthritis. There have also been reports of attempts at anti-cytokine immunotherapy. Adhesion molecules would be another potential target. The ongoing trials have given us much insight into the pathogenesis of rheumatoid diseases and led us to the stage where we are now attempting to identify appropriate therapeutic regimes and combinations to maximise patient benefit. At present, we must continue our research for the causative antigen.
8774550 Combination therapy of cyclosporine A with methotrexate or hydroxychloroquine in refractor 1996 We evaluated the efficacy and toxicity of cyclosporine A (CsA) in combination with methotrexate (MTX) or hydroxychloroquine (HCQ) in patients with refractory rheumatoid arthritis (RA). Fourteen patients with active RA who had failed to respond adequately to injectable MTX and 14 who had failed to respond to oral HCQ had CsA added to their regimens for 6 months. Adverse effects were monitored every 2 weeks for 2 months, and monthly thereafter; outcome parameters were assessed at 0, 3, and 6 months. The starting dose of CsA was 2.5 mg/kg/day in both groups. Twenty-four patients (12 in each group) completed the 6-month study. All clinical variables (except grip strength in the HCQ + CsA group) significantly improved with both treatment regimens. Global efficacy was evaluated by means of the composite Chronic Arthritis Systemic Index. Fifteen patients (9 in the MTX + CsA and 6 in the HCQ + CsA group) could be considered responders, and 9 non-responders. The final mean daily dose of CsA was 3.3 +/- 0.8 mg/kg in the HCQ + CsA group and 3.1 +/- 0.9 mg/kg in the MTX + CsA group. Mild adverse events were more frequently observed in the MTX-CsA than in HCQ + CsA-treated patients (33 events in 11 patients as against 20 in nine). In combination with HCQ or MTX, CsA, over a 6 month period, may improve efficacy in patients with refractory RA without any significant increase in toxicity; MTX + CsA seems to be slightly more efficacious and more toxic than HCQ + CsA. Larger prospective controlled trials are necessary to define the efficacy of these combinations.
1523527 [Cricoarytenoid joint involvement in rheumatoid arthritis]. 1992 Jun The cricoarytenoid (CA) joint, which controls the vocal cords, is diarthrodial; it is composed of two cartilages with a ligamentous capsule lined by synovial membrane. It has been known that inflammation of CA joint occurs sometimes in patients with rheumatoid arthritis (RA). Yet, so far, no detailed full-report on this subject has ever been made in this country. Here we report four RA cases with CA joint ankylosis or abduction disturbance due to progression of CA arthritis. Episodes of inspiratory dyspnea were observed in all cases and tracheostomy was performed in case 1 and case 2. Further surgical intervention i.e., tracheoplasty was necessary in case 2. Case 3 and case 4 have been followed conservatively thus far. Clinical surgical interventions were necessitated mainly with joint replacement, 3) there exists severe destruction of cervical spines as well as temporomandibular joints. Rheumatologist must be fully aware of how urgent this clinical entity is and not miss-diagnose+ these patients.
1455366 [Immunological disorders in different clinical variants of rheumatoid arthritis]. 1992 The authors present the current data on the disorders of immune functions in patients suffering from rheumatoid arthritis (RA). Provide evidence for the pathogenetic heterogeneity of the known clinical patterns of RA, mainly seronegative and seropositive varieties, with special reference to the differences in the lowering of the activity of nonspecific T suppressors, to the influence of the factor of necrosis of alpha-tumor and alpha- and beta-interferons on B lymphocyte proliferation, and to the effects of synovial exudate from seropositive and seronegative patients. Demonstrate the results of integral estimation of the disorders of several characteristics of the immune system in RA patients with the use of the image recognition program. It is concluded that the clinical polymorphism of RA is specified by the pathogenetic heterogeneity of the disease based on varieties of combined normal and altered functions of different components of the immune system.
8549033 Comparison of the dapsone recovery ratio and the erythromycin breath test as in vivo probe 1996 Jan INTRODUCTION: Cytochrome P4503A (CYP3A) is primarily responsible for the metabolism of cyclosporine and that of many other drugs. Several substrates of CYP3A have been investigated for use as pharmacologic probes to predict the CYP3A-metabolizing capacity of an individual and, therefore, the disposition of other CYP3A substrate drugs. One such measure of CYP3A activity is the 14C erythromycin breath test, which has been applied to the prediction of cyclosporine disposition. However, the test has practical limitations. Because of this, the 0- to 8-hour urinary dapsone recovery ratio has been studied as an alternative and more practical probe of CYP3A activity. METHODS: The dapsone recovery ratio and the 14C erythromycin breath test were correlated with cyclosporine concentrations in 16 patients with rheumatoid arthritis to determine the usefulness of the dapsone recovery ratio as an alternative to the 14C erythromycin breath test. The erythromycin breath test showed a fourfold variation between subjects and correlated weakly with trough cyclosporine concentrations (r = -0.50, p < 0.05), whereas the dapsone recovery ratio varied only approximately twofold between subjects and did not correlate with trough cyclosporine concentrations (r = 0.02, p = 0.94). The correlation between the dapsone recovery ratio and the erythromycin breath test (r = 0.22, p = 0.41) was not significant. CONCLUSIONS: These data suggest that results obtained with one probe in vivo may not apply to another CYP3A substrate. The poor quantitative relationship between cyclosporine concentrations and the erythromycin breath test limits its usefulness in the prediction of an individual's cyclosporine dose requirement.
7801202 [Primary biliary cirrhosis, rheumatoid arthritis and Sjögren's syndrome following implant 1994 Oct A 73-year old male was received implantation of ventriculoperitoneal shunt tube (made with silicone) following subarachnoid hemorrhage in March 1991. Alkaline phosphatase was elevated gradually and he was diagnosed as having primary biliary cirrhosis by antimitochondria antibody and liver biopsy. He had been taking urso acid after that time on. He was admitted to our hospital because of stiffness and edema of both hands in November 1993. He was diagnosed as rheumatoid arthritis by morning stiffness with duration of few hours bilateral swelling of metacarpal, proxymal intrapharangeal and wrist joints and positive rheumatoid factor. In addition he felt dry mouth and laboratory data revealed that antinuclear antibody was 640x, centromere type, anti-SS-A antibody positive and elevation of circulating immune complex. A salivary gland disfunction was showed by gum test and salivary gland scintigraphy. Therefore the diagnosis of Sjögren's syndrome was made also. Connective tissue diseases have been reported to occur following cosmetic surgery with injection of the foreign substances paraffin and silicone. Now it is supposed to be the first case tcat connective tissue disease following ventriculoperitoneal shunt tube implantation.
8670316 Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist 1996 Jul OBJECTIVE: To preliminarily evaluate the safety and efficacy of different dose levels and dosing frequencies of recombinant human interleukin-1 receptor antagonist (rHuIL-1Ra) in the treatment of patients with rheumatoid arthritis (RA). METHODS: One hundred seventy-five patients with active RA were enrolled in a randomized, double-blind trial of rHuIL-1Ra administered by subcutaneous injection. There were 9 treatment groups in the trial. During the initial 3-week treatment phase, patients were treated with 20, 70, or 200 mg rHuIL-1Ra, administered either once, 3 times, or 7 times per week, followed by a 4-week maintenance phase, during which all patients received the treatment-phase dose once per week. To maintain the blindness of the study, patients received daily injections of either rHulL-1Ra or placebo on the days rHuIL-1Ra was not administered. RESULTS: Recombinant HuIL-1Ra was well tolerated. The most frequent adverse event was injection-site reactions, which were reported in 62% of patients and caused 8 patients (5%) to withdraw prematurely from the study. Five patients (3%) developed serious adverse reactions unrelated to dose or dosing frequency. Due to the lack of a placebo arm and to the multiple small treatment groups, a definitive statement regarding efficacy could not be made. However, by the end of the 3-week treatment phase, daily dosing appeared more effective than weekly dosing when assessed by the number of swollen joints, the investigator and patient assessments of disease activity, pain score, and C-reactive protein levels. CONCLUSION: These preliminary data suggest that rHuIL-1Ra may be safely administered by subcutaneous injection to RA patients. The frequency of dosing appears to be important in determining clinical response, with daily administration providing the most benefit. A placebo-controlled trial is in progress to further assess the clinical usefulness and to better define appropriate doses of rHuIL-1Ra in patients with RA.
1285039 Prevalence of thyroid abnormalities in patients with rheumatoid arthritis. 1992 Dec The prevalence of thyroid abnormalities was determined in 131 patients: group I = rheumatoid arthritis, 68 patients, group II = systemic immunological diseases (IIa Sjögren's syndrome, n = 6; IIb other rheumatic autoimmune disease, n = 17), group III = other rheumatic diseases n = 13 and control group (n = 27). Thyroid abnormalities (hypo, hyperthyroidism, nodular goiter) were frequent: 33.8% in group I, 100% in group IIa, 11.7% in group IIb. Hypothyroidism was present in 19.1% (group I), 50% (group IIa). 6% (group IIb). Autoimmune thyroiditis was found in 16.2% in group I, 100% in group IIa, 11.7% in group III. Thyroid diseases are frequent in patients with rheumatoid arthritis. Therefore thyroid tests might be performed in patients with rheumatoid arthritis.
7699616 Levels of hepatocyte growth factor in synovial fluid and serum of patients with rheumatoid 1994 Dec OBJECTIVE: To determine the levels of hepatocyte growth factor (HGF) in synovial fluids (SF) and sera from patients with rheumatoid arthritis (RA); to examine how these correlate with several disease variables in patients with RA and with levels of interleukin-6 (IL-6) in SF of these patients; and to examine whether HGF is released from adherent synovial cells (ASC) and synovial fluid cells (SF cells). METHODS: An enzyme linked immunosorbent assay was used to measure levels of HGF and IL-6. SF samples were obtained from 22 patients with RA, 12 with osteoarthritis (OA), and one with septic arthritis. Serum samples were collected from 40 patients with RA. HGF levels in culture supernatants from ASC and SF cells were measured. RESULTS: The mean values of HGF in SF were 1.21 ng/ml for patients with RA, 0.19 ng/ml for those with OA and 0.18 ng/ml for the one with septic arthritis. HGF levels in SF of patients with RA were significantly higher than of those with OA (p < 0.01). The levels for patients with RA correlated with the serum C-reactive protein concentrations (r = 0.626, p < 0.01) and IL-6 levels in SF (r = 0.476, p < 0.05). The mean value of HGF in sera from patients with RA was 0.28 ng/ml. HGF levels in SF were higher than those in sera drawn simultaneously from the same patients with RA. In vitro, release of HGF from rheumatoid ASC was not detected. However, SF cells from patients with RA released HGF spontaneously. CONCLUSION: Our observations suggest that HGF in SF of patients with RA is produced by SF cells and is related to disease activity of RA, and thus that HGF may play a role in RA.
8541818 Chronic eosinophilic pneumonia in rheumatoid arthritis. 1995 Oct We report the case of a 47 year old woman with rheumatoid arthritis and infiltrates on chest radiogram. Typical features of eosinophilic pneumonia were detected upon open lung biopsy, probably unrelated to hydroxychloroquine, the only drug administered to the patient. Good response to steroids was obtained. This case brings to light one more example of the rare association between chronic eosinophilic pneumonia and rheumatoid arthritis.
8144071 [Swanson prosthesis or resection arthroplasty? A comparative study]. 1993 Sep Two different surgical methods for basal joint arthrosis (implantation of a Swanson condylar prosthesis and resection arthroplasty) are compared. The medium-term results are roughly comparable. However, the indication for prosthesis implantation is much more limited than that of resection arthroplasty.
7509350 Rheumatoid factors from the peripheral blood of two patients with rheumatoid arthritis are 1994 Feb We report the DNA sequences of the heavy and light chain immunoglobulin genes of 11 monoclonal rheumatoid factor (RF)-secreting lines derived from the peripheral blood of two patients with rheumatoid arthritis (RA). It is evident from immunogenetic analysis of these lines that RA-associated RF activity can arise from a wide variety of heavy and light chain genes and gene combinations. Although the RF response from our two patients shows a bias in gene usage toward those genes used to encode monoclonal RF, particularly VkIII, relatively few of these RFs are reactive with the monoclonal antiidiotypes 6B6.6 and 17.109 that define VkIII germline-encoded light chains and the loss of this idiotypic reactivity is clearly related to somatic mutation. Finally, RFs derived from peripheral blood of RA patients show a similar heterogeneity of epitope binding to Fc as that seen for synovium-derived RF and some are clearly different in binding specificity from the restricted RF population found in patients with B cell malignancies. Somatic mutations as well as different VH/VL combinations contribute to the heterogeneity in the binding patterns of these RA-derived RF.