Search

Objective: To test the OMERACT 8 draft validation criteria for soluble biomarkers by assessing the strength of literature evidence in support of 5 candidate biomarkers., Methods: A systematic literature search was conducted on the 5 soluble biomarkers RANKL, osteoprotegerin (OPG), matrix metalloprotease (MMP-3), urine C-telopeptide of types I and II collagen (U-CTX-I and U CTX-II), focusing on the 14 OMERACT 8 criteria. Two electronic voting exercises were conducted to address: (1) strength of evidence for each biomarker as reflecting structural damage according to each individual criterion and the importance of each individual criterion; (2) overall strength of evidence in support of each of the 5 candidate biomarkers as reflecting structural damage endpoints in rheumatoid arthritis (RA) and identification of omissions to the criteria set., Results: The search identified 111 articles. The strength of evidence in support of these biomarkers reflecting structural damage was low for all biomarkers and was rated highest for U-CTX-II [score of 6.5 (numerical rating scale 0-10)]. The lowest scores for retention of specific criteria in the draft set went to criteria that refer to the importance of animal studies, correlations with other biomarkers reflecting damage, and an understanding of the metabolism of the biomarker., Conclusion: Evidence in support of any of the 5 tested biomarkers (MMP-3, CTX-I, CTX-II, OPG, RANKL) was inadequate to allow their substitution for radiographic endpoints in RA. Three of the criteria in the draft criteria set might not be required, but few omissions were identified.

Objectives: A draft set of criteria for the validation of soluble biomarkers reflecting damage endpoints was proposed at OMERACT 8. At OMERACT 9 we aimed to scrutinize the necessity for each of these criteria according to the objectives of the working group., Methods: The OMERACT 8 draft criteria and the principle objectives of the validation process were clarified at a meeting of the working group in London, December 2007. A new framework was proposed after the following steps were conducted: (A) A systematic review of the literature focusing on the draft criteria and a preselected group of biomarkers (MMP3, CTX-II, RANKL, OPG, CTX-I) followed by a Delphi consensus exercise addressing the importance of individual criteria and identification of omissions in the draft set. (B) Formal debate as well as group discussion centered on the key arguments for inclusion/exclusion of specific criteria. (C) Onsite interactive electronic voting on the importance of specific criteria. The framework was presented and discussed at OMERACT 9 in both breakout and plenary sessions followed by a vote on its acceptance., Results: The objectives of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis biomarkers in relation to their predictive validity for damage endpoints was clarified and supported by OMERACT 9 participants. The OMERACT 8 draft validation criteria were reformulated into an essential category focused on criteria addressing the OMERACT Filter elements of discrimination (incorporating truth) and feasibility, and a desirable but nonessential category of other criteria addressing truth. This revised draft set was endorsed by participants at OMERACT 9., Conclusion: A revised set of validation criteria has been drafted by consensus at OMERACT 9 that focuses on the performance characteristics of biomarker assays, the importance of addressing potential confounders, and the essential requirement for clinical validation studies.

Objective: At OMERACT 8 a framework for levels of evidence was proposed for the validation of biomarkers as surrogate outcome measures. We aimed to adapt this scheme in order to apply it in the setting of soluble biomarkers proposed to replace the measurement of damage endpoints in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We also aimed to generate consensus on minimum standards for the design of longitudinal studies aimed at validating biomarkers., Methods: Before the meeting, the Soluble Biomarker Working Group prepared a preliminary framework and discussed various models for association and prediction related to the statistical strength domain. In addition, 3 Delphi exercises addressing longitudinal study design for RA, PsA, and AS were conducted within the working group and members of the Assessments in SpondyloArthritis International Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). This formed the basis for discussions among OMERACT 9 participants., Results: The proposed framework was accepted by consensus. In the study design domain a requirement for both prospective observational studies and randomized controlled trials (RCT) in different drug classes was noted. A template for determining the level of statistical strength was proposed. The addition of a new domain on biomarker assay performance was considered essential, and participants suggested that for any biomarker this domain should be addressed first, i.e., before starting clinical validation studies. Participants agreed on most elements of a longitudinal study design template. Where consensus was lacking the working group has drafted solutions that constitute a basis for prospective validation studies., Conclusion: The OMERACT 9 Soluble Biomarker Group has successfully formulated a levels of evidence scheme and a study design template that will provide guidance to conduct validation studies in the setting of soluble biomarkers proposed to replace the measurement of damage endpoints in RA, PsA, and AS.

Objective: To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with methotrexate with or without infliximab., Methods: Patients (n = 1049) with active RA for 3 years or less and no previous methotrexate treatment were randomly assigned (4 : 5 : 5) to receive methotrexate plus placebo or methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter to week 46. Disease activity was classified by the simplified disease activity index as remission (< or =3.3), low (>3.3 to < or =11), moderate (>11 to < or =26), high (>26). Radiographic progression was measured as a change from baseline to week 54 in total Sharp score., Results: At weeks 14 and 54, more patients receiving methotrexate plus infliximab than methotrexate plus placebo were in remission (10.7% versus 2.8% week 14; 21.3% versus 12.3% week 54; p<0.001 for both). Methotrexate plus placebo halted radiographic progression only if patients achieved remission within 3 months, whereas methotrexate plus infliximab also halted or minimised progression in patients with low or moderate activity, respectively. Patients with persistently high disease activity levels had much less progression of joint damage if treated with methotrexate plus infliximab versus methotrexate monotherapy. Even with infliximab plus methotrexate there was a direct relationship between disease activity and radiographic changes, although the slope was deflected when compared with methotrexate monotherapy., Conclusion: With methotrexate, joint damage progresses even at low and moderate disease activity levels, whereas methotrexate plus infliximab inhibits radiographic progression across all disease activity states.

Objective: To test the hypothesis that early knee and hand osteoarthritis (OA) development is characterized by detectable changes in serum proteins relevant to inflammation, cell growth, activation, and metabolism several years before OA becomes radiographically evident., Methods: Using microarray platforms that simultaneously test 169 proteins relevant to inflammation, cell growth, activation and metabolism, we conducted a case-control study nested within the Baltimore Longitudinal Study of Aging (BLSA). Subjects included 22 incident cases of OA and 66 age-, sex- and body mass index (BMI)-matched controls. Serum samples tested were obtained at the time of radiographic classification as either case or control, and up to 10 years earlier at a time when all participants were free of radiographic OA. Proteins with mean signal intensities fourfold higher than background were compared between cases and controls using multivariate techniques., Results: Sixteen proteins were different between OA cases compared to controls. Four of these proteins [matrix metalloproteinase (MMP)-7, interleukin (IL)-15, plasminogen activator inhibitor (PAI)-1 and soluble vascular adhesion protein (sVAP)-1] were already different in samples obtained 10 years before radiographic classification and remained different at the time of diagnosis. Six additional proteins were only associated with subsequent OA development and not with established OA., Conclusions: Changes in serum proteins implicated in matrix degradation, cell activation, inflammation and bone collagen degradation products accompany early OA development and can precede radiographic detection by several years.

Introduction: Although cardiovascular morbidity and mortality are increased in rheumatoid arthritis, little is known about the burden of subclinical coronary atherosclerosis in these patients., Methods: Using computed tomography, coronary artery calcification was measured in 195 men and women with rheumatoid arthritis aged 45 to 84 years without clinical cardiovascular disease and compared with 1,073 controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis., Results: The prevalence of coronary calcification (Agatston score > 0) was significantly higher in men, but not women, with rheumatoid arthritis after adjusting for sociodemographic and cardiovascular risk factors (prevalence ratio = 1.19; P = 0.012). Among participants with prevalent calcification, those with rheumatoid arthritis had adjusted mean Agatston scores 53 units higher than controls (P = 0.002); a difference greater for men than women (P for interaction = 0.017). In all analyses, serum IL-6 attenuated the association between rheumatoid arthritis and coronary calcification, suggesting its role as a potential mediator of enhanced atherosclerosis. Notably, increasing severity of rheumatoid arthritis was associated with a higher prevalence and extent of coronary calcification among both men and women with rheumatoid arthritis, and for all age categories. The largest percentage difference in coronary arterial calcification between rheumatoid arthritis patients and their nonrheumatoid arthritis counterparts was observed in the youngest age category., Conclusions: Increasing rheumatoid arthritis disease severity was associated with a higher prevalence and greater extent of coronary artery calcification, potentially mediated through an atherogenic effect of chronic systemic inflammation. Gender and age differences in association with coronary calcification suggest that preventive measures should be emphasized in men with rheumatoid arthritis, and considered even in younger rheumatoid arthritis patients with low levels of traditional cardiovascular risk factors.

Objective: The serum C-reactive protein (CRP) concentration is commonly used in rheumatoid arthritis (RA) as a surrogate marker of systemic inflammation, presumably induced by synovitis. However, other tissues, such as adipose tissue, can induce CRP production. This study was undertaken to explore the associations between measures of adiposity and CRP levels in RA., Methods: One hundred ninety-six men and women with RA underwent anthropometric assessment and total body dual-energy x-ray absorptiometry for measurement of total and regional body fat and lean mass. The associations between measures of fat and lean mass and serum levels of CRP and interleukin-6 (IL-6) were determined in analyses stratified by sex, with adjustment for pertinent demographic, lifestyle, and RA disease and treatment covariates as well as for the potential modifying effects of articular activity and biologic pharmacotherapeutic agents., Results: All measures of adiposity were significantly associated with the level of CRP in women, but not in men. In women, the measure of adiposity that showed the strongest association with the CRP level was truncal fat, in which, in adjusted analyses, each kilogram increase was associated with a 0.101-unit increase in the logarithmically transformed CRP level (P < 0.001). Neither the level of articular activity nor the use of biologic agents significantly modified this association in women. However, in men, elevated articular involvement was associated with a decreasing CRP level as truncal fat increased. For all analyses, substitution of IL-6 for CRP produced similar findings., Conclusion: Adiposity is independently associated with CRP levels in women with RA, and thus may confound the estimation of RA disease activity when serum CRP concentration is used as a surrogate for systemic inflammation.

Objective: To compare measures of body fat and lean mass and the prevalence of abnormal body composition phenotypes (sarcopenia, overfat, and sarcopenic obesity) in men and women with rheumatoid arthritis (RA) versus matched controls, and to explore the disease-related predictors of abnormal body composition in patients with RA., Methods: A total of 189 men and women with RA and 189 age-, sex-, and race-matched non-RA controls underwent dual-energy x-ray absorptiometry for measurement of total and regional body fat and lean mass. Continuous and categorical measures of body composition were compared between RA and control subjects by sex and according to categories of body mass index (BMI). Within the group of RA patients, demographic, lifestyle, and RA disease and treatment characteristics were compared for RA patients with healthy body composition versus those with abnormal body composition phenotypes., Results: Compared with non-RA controls, RA status was significantly associated with greater odds of sarcopenia, overfat, and sarcopenic obesity in women, but not in men. Relative differences in body composition phenotypes between RA and control subjects were greatest for patients in the normal weight BMI category (<25 kg/m(2)). Among RA characteristics, increasing joint deformity, self-reported disability scores, C-reactive protein levels, rheumatoid factor seropositivity, and a lack of current treatment with disease-modifying antirheumatic drugs were significantly associated with abnormal body composition., Conclusion: Abnormal body composition phenotypes are overrepresented in patients with RA, particularly in those in the normal weight BMI range. RA-associated disease and treatment characteristics contribute to this increase in abnormal body composition.

Objective: To evaluate the relationship between hemoglobin concentration and physical disability in patients with rheumatoid arthritis (RA)., Methods: Data were derived from 2495 patients with RA enrolled in 3 clinical trials (ATTRACT, ASPIRE, and START) and treated with infliximab (3 to 10 mg/kg) plus methotrexate (MTX), or MTX plus placebo. The association of hemoglobin and the Health Assessment Questionnaire (HAQ) score was assessed at baseline (n = 2471) and Week 22 (n = 2458) by Spearman correlation, and multivariate linear regression models were employed to control for confounding effects from demographic and other clinical variables. A logistic regression model was used to estimate the odds ratio (OR) for a clinically meaningful improvement (> or = 0.25 point increase) in HAQ associated with a > or = 1 g/dl improvement in hemoglobin from baseline at Week 22., Results: About 37% of patients with RA had anemia based on World Health Organization criteria: hemoglobin < 12 g/dl in women (39%) and < 13 g/dl in men (32%). Low hemoglobin level was significantly associated with more severe physical disability at baseline (p < 0.001), and both male and female patients with anemia had more severe disability at baseline. Improvement in hemoglobin after treatment at Week 22 was an independent contributor to improvement in HAQ, and a > or = 1 g/dl improvement in hemoglobin after treatment was associated with a clinically meaningful improvement in the HAQ score at Week 22 (OR 1.43, 95% CI 1.10-1.86; p < 0.01)., Conclusion: Anemia is one of the independent factors contributing to physical disability in patients with RA. Improvement in anemia following effective RA treatment may play an independent role in improving physical function.

Chronic low-grade inflammation was recognized during the past decade as an important risk factor for the development of atherosclerosis and, more recently, for the development of heart failure. Patients with rheumatoid arthritis (RA) are at increased risk of morbidity and mortality from ischemic cardiovascular events and heart failure. Epidemiologic and clinical studies indicate that RA is an independent risk factor for cardiovascular disease, which suggests that chronic exposure to high levels of inflammatory mediators contributes to this enhanced risk. The relative contribution of conventional risk factors to the acceleration of cardiovascular disease does not seem to be increased in patients with RA compared with control populations. Nonetheless, some preclinical laboratory measures of risk factors (e.g. insulin sensitivity) are adversely modulated in the context of the highly inflammatory rheumatoid microenvironment. Discerning the net effect of RA therapies on cardiovascular disease is also challenging because, theoretically, their biologic effects could either promote or attenuate atherosclerosis and ventricular dysfunction; however, available data suggest a beneficial effect on cardiovascular morbidity and mortality in patients with RA. This review provides an overview of the potential influence of RA and its treatment on the development and progression of cardiovascular disease, and outlines some preliminary recommendations for prevention and management of this complication in patients with RA.

Objective: To assess the impact of lower extremity osteoarthritis (OA) on transitions to mobility difficulty, and to assess the influence of pain, excess weight, and quadriceps strength on these transitions., Methods: We analyzed longitudinal data acquired from 199 participants in the Women's Health and Aging Study II (ages 70-79 years) who initially reported no lower extremity limitation (e.g., difficulty walking one-quarter mile) or difficulty in activities of daily living (ADL; e.g., transferring). Prevalent lower extremity OA was determined from validated algorithms encompassing multiple data sources. Markov transition models were created to analyze the first transition from no difficulty at baseline to lower extremity limitations, ADL difficulty, or both 18, 36, and 72 months later., Results: Compared with women without OA (n = 140), a higher proportion of women with lower extremity OA (n = 59) initially reported pain on most days and more severe pain while walking (P < 0.05). Women with OA were also heavier, with a higher proportion being obese or overweight (P < 0.001). Lower extremity OA, higher body mass index, and lower knee extensor strength independently increased the risk of transition to combined lower extremity and ADL difficulty first over 72 months., Conclusion: Lower extremity OA increased the likelihood of developing difficulty in both lower extremity tasks and ADL over 72 months in a cohort of initially high functioning older women. Two modifiable factors, higher relative weight and lower knee extensor strength, substantially impacted these transitions, and therefore warrant increased attention in the management of lower extremity OA.

Objective: To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis (RA)., Methods: Methotrexate (MTX)-naive patients with active early RA were randomly allocated to receive MTX plus placebo or MTX plus infliximab (3 mg/kg or 6 mg/kg) at weeks 0, 2, and 6 and then every 8 weeks through week 46. Data for patients younger than age 65 years were included in the analyses. A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available., Results: The change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo (0.5% versus 1.3%; P > 0.5). However, the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone (8% versus 14%; P = 0.05). Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability (odds ratio 2.4; P < 0.001); this likelihood was not significantly greater in patients receiving MTX alone. The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX-alone group (P = 0.010)., Conclusion: The actual employment rates among patients in the 2 treatment groups were not different. However, patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone.

Objective: To evaluate safety and efficacy of etanercept treatment in elderly (age > or = 65 yrs) and younger adult subjects (age < 65 yrs) with rheumatoid arthritis (RA)., Methods: Subset analyses were used to describe the safety and efficacy of etanercept in elderly and younger subjects treated for early and disease modifying antirheumatic drug-resistant or late-stage RA (ERA and LRA) in one of 4 randomized controlled clinical studies (N = 1353) or 2 longterm extensions (N = 1049)., Results: Rates of serious adverse events tended to be higher in elderly than younger subjects; however, rates of safety events observed in elderly etanercept-treated subjects did not exceed rates in elderly placebo or methotrexate (MTX)-treated subjects. With regard to efficacy measures [American College of Rheumatology 20% response (ACR20), ACR50, and ACR70], elderly subjects tended to have somewhat less robust responses to treatment than younger subjects. However, for both age groups, treatment with etanercept resulted in improved efficacy and function compared with control treatment, and combination therapy with etanercept plus MTX resulted in greater efficacy than either etanercept or MTX used alone. Efficacy responses of elderly subjects were sustained for up to 6 years. Radiographic progression (measured using modified Sharp Score) after one year of treatment was lower in subjects treated with both etanercept and MTX compared with subjects treated with either agent used alone, and this pattern was similar in both age groups., Conclusion: Consistent with responses in younger subjects, elderly subjects with RA treated with etanercept experienced significant improvement in disease activity and function without incurring additional safety concerns.

Objective: To evaluate safety, efficacy, and radiographic progression in patients with early rheumatoid arthritis (RA) undergoing longterm treatment with etanercept., Methods: Patients with early RA (disease duration of 3 years or less) who had completed a 2-year efficacy study comparing etanercept and methotrexate (MTX) were followed in an extension where they received 25 mg etanercept twice weekly. Safety was summarized descriptively and compared with data from the efficacy study. Efficacy and radiographic progression were assessed using American College of Rheumatology response criteria, disease activity scores, and Total Sharp Score (TSS)., Results: Rates of serious adverse events and serious infections did not increase with longterm exposure to etanercept, and were similar to rates reported for the blinded portion of the efficacy study. Efficacy was sustained in patients who completed 5 years of etanercept treatment at the time of this report (N = 201), even in those who decreased or discontinued use of MTX or corticosteroids. No radiographic progression (change in TSS < or = 0) was seen in 55% of patients with 5-year radiographs; negative change (TSS < 0) was seen in 11%., Conclusion: Etanercept treatment in patients with early RA was generally well tolerated for up to 5 years. The results indicate sustained efficacy and decreased rate of radiographic progression. The rate of radiographic progression was low compared with other studies, emphasizing the benefit gained in patients with early aggressive RA who undergo longterm treatment with etanercept.

Recent emphasis on early diagnosis and treatment of rheumatoid arthritis (RA) to improve long-term disease outcome has raised important questions about optimal therapy for early RA. With an expanding armamentarium of disease-modifying antirheumatic drugs including biological agents, there are now several therapeutic choices available to clinicians. However, at early stages of arthritis, difficulty in accurately predicting individual prognosis and response to therapy continues to pose a significant challenge. Future research in biomarkers of progressive, erosive disease and controlled trials to establish the most effective therapies in early RA will greatly enhance our ability to minimize the impact of this potentially disabling disease.

Data from population- and clinic-based epidemiologic studies of rheumatoid arthritis patients suggest that individuals with rheumatoid arthritis are at risk for developing clinically evident congestive heart failure. Many established risk factors for congestive heart failure are over-represented in rheumatoid arthritis and likely account for some of the increased risk observed. In particular, data from animal models of cytokine-induced congestive heart failure have implicated the same inflammatory cytokines produced in abundance by rheumatoid synovium as the driving force behind maladaptive processes in the myocardium leading to congestive heart failure. At present, however, the direct effects of inflammatory cytokines (and rheumatoid arthritis therapies) on the myocardia of rheumatoid arthritis patients are incompletely understood.

The ability to target and neutralize macrophage-derived inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-alpha), has emerged in recent years as one of the most important advances in the treatment of rheumatoid arthritis, Crohn's disease, and several other systemic inflammatory diseases. In rheumatoid arthritis, for example, these biological agents rapidly reduce signs and symptoms of joint inflammation and profoundly slow the progression of joint damage. However, data that have emerged following Food and Drug Administration approval of these agents have alerted clinicians to an increased likelihood of opportunistic infections in patients treated with these agents, particularly tuberculosis. The effect of TNF inhibition on the frequency of infection with more common bacterial pathogens is less clear. Animal models of tuberculosis and other opportunistic infections have demonstrated the importance of TNF-alpha in controlling and containing intracellular pathogens. The spectrum of infections reported to date in the setting of anti-TNF-alpha treatment is reviewed here. In addition, relevant animal data illustrating potential mechanistic roles for TNF-alpha in host responses to infection are also reviewed.

The recent development of inhibitors of TNF-alpha has provided the opportunity for a more targeted and highly effective approach to the treatment of chronic inflammatory illnesses such as rheumatoid arthritis. Since the initial approval of etanercept as a treatment for rheumatoid arthritis, additional indications, including psoriatic arthritis, juvenile rheumatoid arthritis and ankylosing spondylitis, have also received FDA approval. More than 220,000 patients have been treated with etanercept so far. This review summarises the body of knowledge accumulated so far on etanercept (Enbrel) since it entered the market 5 years ago.

Objective: To examine the association between BMI (kilograms per meter squared) and reports of significant knee, hip, and back pain using data from a nationally representative sample of U.S. adults 60 years or older., Research Methods and Procedures: Population-based survey data from the Third National Health and Nutrition Examination Survey, involving 5724 adults 60 years or older, were used. BMI, calculated from measured weight (kilograms) and height (meters squared), was used to categorize participants into six BMI-defined groups: underweight (<18.5), desirable weight (18.5 to 24.9), overweight (25 to 29.9), obese class I (30 to 34.9), obese class II (35 to 39.9), and obese class III (>/=40). The presence of significant knee, hip, and back pain in the groups was studied., Results: The overall prevalences of knee, hip, and back pain were 21%, 14%, and 22%, respectively. Prevalence estimates for knee (underweight 12.1% to obesity class III 55.7%), hip (underweight 10.4% to obesity class III 23.3%), and back (underweight 20.2% to obesity class III 26.1%) pain increased with increased BMI. Sex-, race-, and age-specific pain prevalence estimates also generally increased at increased levels of BMI., Discussion: Among U.S. adults 60 years or older, the prevalence of significant knee, hip, and back pain increases with increased levels of BMI.

The Early Rheumatoid Arthritis (ERA) trial compared monotherapy with etanercept or methotrexate in patients with early erosive rheumatoid arthritis. Over the initial period of 12, and subsequently 24, months both treatments were associated with a profound reduction in radiographic progression of joint damage, as well as a reduction in signs and symptoms of disease. Etanercept showed slight superiority to methotrexate in reducing subsequent radiographic erosions and in the rapidity of the clinical response. Both therapies proved to be safe and well tolerated and, importantly, the relative safety and tolerance of a rapidly escalated dosing regimen for methotrexate was demonstrated. In summary, early aggressive treatment of RA is associated with clinical and radiographic benefit that can be demonstrated after a relatively short period of treatment.

Objective: To examine associations between osteoarthritis (OA) of the knee and early functional limitations in a cohort of high-functioning older women, and evaluate the contributions of muscle strength, body weight, and pain severity to these limitations. Methods. Cross sectional analyses were conducted on baseline data of the Women's Health and Aging Study II (WHAS II), an observational study of disability transitions in a cohort of women aged 70-79 upon entry and who were representative of the one-third highest-functioning community-resident women. Standardized questionnaires and examinations were used to assess knee OA features, medication use, pain severity, knee extensor muscle strength, and body weight. Functional limitation was assessed using validated performance measures and self-report measures of task modification and task difficulty., Results: Sixty-nine women classified as "symptomatic" for knee OA, 48 with "asymptomatic/intermittently symptomatic," knee OA, and 285 with "no knee OA" were included in the final analysis. Despite selection for their high level of self-reported function, performance was slower and task modification was more frequently reported among women with knee OA than women without knee OA. Lower knee extensor strength, higher body weight, and greater pain severity were associated with knee OA, and also with functional limitations. Conclusion. Knee OA appeared to be associated with early functional limitations in this cohort of high-functioning, older, community-resident women. Lower knee extensor strength, higher body weight, and pain severity were closely associated with these limitations. The extent to which modification of these factors attenuates knee OA associated functional decline should be investigated.

Background: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate., Objective: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis., Design: 24-week, multicenter, randomized, double-blind, placebo-controlled trial., Setting: 20 centers in the United States and Canada., Patients: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months., Intervention: Leflunomide or matching placebo added to existing methotrexate therapy., Measurements: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis., Results: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate., Conclusions: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Objective: To determine the incidence of self-reported significant hip pain using a nationally representative sample of older adults in the United States., Study Design: Subjects were interviewed to determine their leisure time physical activity levels and whether they experienced severe hip pain. Sampling weights were calculated to account for unequal selection probabilities. The impact of race, age, and physical activity status was examined as influential factors affecting hip pain., Population: We interviewed 6596 adults aged 60 years and older as part of the third National Health and Nutrition Examination Survey (NHANES III)., Outcome Measured: We measured the prevalence of hip pain., Results: A total of 14.3% of participants aged 60 years and older reported significant hip pain on most days over the past 6 weeks. Men reported hip pain less frequently than women. Age did not influence self-reported hip pain in men. The lowest prevalence of hip pain was found in women aged 60 to 70 years. Sixteen percent of non-Hispanic white women reported hip pain, compared with 14.8% of black women and 19.3% of Mexican American women. Among non-Hispanic white men, 12.4% reported hip pain, a proportion no different from that of their black and Mexican American male counterparts. Among older US adults, 18.4% of those who had not participated in leisure time physical activity during the previous month reported severe hip pain; 12.6% of those who did engage in physical activity reported hip pain., Conclusions: Self-reported hip pain has increased since NHANES I (1971-1975). Further studies are needed to identify individuals at highest risk for severe hip pain and to identify optimal treatment of hip pain.

Objective: To assess the prevalence of persistent knee pain among older adults in the US., Design: A nationally representative cross-sectional survey with an in-person interview and medical examination, Setting and Participants: Between 1988 and 1994, 6596 adults aged 60 to 90+ years were examined as part of the National Health and Nutrition Examination Survey III. Mexican Americans and non-Hispanic blacks were over-sampled to produce reliable estimates for these groups., Main Outcome Measurements: Participants were asked to report whether they had experienced knee pain on most days for the 6 weeks preceding their medical exam., Results: Overall, 18.1% of US men and 23.5% of US women aged 60 years and older reported knee pain. Sixty- to ninety-year-old men reported knee pain less frequently than their age-matched female counterparts. There was a trend for reports of knee pain to increase steadily as these adults aged from 60 to 85 years. The highest prevalence of knee pain was reported among 85- to 90-year-old men (23.7%) and women (30.0%). Among non-Hispanic white adults older than age 60, 18.4% of men and 22.0% of women reported knee pain. Reports of knee pain among non-Hispanic black men and Mexican American men were similar to those of their non-Hispanic white counterparts. In contrast, 26.4% of Mexican American women and 32.8% of non-Hispanic black women reported knee pain. We also found that difficulty in performing physical functioning activities was associated with a higher prevalence of knee pain., Conclusions: Many US adults older than age 60 years report knee pain, and the prevalence is higher in older adults. Reports of knee pain are highest among non-Hispanic black women and the oldest Americans. Intervention strategies are needed to prevent and better manage knee pain among older US adults to stem the adverse health consequences and diminished quality of life associated with this common problem.

The human B2 kinin receptor (B2KR), stably expressed in Chinese hamster ovary cells, responded to bradykinin stimulation with rapid (within minutes) ligand internalization and loss of cell surface receptors (sequestration). By contrast, B1 kinin receptors (B1KR) showed almost no ligand internalization or receptor sequestration upon stimulation with des-Arg10-Kallidin (DAK). The ability of the B2KR to internalize and sequester is conferred by information in the cytoplasmic tail of the receptor. It is normally impossible to determine receptor affinity at 37 degrees C because of internalization and sequestration processes. We created a mutant B2KR, truncated at K315 of the cytoplasmic tail, that was no longer able to internalize or sequester, and compared the affinity of this mutant, and of the B1KR, at 0 degrees C and 37 degrees C. The B1KR receptor showed the same affinity (Kd = 0.4 nM) at both 0 degrees C and 37 degrees C. By contrast, the K315 mutant of the B2KR showed a lower affinity (Kd = 2.9 nM) at 37 degrees C than at 0 degrees C (Kd = 1.4 nM), indicating more rapid ligand dissociation at 37 degrees C. After ligand exposure, clones expressing B1KR exhibited a very slow dissociation of DAK, even at 37 degrees C. Although both kinin receptor subtypes induce the generation of inositol phosphates, functional responses showed clear differences. The response to stimulation of the B2KR comprises a rapid loss of functional responses, receptor sequestration, and ligand dissociation, and, upon long term stimulation, downregulation. By contrast, ligand stimulation of the B1KR, once this receptor is expressed de novo under pathological conditions, results in persistent signaling due to lack of ligand dissociation, desensitization and receptor sequestration. Moreover, long term stimulation of this receptor actually leads to increased expression.

Parathyroid hormone (PTH) elicits many of its physiological effects by activating distinct, G-protein-coupled signaling cascades that lead to synthesis of cyclic AMP and hydrolysis of phosphatidylinositol 4,5-bisphosphate. Using the nonhydrolyzable photo-reactive GTP analog [alpha-32P]GTP-gamma-azidoanilide (GTP-AA) and peptide antisera raised against G-protein alpha-subunits, we studied coupling of the PTH receptor to G-proteins in rat osteoblast-like cells (ROS 17/2.8), and in human embryonal kidney cells expressing the cloned human PTH/parathyroid hormone-related peptide (PTHrP) receptor at 40,000 receptors/cell (C20) or 400,000 receptors/cell (C21). Incubation of C21 membranes (but not C20 membranes) with [Nle8,18, Tyr34]-bovine PTH(1-34) amide (bPTH[1-34]) led to concentration-dependent incorporation of GTP-AA into the two isoforms of G alpha s, into G alpha q/11, and to a much lesser extent into G alpha i(1). In ROS 17/2.8 cells, bPTH(1-34) increased the incorporation of GTP-AA into G alpha s, but not into G alpha q/11 or G alpha i. The ability of bPTH(1-34) to increase labeling of G alpha s and G alpha q/11 was correlated with the receptor-dependent sensitivity of the adenylyl cyclase and phospholipase C signaling pathways to the hormone.

Several endogenous peptides, including bradykinin and substance P, have potent inflammatory effects in the joint. Levels of these peptides are regulated by plasma and cell-associated peptide degrading enzymes. One of these peptidases, neutral endopeptidase-24.11 (NEP-24.11), is expressed constitutively and in high density on human synovial cells and is presumed to play a critical role in local regulation of peptide levels in the joint. We examined the role of endogenous NEP-24.11 in regulating bradykinin-mediated effects in an articular model, and investigated the ability of soluble, recombinant human NEP-24.11 to augment the effects of the endogenous enzyme. Our studies demonstrate that endogenous synovial NEP-24.11 does not significantly modulate inflammatory peptide effects on cells when competing with colocalizing peptide receptors expressed in high density. Administration of excess, soluble recombinant NEP-24.11 can overcome this problem, however. Furthermore, the activity of the recombinant enzyme was not compromised in the presence of oxidants or inflammatory joint fluids. Recombinant NEP-24.11 holds promise as a novel therapeutic strategy for the treatment of inflammatory arthritis.

Objective: This review highlights the clinical and pathophysiologic features of osteoarthritis (OA) of the peripheral joints and discusses the current and future management options for this common but potentially disabling disease. This article also addresses the contribution of osteoarthritis to falls and functional impairment in older people., Design: A critical assessment of current data regarding the pathogenesis of osteoarthritis, current and future therapies, and the potential role of OA in falls and functional impairment in older people., Conclusions: Osteoarthritis is the most prevalent articular disease in older adults. Disease markers that will detect early disease and allow early intervention with pharmacologic agents that modify, if not halt, disease progression are much needed, but they are presently unavailable. Current management should include safe and adequate pain relief using systemic and local therapies and should also include medical and rehabilitative interventions to prevent, or at least compensate for, functional deficits. Although OA can result in impaired mobility and lower extremity function, its contribution as a cause of recurrent falls or impaired self-care, relative to other comorbid conditions, remains ill-defined. Further analysis of the determinants of disability, loss of mobility and falls in older patients with OA is needed.

To determine the role of the cytoplasmic carboxyl termini of human B1 and B2 kinin receptors (B1KR and B2KR, respectively) in the internalization of their respective ligands, des-Arg10-kallidin and bradykinin (BK), both wild type receptors, as well as truncated B2KRs, a mutated B2KR, and chimeric receptors were stably expressed in Chinese hamster ovary cells. Incubation of [3H]BK at 37 degrees C with cells expressing wild type B2KR resulted in pronounced and rapid ligand internalization ( approximately 80% after 10 min). By contrast, incubation of 3H-labeled des-Arg10-kallidin with cells expressing B1KR resulted in a modest, slow internalization of the ligand (<20% after 10 min). Replacement, from Cys324, of the cytoplasmic carboxyl terminus of the B2KR with that of the B1KR from Cys330 (both Cys residues are putative palmitoylation sites) greatly reduced ligand internalization ( approximately 40% after 10 min) without significantly altering Kd or ligand-induced signal activation. By marked contrast, the corresponding replacement, of the sequence from Cys330 of the cytoplasmic carboxyl terminus of the B1KR with the segment of the B2KR, led to a striking increase of ligand internalization ( approximately 75% within 10 min) without altering Kd or ligand-induced signal activation. Truncation of the B2KR to within three amino acids of Cys324 (truncation at Gly327) led to strongly reduced ligand internalization ( approximately 40% after 10 min). Truncation of the B2KR up to Lys315 almost completely abolished internalization of [3H]BK (10% after 10 min). This additional reduction is apparently not caused by the loss of the potential palmitoylation site at Cys324, since a B2KR with a point mutation of Cys324 to Ala internalized [3H]BK as rapidly as the wild type B2KR. From these results we conclude that the cytoplasmic carboxyl terminus of the human B2KR contains sequences that are necessary and sufficient to permit rapid ligand-induced sequestration of human kinin receptors and internalization of their agonists.

To delineate ligand binding and functional characteristics of the human B1 kinin receptor, a stable clone of Chinese hamster ovary cells expressing a single class of binding sites for [3H]des-Arg10-lysylbradykinin with a Kd of 0.3 nM and a Bmax of 38 fmol/mg protein ( approximately 40,000 receptors/cell) was isolated. Studies with peptide analogs showed that a lysine residue at position 1 (based on the lysylbradykinin sequence) of ligands was essential for high affinity binding to the human B1 receptor. In marked contrast to cloned Chinese hamster ovary cells expressing the human kinin B2 receptor, which internalized approximately 80% of the ligand within 5 min upon exposure to 2 nM [3H]bradykinin, exposure of cells expressing the B1 receptor to 1 nM [3H]des-Arg10-lysylbradykinin resulted in minimal ligand internalization. Stimulation of the B1 receptor led to inositol phosphate generation and transient increases in intracellular calcium, confirming coupling to phospholipase C, while immunoprecipitation of photoaffinity-labeled G-proteins from membranes indicated specific coupling of the receptor to Galphaq/11 and Galphai1,2. The B1, unlike the B2, receptor does not desensitize (as demonstrated by continuous phosphoinositide hydrolysis), enhancing the potential role of this receptor during inflammatory events.

Bradykinin (BK)2 and interleukin-1 (IL-1) interact synergistically to stimulate prostaglandin synthesis in human synovial fibroblast-like cells. The effect of BK is rapid and correlates with its capacity to elevate cytosolic levels of calcium ([Ca2+]i), while IL-1's effect is slow and s dependent upon de novo protein synthesis. The mechanism of this synergistic interaction was investigated. In the basal state, high levels of arachidonic acid (AA) were spontaneously released from synovial cells but near absent levels of cyclooxygenase activity prevented metabolism of AA to prostanoid. BK was a potent stimulus for elevating AA, but not prostaglandins, above basal levels. IL-1, in contrast, increased prostaglandins but not AA, above basal levels. IL-1 treatment was not associated with a loss or redistribution of AA among phospholipid classes. These results are consistent with high basal phospholipase activity in synovial cells and demonstrate the ability of BK, presumably via its ability to raise [Ca2+]i, to further elevate this activity(ies). Metabolism of AA to prostanoid is minimal in resting and BK-stimulated synovial cells, however, without the concomitant induction of cyclooxygenase activity by IL-1. These studies clarify the different, but synergistic, mechanisms of action of a peptide and cytokine in stimulating prostanoid synthesis in synovial cells. In addition, these data extend the results of previous investigations in demonstrating that basal phospholipase activity provides sufficient AA substrate for IL-1 induced prostanoid synthesis without invoking the concomitant induction of phospholipase activity by IL-1.

The present studies were undertaken as a first step to evaluate the potential usefulness of the bradykinin antagonist HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis. Intranasal single-dose administration of HOE-140, at doses up to 500 micrograms, was safe and well tolerated. Bradykinin-induced symptoms and increased vascular permeability could be inhibited, in a dose-dependent manner, by preadministration of HOE-140 5 min prior to kinin challenge. The results of dose-ranging experiments suggested that bradykinin and HOE-140 were approximately equipotent at bradykinin receptors. Preadministration of HOE-140 2 h before kinin challenge caused a significant but much weaker level of inhibition than that seen with 5-min preadministration. Comparison of data with those obtained during dose-ranging studies suggested that more than 90% of the administered HOE-140 was lost during this 2-h period. We conclude that topical HOE-140 is an effective inhibitor of the effects of bradykinin on the nasal mucosa but that the short duration of action of this drug may severely limit the utility of HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis.

Previously, we have shown that bradykinin elicits the production of prostaglandin E2 (PGE2) in human synovial cells only after pre-exposure of the cells to IL-1. The observation that calcium ionophores, but not a variety of physiologic receptor-mediated agonists, can mimic bradykinin in its synergy with IL-1 led us to hypothesize that the ability of bradykinin to induce prostanoid synthesis was a result of its selective ability (among physiologic agonists) to raise the cytosolic free ionized calcium concentration ([Ca2+]i) levels of synovial cells. Extending this hypothesis, it follows that the relative potency of an agonist in inducing PGE2 production from IL-1-treated cells should be dependent on its ability to raise [Ca2+]i. In these studies, we have confirmed the potent ability of bradykinin to elevate [Ca2+]i in resting human synovial cells. That the effect of bradykinin on [Ca2+]i was mediated through the previously described synovial cell kinin receptor was confirmed by a pharmacologic profile consistent with a high affinity B2 kinin receptor. Furthermore, the relative specificity and potency of the PGE2 response of bradykinin in IL-1-treated cells was paralleled, in resting cells, by a similar pattern in the [Ca2+]i response. Finally, IL-1 had no direct effect on [Ca2+]i levels, nor did it alter agonist-induced elevations in [Ca2+]i. We conclude that the potency of a receptor-mediated agonist in inducing prostanoid synthesis in synovial cells is dependent on its ability to raise [Ca2+]i. However, this effect is not enough, in and of itself, to induce prostanoid synthesis; the concomitant induction by IL-1 of a PG-generating enzyme is also required.

Objective: Type VI collagen is a prominent constituent of the synovial extracellular matrix. The cellular source of this matrix protein and the identity of local factor sin synovium that may regulate its expression have not been delineated, however. We examined the capacity of human fibroblast-like synovial cells to synthesize type VI collagen as well as the effect of interleukin-1 (IL-1) on this expression., Methods: RNA was extracted from cultured human synovial cells derived from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Northern blots were analyzed using sequence-specific probes, and steady-state messenger RNA (mRNA) levels of the 3 alpha (VI) procollagen chains were measured. The effect of IL-1 treatment on these levels was determined., Results: Abundant expression of 3 characteristic mRNA transcripts, corresponding to the alpha 1 (4.2-kb), alpha 2 (3.5-kb), and alpha 3 (8.5-kb) chains of type VI procollagen, was observed in untreated cells derived from RA and OA patients. IL-1 treatment consistently suppressed steady-state mRNA levels for all 3 alpha (VI) procollagen chains in a time- and dose-dependent manner. Tumor necrosis factor alpha induced a response similar to that of IL-1, while IL-2 was ineffective in this regard. Indomethacin partially restored alpha (VI) mRNA expression in IL-1--treated cells., Conclusion: These studies provide novel data demonstrating abundant steady-state levels of mRNA transcripts coding for all 3 type VI procollagen polypeptides in human synovial fibroblast-like cells, as well as coordinated down-regulation of these transcripts by IL-1. Local production of IL-1 may thus constitute an important means in vivo of regulating the production of type VI collagen.

Attempts to evaluate the role of kinins in airway inflammation in humans using the bradykinin receptor antagonist [DArg0-Hyp3-DPhe7]-bradykinin (NPC 567) were unsuccessful, possibly because of the low potency and poor stability of this compound. Recently, [DArg0-Hyp3-Thi5-DTic7-Oic8]-bradykinin (Hoe 140), a novel antagonist that seems to overcome these weaknesses, has been developed. The present study was performed to compare the potency and efficacy of Hoe 140 to those of NPC 567 and another antagonist, [DArg0-Hyp3-DPhe7-Ile8]-bradykinin (B7418), on kinin receptors on guinea pig tracheal epithelial cells. Radioligand binding studies showed the presence of two types of B2 kinin receptors on guinea pig tracheal epithelial cells: a high-affinity site with a Kd of 0.44 nM and Bmax of 12.1 fmol/10(6) cells (4000 sites/cell), and a lower affinity site with a Kd of 10 nM and Bmax of 16 fmol/10(6) cells (9600 sites/cell). Bradykinin-induced prostaglandin E2 production seemed to be associated primarily with the lower affinity site. All three B2 receptor antagonists displaced labeled bradykinin from both classes of binding sites and inhibited bradykinin-induced prostaglandin E2 production, but Hoe 140 was up to 40-fold more potent than NPC 567 and showed an affinity comparable to that of bradykinin for both binding sites. This higher potency of Hoe 140, and its stability against peptidases, suggests that this compound will be useful in evaluating the role of bradykinin in inflammatory diseases of the airways.

Kinins and substance P have been implicated in the pathogenesis of inflammatory arthritis by virtue of their abilities to induce vasodilation, edema, and pain. The relative biological potencies of these peptides in vivo would depend at least in part upon their rates of catabolism in the joint. We hypothesized that human synovial lining cells may regulate intraarticular levels of kinins and neuropeptides via degradation by cell surface-associated peptidases. We exposed intact human synovial fibroblasts to kinins and substance P, in the presence or absence of specific peptidase inhibitors, and measured the amount of intact substrate remaining and degradation product(s) generated over time. Aminopeptidase M (AmM; EC 3.4.11.2), neutral endopeptidase-24.11 (NEP-24.11; EC 3.4.24.11), and dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) were identified on the cell surface of synovial cells. Bradykinin degradation was due entirely to NEP-24.11 (1.39 +/- 0.29 nmol/min per well). Lysylbradykinin was also degraded by NEP-24.11 (0.80 +/- 0.19 nmol/min per well); however, in the presence of phosphoramidon, AmM-mediated conversion to bradykinin (3.74 +/- 0.46 nmol/min per well) could be demonstrated. The combined actions of NEP-24.11 (0.93 +/- 0.15 nmol/min per well) and DAP IV (0.84 +/- 0.18 nmol/min per well) were responsible for the degradation of substance P. AmM (2.44 +/- 0.33 nmol/min per well) and NEP-24.11 (1.30 +/- 0.45 nmol/min per well) were responsible for the degradation of the opioid peptide, [Leu5]enkephalin. The identity of each of the three peptidases was confirmed via synthetic substrate hydrolysis, inhibition profile, and immunological identification. The profiles of peptidase enzymes identified in cells derived from rheumatoid and osteoarthritic joints were identical. These data demonstrate the human synovial fibroblast to be a rich source of three specific peptidases and suggest that it may play a prominent role in regulating peptide levels in the joint.

Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of its potent proinflammatory properties. We have previously shown bradykinin to be a potent stimulus for the release of prostanoids from interleukin-1 (IL-1)-treated, but not untreated, human synovial cells. We hypothesize that one mechanism by which IL-1 induces responsiveness to bradykinin is by upregulation of number or affinity of kinin receptors on human synovial cells. We performed [3H]bradykinin binding studies in intact human synovial tissue and in cultured human synovial cells. Specific, saturable [3H]bradykinin binding sites in intact synovia were identified by autoradiographic localization and were present in much higher density in rheumatoid, than in osteoarthritis, synovia. In untreated human synovial cells in culture, a single (B2) class of kinin binding sites with a Kd of 2.3 nM and Bmax of 58 +/- 9 fmol/10(6) cells was demonstrated. In matched experiments, IL-1 treatment enhanced specific [3H]bradykinin binding 1.5- to 2.0-fold above that observed in untreated cells. This enhancement was attributable to an increase in Bmax (53 +/- 4 vs. 105 +/- 24 fmol/10(6) cells in untreated and IL-1-treated cells, respectively), rather than an alteration in Kd (1.7 and 1.4 nM, respectively). The potencies of a series of kinin analogs and antagonists and unrelated peptides in displacing [3H]bradykinin from IL-1-treated cells correlated well with their abilities to induce prostanoid release. These studies provide novel information regarding the nature of kinin receptors in intact human synovia and in cultured human synovial cells, their regulation by IL-1 and their role in IL-1-treated cells in kinin-mediated prostaglandin E2 production.

Bradykinin (BK) is a weak stimulus for prostaglandin E2 (PGE2) release in untreated human synovial cells, but a potent stimulus in interleukin-1 (IL-1) pretreated cells. The mechanism(s) by which IL-1 induces responsiveness of synovial cells to BK appears to be multifactorial. IL-1 not only upregulates the number of kinin receptors on these cells, but may also upregulate a calcium-dependent process involved in the synthesis of prostaglandins.

Anti-histone antibodies have been reported in a number of human autoimmune diseases, most notably idiopathic and drug-induced lupus erythematosus. In the current study, anti-histone antibody activity was detected using ELISA and electroblotting techniques in sera from autoimmune NZB/W, MRL-lpr, and MRL-(+)/+ mice. Anti-histone activity increased with age, maturing earlier in females, in both NZB/W and MRL-lpr mice. Testosterone treatment decreased anti-histone activity in NZB/W mice and estrogen treatment from 2 weeks of age increased anti-histone activity in MRL-lpr mice, suggesting that gonadal hormones modified the expression of autoantibodies recognizing these protein antigens. Estrogen also increased serum IgG levels in MRL-lpr mice. Sex hormones affected expression of antibodies recognizing soy milk proteins but not ovalbumin in a similar manner. Nitrocellulose Western blots of SDS gels probed with sera from both types of autoimmune mice most often demonstrated reactivity with histone1. Some mice, usually mature females, also recognized histone4, histone3, and histone2.

We describe a patient with seropositive rheumatoid arthritis who developed pachymeningitis resulting in optic atrophy. Clinical, histopathologic, and radiologic findings in 18 additional cases of inflammatory CNS disease associated with rheumatoid arthritis are reviewed. The three characteristic neuropathologic findings were rheumatoid nodules, pachymeningitis or leptomeningitis, and vasculitis. In most cases, more than one of these histopathologic processes were found. The typical host was middle-aged with long-standing severe nodular disease. However, contrary to previous reports, CNS disease occurred in a significant number of patients without active synovitis and extracranial vasculitis and nodules. Although no correlation between specific neurologic symptoms and neuropathology was noted, patients with CNS nodules tended to be asymptomatic more often than patients with vasculitis or meningitis. CSF analysis and computed axial tomography were helpful diagnostic tools, but diagnosis was ultimately made only by directed biopsy or at autopsy. Treatment with surgical decompression and/or corticosteroids has proved beneficial in several cases. Inflammatory CNS involvement in rheumatoid arthritis should be considered in any patient with neurologic symptoms in whom infectious and malignant processes are ruled out. An aggressive, invasive approach for diagnostic biopsies seems warranted.

Kinins are vasoactive peptides whose potent inflammatory and bone resorbing properties suggest a role for these autacoids in the pathogenesis of inflammatory arthritis. We used cultured human synovial cells as a model to evaluate the effects of bradykinin on articular tissue. In resting synovial cells, bradykinin was a relatively ineffective stimulus for PGE2 production. However, after a period of preincubation with the cytokine, IL-1, which is itself a stimulus for PGE2 production, synovial cells exhibited a further striking time- and dose-dependent response to bradykinin. Maximal release of PGE2 was observed in response to 10(-7) to 10(-6) M bradykinin after first pretreating the cells for 24 h with 5 to 10 U/ml of IL-1. rIL-1 alpha and IL-1 beta, as well as rTNF-alpha, induced a similar response to bradykinin in synovial cells, whereas recombinant IL-2 did not. The bradykinin analog, lysylbradykinin, was equipotent in inducing PGE2 release from IL-1 pretreated synovial cells, whereas des(Arg9) bradykinin, substance P, and neurokinins A and B were ineffective in this regard in both IL-1-pretreated and in resting cells. Synovial cells derived from patients with rheumatoid arthritis and osteoarthritis responded similarly to bradykinin. The synergistic response in PGE2 production induced by IL-1 and bradykinin was significantly inhibited by pretreatment with 1 microM indomethacin or dexamethasone (96 and 94% inhibition, respectively). In addition, the response was abrogated by pretreatment with 10 micrograms/ml of cycloheximide or actinomycin D (81 and 97% inhibition, respectively). These data provide the first description of synergism of IL-1 with a noncytokine peptide in human synovial cells. The ability of IL-1 to increase the responsiveness of synovial tissues to bradykinin may play an important role in potentiating inflammatory responses within the joint.