Severity Of Joint Destruction Research Articles

Mangiferin exert protective effects on joints of adjuvant-induced arthritis rats by regulating the MAPKs/NF-κB pathway of fibroblast-like synoviocytes

BackgroundMangiferin (MF) is a bioactive ingredient predominantly isolated from the mango tree, that has been reported to have antioxidant, anti-inflammatory, and immunomodulatory effects. This study was aimed to investigate the protective effect of MF on the joints of arthritic rats and explore the underlying mechanisms of this function. MethodsAdjuvant-induced arthritis (AA) rat model was established and clinical severity of AA was evaluated by arthritis index, paw edema, plasma, and synovium homogenate parameters. The severity of joint destruction was assessed by radiological and histopathological. Immunohistochemical analysis was employed to detect the protein expression of MMP-3, MMP-13 in synovium and cartilage tissues. The vitro effects of MF on proliferation, migration, apoptosis, and production of inflammatory mediators in RA- FLSs were determined by the CCK8 assay, transwell assay, flow cytometry, and real-time PCR, respectively. ResultsThe results demonstrated that MF treatment significantly alleviated arthritis index, paw swelling and decreased the secretion of inflammatory cytokines in plasma and synovium. Meanwhile, MF inhibited synovial inflammation, pannus formation, and bone erosion in AA rats. It also ameliorated the oxidative stress state of arthritic rats via modulating the level of MDA, SOD, CAT, GSH, NO. In addition, MF effectively attenuated the destructive behavior of RA-FLSs by inhibiting proliferation, migration, and secretion of inflammatory mediators, and promoting apoptosis. The further mechanistic analysis demonstrated that MF might exert an antiarthritic effect via inhibiting the pathway of MAPKs (ERK2 and p38) and NF-κ B. ConclusionTaken together, our results demonstrated that MF would be a promising anti-arthritic agent candidate for further research.

Mass-spectrometric identification of carbamylated proteins present in the joints of rheumatoid arthritis patients and controls

Antibodies targeting post-translationally modified proteins, such as anti-carbamylated protein antibodies (anti-CarP antibodies) are present in the sera of rheumatoid arthritis (RA) patients. These autoantibodies associate with increased risk of RA development and with severity of joint destruction. It is not known which proteins in the RA joint are recognised by anti-CarP antibodies. Therefore, we investigated the presence and identity of carbamylated proteins in the human (inflamed) joint. We obtained synovium, cartilage and synovial fluid from RA joints. Cartilage and synovium were obtained from controls. Samples were processed and used for immunohistochemistry or mass-spectrometric analysis to investigate the presence of carbamylated proteins. Anti-CarP antibody reactivity towards identified carbamylated proteins was tested by ELISA. Immunohistochemistry showed extensive staining of RA and control synovial tissue. Whole proteome analyses of the joint tissues revealed a large number of carbamylated peptidyllysine residues. We identified many carbamylated proteins in cartilage and were also able to detect carbamylation in synovial tissue and synovial fluid. Carbamylation was not exclusive to the RA joint and was also present in the joints of controls. Anti-CarP antibodies in the sera of RA patients were able to recognise the identified carbamylated proteins. We conclude that numerous carbamylated proteins are present in the RA joint. These carbamylated proteins can be recognised by anti-CarP antibodies, substantiating the notion that anti-CarP antibodies may play a role in the pathogenesis of RA.

Blockade of Discoidin Domain Receptor 2 as a Strategy for Reducing Inflammation and Joint Destruction in Rheumatoid Arthritis Via Altered Interleukin-15 and Dkk-1 Signaling in Fibroblast-Like Synoviocytes.

This study was undertaken to uncover the pathophysiologic role of discoidin domain receptor 2 (DDR-2), a putative fibrillar collagen receptor, in inflammation promotion and joint destruction in rheumatoid arthritis (RA). In synovial tissue from patients with RA and from mice with collagen antibody-induced arthritis (CAIA) (using Ddr2-/- and DBA/1 mice), gene and protein expression levels of DDR-2, interleukin-15 (IL-15), and Dkk-1 were measured by quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Gene knockdown of DDR2 in human RA fibroblast-like synoviocytes (FLS) was conducted via small interfering RNA. Interaction between the long noncoding RNA H19 and microRNA 103a (miR-103a) was assessed in RA FLS using RNA pulldown assays. Cellular localization of H19 was examined using fluorescence in situ hybridization assays. Chromatin immunoprecipitation and dual luciferase reporter assays were applied to verify H19 transcriptional and posttranscriptional regulation by miR-103a. DDR2 messenger RNA (mRNA) expression was significantly associated with the levels of IL-15 and Dkk-1 mRNA in the synovial tissue of RA patients (r2 = 0.2022-0.3293, all P < 0.05; n = 33) and with the serum levels of IL-15 and Dkk-1 in mice with CAIA (P < 0.05). In human RA FLS, activated DDR-2 induced the expression of H19 through c-Myc. Moreover, H19 directly interacted with and promoted the degradation of miR-103a. These results indicate a novel role for activated DDR-2 in RA FLS, showing that DDR-2 is responsible for regulating the expression of IL-15 and Dkk-1 in RA FLS and is involved in the promotion of inflammation and joint destruction during pathophysiologic development of RA. Moreover, DDR-2 inhibition, acting through the H19-miR-103a axis, leads to reductions in the inflammatory reaction and severity of joint destruction in mice with CAIA, suggesting that inhibition of DDR-2 may be a potential therapeutic strategy for RA.

The Influence of LPS-Induced Maternal Inflammation on Postnatal Collagen-Induced Arthritis.

Maternal health and nutritional status influence offspring health and the diseases that may develop in them. The effects of maternal inflammation on offspring from the perspective of the inflammatory response and immune changes are not fully understood. We hypothesized that maternal inflammation modulates immune and metabolic functions, affecting the pathophysiology of inflammatory diseases in offspring. This study investigated whether maternal inflammation affects the onset of collagen-induced arthritis (CIA), a murine model of human rheumatoid arthritis. Female DBA/1J mice received a single intraperitoneal injection of lipopolysaccharide (LPS) 5days before conception. Male offspring of LPS-treated dams were placed in the maternal LPS group (MLG). To induce CIA, type II collagen (CII) was emulsified with Freund's complete adjuvant and injected twice into each mouse, at 13 and 16weeks. The offspring were sacrificed at 26weeks to analyze immunological and metabolic parameters. The degree of joint swelling at an early stage of CIA was lower in the MLG than in the control group. From histological analysis, the severity of joint destruction (severity of arthritis score) and CII-specific IgG titer were significantly lower in the MLG. However, at 26weeks, serum interleukin (IL)-6 levels, an index of CIA disease activity, were significantly higher in the MLG. Moreover, serum leptin levels were lower in the MLG, and a negative correlation between leptin and serum IL-6 was observed. In conclusion, maternal inflammation does not merely suppress inflammation; it may delay CIA in offspring. The analysis of inflammatory cytokines and leptin concentrations at 26weeks suggests that the pathophysiology of arthritis was worsening. This study also suggests that maternal inflammation modulates postnatal inflammatory response patterns in offspring.

Serum levels of the bone turnover markers dickkopf-1, osteoprotegerin, and TNF-α in knee osteoarthritis patients.

Knee osteoarthritis (KOA) is a common degenerative joint disease causing pain, stiffness, reduced motion, swelling, crepitus, and disability. Several inflammatory markers and cartilage degradation products can be used as biomarkers in OA. The key factors of bone metabolism in normal joint bone, dickkopf-1 (DKK1) and osteoprotegerin (OPG), interact with Wnt signaling pathway, balancing between bone absorption and bone reconstruction. TNF-α is a key inducer of DKK-1, which belongs to the family of proteins involved in joint remodeling. The present study compared the serum levels of DKK1, TNF-α, and OPG in patients with KOA and healthy controls to analyze the interrelationship and the severity of joint destruction. One hundred forty-eight patients with KOA and 101 healthy controls were enrolled in this study. Anteroposterior knee radiographs determined the severity of the disease in the affected knee. The radiographic grading of KOA was performed by the Kellgren-Lawrence criteria. Serum levels of DKK-1, TNF-α, and OPG were estimated using the multiplex particle-based flow cytometry. Higher serum levels of OPG and TNF-α were observed in KOA than the controls; KOA patients showed a lower serum level of DKK-1, whereas the serum levels of DKK1 correlated with the progression of KOA. The serum levels of TNF-α, OPG, and DKK-1 correlated with incident KOA. In the ROC curve analysis, DKK1 levels showed 78.6% sensitivity and 40% specificity, TNF-α levels showed 74.1% sensitivity and 76.0% specificity, and OPG showed 88.1% sensitivity and 81% specificity in predicting severe KOA. In the univariate and multivariate analyses, TNF-α and OPG emerged as independent predictors of severe KOA. This study, for the first time, combined TNF-α, DKK1, and OPG as valuable biological markers in predicting the severity of KOA radiographically in the clinic. This study also supported the inflammation-induced DKK1 and OPG in OA pathogenesis.

Dynamics of Destructive Joint Changes in Juvenile Idiopathic Arthritis in Children who Received Methotrexate or Methotrexate-Tocilizumab Combination: a Cohort Study

Background. Destructive joint damages in juvenile arthritis inevitably lead to persistent disability in adulthood. These consequences can be avoided by resorting to early therapy of the disease. Objective . Our aim was to assess the dynamics of destructive joint changes in juvenile idiopathic arthritis (JIA) in children, depending on a basic therapy. Methods . We studied the treatment results of children with systemic-onset JIA with active joint syndrome without active systemic manifestations hospitalized in the regional clinical cardiological health center. JIA activity criteria at the time of hospitalization: 3 joints with active arthritis; the assessment of the disease activity by a doctor 3 points out of 10; the assessment of wellbeing by the patient or a parent 3 points out of 10; the appointment of basic therapy no later than 6 months from the disease onset. Treatment results were compared in the groups of methotrexate (hospitalization from January 2008 to December 2010) and methotrexate + tocilizumab (January 2014 — September 2016). The main outcome of JIA therapy was the severity of joint destruction in 6, 12 and 24 months as determined by the modified Sharpe ratio according to radiographs obtained from patients' medical records. Results. The study groups were comparable in terms of sex and age of the patients, JIA onset age, the disease activity at the time of hospitalization, and the initial assessment of joint destruction — (median) 165 (131; 187) and 162 (124; 171) (p = 0.116). Under pressure of therapy, the modified Sharpe score in the group of methotrexate monotherapy was higher than in the group of combined therapy: in 6 months — 142 (126; 163) and 87 (72; 112) (p &lt; 0.001); in 12 months — 166 (121; 210) and 75 (29; 89) (p &lt; 0.001); in 24 months — 165 (113; 198) and 52 (26; 73) (p &lt; 0.001). At the first administration of tocilizumab, 4 children had nausea and abdominal pain, and 3 children had headache. Conclusion . Basic therapy with methotrexate and tocilizumab inhibits the destruction of joints in patients with systemic-onset JIA with active joint syndrome without active systemic manifestations.

An investigation of the added value of an ACPA multiplex assay in an early rheumatoid arthritis setting

IntroductionRecently, arrays have become available that allow the simultaneous analysis of several anti-citrullinated protein antibody (ACPA) reactivities using distinct citrullinated peptides. Such assays are designed for exploratory studies. The interpretation of positive antibody reactivities can best be made if the diagnostic and prognostic value of a multiplex array in an early arthritis setting is known and if the multiplex-positive patients who are negative according to three commonly used commercial ACPA assays are characterized.MethodsUsing Thermo Scientific’s ImmunoCap ISAC (Immuno Solid-phase Allergen Chip) system, a multiplexed array that determines reactivities to 11 citrullinated peptides, we analysed serum/plasma of 195 healthy controls and 1282 early arthritis patients from two independent cohorts: the Leiden Early Arthritis Clinic (n = 1013) and the IMPROVED (n = 269) cohort. Findings were compared with results primarily of the anti-citrullinated cyclic peptide 2 (anti-CCP-2) assay but also with anti- CCP-3 and anti-mutated citrullinated vimentin (anti-MCV) assays. The associations between ACPA reactivities and patient characteristics, risk factors (shared epitope, smoking) and disease outcomes (progression of undifferentiated arthritis to rheumatoid arthritis (RA) and severity of joint destruction) were assessed.ResultsThirty-one percent of anti-CCP-2-negative RA patients displayed reactivity toward citrullinated peptides in the multiplex assay. These patients had a positive signal toward a more restricted peptide repertoire than anti-CCP-2-positive RA patients (median of 1 versus 5). Within anti-CCP-2-negative patients, ACPA reactivity as detected by multiplex array was not significantly associated with known risk factors or clinical or prognostic parameters. The frequency of sera from anti-CCP-2-negative RA patients who were positive for the multiplexed peptides was comparable to the frequency in non-RA arthritic patients (27 %).ConclusionsAdditive citrulline peptide reactivities detected by the current multiplex system did not reach significant power to be RA-specific. The presence of residual citrulline reactivities detected by this multiplex system in arthritis patients who are negative in commercial ACPA assays needs to be interpreted with caution.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0786-z) contains supplementary material, which is available to authorized users.

Genetic Factors for the Severity of ACPA-negative Rheumatoid Arthritis in 2 Cohorts of Early Disease: A Genome-wide Study.

Rheumatoid arthritis (RA) that is negative for anticitrullinated protein antibodies (ACPA) is a subentity of RA, characterized by less severe disease. At the individual level, however, considerable differences in the severity of joint destruction occur. We performed a study on genetic factors underlying the differences in joint destruction in ACPA-negative patients. A genome-wide association study was done with 262 ACPA-negative patients with early RA included in the Leiden Early Arthritis Clinic and related to radiographic joint destruction over 7 years. Significant single-nucleotide polymorphisms (SNP) were evaluated for association with progression of radiographic joint destruction in 253 ACPA-negative patients with early RA included in the Better Anti-Rheumatic Farmaco Therapy (BARFOT) study. According to the Bonferroni correction of the number of tested SNP, the threshold for significance was p < 2 × 10(-7) in phase 1 and 0.0045 in phase 2. In both cohorts, joint destruction was measured by Sharp/van der Heijde method with good reproducibility. Thirty-three SNP associated with severity of joint destruction (p < 2 × 10(-7)) in phase 1. In phase 2, rs2833522 (p = 0.0049) showed borderline significance. A combined analysis of both the Leiden and BARFOT datasets of rs2833522 confirmed this association with joint destruction (p = 3.57 × 10(-9)); the minor allele (A) associated with more severe damage (for instance, after 7 yrs followup, patients carrying AA had 1.22 times more joint damage compared to patients carrying AG and 1.50 times more joint damage than patients carrying GG). In silico analysis using the ENCODE and Ensembl databases showed presence of H3K4me3 histone mark, transcription factors, and long noncoding RNA in the region of rs2833522, an intergenic SNP located between HUNK and SCAF4. Rs2833522 might be associated with the severity of joint destruction in ACPA-negative RA.

THU0469 Genetic Variants in IL-6, IL-10, C5-TRAF1 and FCRL3 and Progression of Joint Damage in Rheumatoid Arthritis; A Study on Six Cohorts

BackgroundThanks to the introduction of novel treatments and up-to-date treatment strategies, the severity of joint destruction in rheumatoid arthritis (RA) has decreased considerably. Nonetheless, in daily clinical practice radiographic progression...

THU0458 Analysis of Genetic Factors Associated with Progression of Functional Disability in Japanese Patients with Rheumatoid Arthritis

BackgroundRheumatoid arthritis (RA) is characterized by chronic inflammation and joint destruction, resulting in deteriorated physical function. Genetic predisposition factors associated with the susceptibility to RA and the severity of joint...

AB0147 Role of Sclerostin in Rheumatoid Arthritis: New Insights

BackgroundRheumatoid arthritis (RA) is an autoimmune-inflammatory disease that may lead to joint destruction and disability Several key molecules are involved in the regulation of osteoclast differentiation, which are induced upon...

THU0020 Serum pyridinoline levels predict the severity of future joint destruction in rheumatoid arthritis

BackgroundThe identification of early rheumatoid arthritis (RA) patients that will develop a progressive destructive disease course is important to enable adjusting the treatment strategy to individual patients’ prospects. Previous studies...

OP0089 Genetic studies on DICKKOPF-1, sclerostin and the severity of joint destruction in rheumatoid arthritis

BackgroundInflammation in Rheumatoid Arthritis leads to impaired bone formation. The activity of the Wnt pathway influences osteoblast differentiation. Dickkopf-1 (Dkk1) and Sclerostin (Sost) are important negative regulators of bone formation,...

Associations between APOE genotypes and disease susceptibility, joint damage and lipid levels in patients with rheumatoid arthritis.

ObjectiveApolipoprotein E (APOE) genotypes are associated with cardiovascular disease (CVD) and lipid levels. In rheumatoid arthritis (RA), an association has been found with disease activity. We examined the associations between APOE genotypes and disease susceptibility and markers of disease severity in RA, including radiographic joint damage, inflammatory markers, lipid levels and cardiovascular markers.MethodA Norwegian cohort of 945 RA patients and 988 controls were genotyped for two APOE polymorphisms. We examined longitudinal associations between APOE genotypes and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) as well as hand radiographs (van der Heijde Sharp Score(SHS)) in 207 patients with 10 year longitudinal data. Lipid levels, cardiovascular markers and history of CVD were compared across genotypes in a cross sectional study of 136 patients. Longitudinal radiological data of cohorts from Lund and Leiden were available for replication. (N = 935, with 4799 radiographs).ResultsIn the Norwegian cohort, associations between APOE genotypes and total cholesterol (TC) and low-density lipoproteins (LDL) were observed (ε2<ε3/ε3<ε4, p = 0.03 and p = 0.02, respectively). No association was present for acute phase reactant or CVD markers, but a longitudinal linear association between APOE genotypes and radiographic joint damage was observed (p = 0.007). No association between APOE genotypes and the severity of joint destruction was observed in the Lund and Leiden cohorts, and a meta- analysis combining all data was negative.Conclusion APOE genotypes are associated with lipid levels in patients with RA, and may contribute to dyslipidemia in some patients. APOE genotypes are not consistently associated with markers of inflammation or joint destruction in RA.

Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis

BackgroundProgression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/β-catenin...

Association of a single‐nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis

The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction. RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n=563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti-citrullinated protein antibody (ACPA)-positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study. The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P=0.003 and P=0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P=0.021). A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non-HLA-related genetic severity factors that has been replicated.

Was macht der Sport mit entzündeten Gelenken?

Vorliegende Studie versucht, anhand der Literatur Antworten zu finden auf die Frage des Einflusses biomechanischer Belastungsfaktoren auf den gelenkzerstörenden Prozess bei entzündlich-rheumatischen Erkrankungen. Zur Beantwortung werden stellvertretend methodisch die Gelenke der Hand in zwei Zuständen untersucht mit jeweils differenter biomechanischer Beanspruchung: der Händigkeit und dem Einfluss einer unterschiedlichen Belastung hervorgerufen durch eine Hemiparese. Da bei arthrotischen Veränderungen der Einfluss biomechanischer Faktoren geläufiger ist, wird jeweils die Literatur zunächst befragt hinsichtlich dem Schweregrad von Fingergelenksarthrosen bei Hemiparese und dem Seitenvergleich von rechts und links. Es zeigt sich erwartungsgemäß ganz klar das Bild einer Abhängigkeit des Schweregrades der Arthrosen von der biomechanischen Belastung. Rechtshänder entwickeln rechts stärkere Arthrosen als links und Linkshänder umgekehrt. Eine Hemiparese führt zu deutlich stärkeren Arthrosen in der nichtparetischen Extremität in Relation zum Schweregrad der Parese und damit der biomechanischen Belastung. Überraschenderweise finden sich ganz ähnliche Verhältnisse bei entzündlich-rheumatischen Erkrankungen mit der Potenz zur Gelenkdestruktion, vor allem bei der rheumatoiden Arthritis. Eine Fülle von Kasuistiken belegt nicht nur den fehlenden entzündlichen Befall paretischer Gelenke, sondern umgekehrt bei manifester und erosiver rheumatoider Arthritis die Rückbildung arthritischer Symptome und erosiver Veränderungen unter dem Bild einer Hemiparese. In gleicher Weise spielt für das Ausmaß der Arthritis und der Gelenkdestruktion die Händigkeit auch bei der rheumatoiden Arthritis eine wichtige Rolle. Somit ergeben sich zahlreiche Befunde, welche die Grundsätze des „Gelenkschutzes” auch bei sportlichen Betätigungen von entzündlich-rheumatisch Erkrankten unterstreichen. Es sollten nur solche Betätigungen durchgeführt werden, die schmerzfrei durchführbar sind.

Lessons from a Genomewide Association Study of Rheumatoid Arthritis

Rheumatoid arthritis is a chronic inflammatory disorder in which the articular joints are gradually destroyed. Occasionally there is systemic involvement, which can include vasculitis in various organs and pulmonary fibrosis. The disease has multifactorial causes to which genetic and environmental factors are thought to contribute. The presence of autoantibodies to cyclic citrullinated peptide (CCP) is specific to rheumatoid arthritis; although the mechanistic significance of these autoantibodies is obscure, their detection contributes both to the differential diagnosis and to a prediction of the severity of joint destruction. Rheumatoid arthritis causes substantial morbidity and mortality and is sometimes accompanied by severe infection . . .

Individual differences in behavior of inbred Lewis rats are associated with severity of joint destruction in adjuvant-induced arthritis

The aim of our study was to test the hypothesis that differences in behavioral characteristics are linked to severity of arthritis in association with neuro-endocrine and immune reactivity in an inbred strain of rats. Lewis rats were selected as high-active (HA) and low-active (LA) animals based on their exploratory activity in the open field. Subsequently, adjuvant-arthritis (AA) was induced in both groups. We observed no differences in the severity of inflammation as determined by paw swelling and redness. However, LA and HA animals differed in the severity of bone destruction as determined on radiographs taken on day 30 after induction of AA. LA rats had more osteoporosis, periostal new bone formation, and bone destruction than HA rats. There were no differences between HA and LA rats in corticosterone response after acute or chronic immune challenge. Splenocytes of LA rats had a lower mitogen-induced IL-10 and IFNγ production during AA. Histological examination revealed more intense factor VIII staining in arthritic joints of LA animals, indicating more pronounced synovial angiogenesis. In addition, LA rats had higher plasma VEGF, an important angiogenic factor. Expression of RANKL, a crucial factor promoting bone resorption, was also higher in joints of LA animals. Our data demonstrate that activity in the open field, a behavioral trait, is associated with the severity of bone destruction in AA. Lower production of bone-protective cytokines and a higher rate of angiogenesis leading to more synovial proliferation may be responsible for the more severe joint destruction in LA animals.

Expansion of unusual CD4+ T cells in severe rheumatoid arthritis.

The repertoire of T cells in patients with rheumatoid arthritis (RA) is characterized by clonal expansion of selected CD4+ T cells, which are autoreactive and lack the expression of the functionally important CD28 molecule. The goal of this study was to determine the contribution of these unusual lymphocytes to the disease process. RA patients (n = 108) and normal controls (n = 53) were examined for the expression of CD4+ CD28- T cells by 2-color fluorescence-activated cell sorter analysis. Clinical data were ascertained by retrospective chart review. The frequencies of CD4+ CD28- T cells displayed a bimodal distribution, defining carriers and noncarriers in normal subjects and RA patients. In longitudinal studies, the noncarrier and carrier phenotypes were stable over time. Carriers of CD4+ CD28- T cells accumulated in the RA population (64% versus 45%; P = 0.02). The expansion of CD4+ CD28- T cells correlated with extraarticular involvement, but not with disease duration, antirheumatic treatment, or severity of joint destruction. The patient subsets with nodular disease (P = 0.02) and rheumatoid organ disease (P = 0.04) had the highest proportion of CD4+ CD28- T cell carriers. The size of the CD4+ CD28- compartment correlated with extraarticular progression of RA (P = 0.001 in nodular RA, P = 0.003 in rheumatoid organ disease). The bimodality of distribution of CD4+ CD28- T cell frequencies is compatible with genetic control of the generation of these unusual T cells. In RA patients, CD4+ CD28- T cells are not an epiphenomenon of the disease process, but predispose patients to developing inflammatory lesions in extraarticular tissues.