Clinical Expression Of Rheumatoid Arthritis Research Articles

Sex-Specific Association of Left Ventricular Hypertrophy With Rheumatoid Arthritis.

Objectives: Clinical expression of rheumatoid arthritis (RA) varies by gender, but whether cardiovascular disease (CVD) is gender related in RA is unknown. Left ventricular (LV) hypertrophy (LVH) is a hallmark of CVD in RA patients. We investigated whether the association of LVH with RA is gender driven.Methods: Consecutive outpatients with established RA underwent echocardiography with measurement of LVH at baseline and one follow-up. All participants had no prior history of CVD or diabetes mellitus. We assessed CVD risk factors associated with LVH at follow-up, including sex, age, arterial blood pressure, and body mass index (BMI). We also evaluated inflammatory markers, autoimmunity, disease activity, and the use of RA medications as predictors of LVH.Results: We recruited 145 RA patients (121 females, 83%) and reassessed them after a median (interquartile range) of 36 months (24–50). At baseline, women were more dyslipidemic but otherwise had fewer CVD risk factors than men, including less prevalent smoking habit and hypertension, and smaller waist circumference. At follow-up, we detected LVH in 42/145 (44%) RA patients. LV mass significantly increased only in women. In multiple Cox regression analysis, women with RA had the strongest association with LVH, independently from the presence of CVD risk factors (OR, 6.56; 95% CI, 1.34–30.96) or RA-specific characteristics (OR, 5.14; 95% CI, 1.24–21.34). BMI was also significantly and independently associated with LVH.Conclusion: Among established RA patients, women carry the highest predisposition for LVH.

C3 Gene Functional Polymorphisms and C3 Serum Levels in Patients with Rheumatoid Arthritis

ABSTRACT The complement system is a key component of the innate immunity that plays a significant role in the development and clinical presentation of Rheumatoid arthritis (RA). Complement protein C3 is a central molecule in the activation of complement with a significant role in the inflammatory processes of RA. Nevertheless, the impact of C3 gene polymorphisms in the development of RA is still unknown. The current study aimed to investigate the possible influence of C3 gene polymorphisms in the susceptibility and clinical expression of RA. Three C3 polymorphisms (rs2250656:A > G, intron 2; rs2230199:C > G [p.Arg102Gly], exon 3 and rs1047286:C > T [p.Pro314Leu], exon 9) were assessed by sequence-specific PCR in a total of 156 RA patients and 270 healthy controls from Southern Brazil. In addition, C3 levels were measured in 60 patients and 60 controls by immunoturbidimetry and clinical features were collected from medical records. The frequency of rs2230199 G allele and GG genotype was significantly higher in RA patients than controls (padj = 0.012 OR = 1.57 [1.11–2.31]; padj = 0.008, OR = 1.60 [1.35–2.33]) as well as the rs1047286 T and TT (padj = 0.010, OR = 1.67 [1.12–2.40]; padj = 0.001, OR = 1.83 [1.27–2.65] and the C3 AGT haplotype (padj = 0.0007 OR = 1.92 [1.32–2.80]). Moreover, C3 serum levels were higher in patients than controls (median: 169 mg/dl vs.155 mg/dl; padj = 0.022), as well as in RF seronegative compared with seropositive patients (172 mg/dl vs. 165 mg/dl; padj = 0.007). Our results suggest that the rs2230199 G (p.102Gly) and rs1047286 T (p.314Leu) alleles play a role in the pathophysiology of RA, possibly impacting complement activation by the alternative pathway.

Rheumatoid arthritis: Stress in RA: a trigger of proinflammatory pathways?

Stressful life events can change the clinical expression of rheumatoid arthritis (RA). Stress increases the proinflammatory load in healthy individuals and patients with RA. A new study demonstrates that short-term experimental stress transiently increases serum IL-1β and IL-2 levels in patients with RA, but how does stress affect chronic inflammation?

The selective estrogen receptor α agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: A phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine

Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity. A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28). Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial. The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists

To investigate the impact of official recommendations regarding the management of latent tuberculosis (TB) infection on the rate of active TB in patients receiving treatment with tumor necrosis factor (TNF) antagonists. Data on active TB rates and on screening and treatment of latent TB infection were extracted from the BIOBADASER (Spanish Society of Rheumatology Database on Biologic Products), a registry of patients with rheumatic conditions treated with TNF antagonists. The rates of active TB among the BIOBADASER patients were compared with those in the background Spanish population, and BIOBADASER patients with rheumatoid arthritis (RA) were compared with a cohort of RA patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) study who were not treated with TNF antagonists and were followed up for 5 years. Active TB developed in 34 patients, of whom 32 started taking TNF antagonists prior to the official recommendations on latent TB infection (pre-OR) and 2 began treatment after the recommendations were issued (post-OR). All cases of TB occurred during treatment with infliximab, and 28 of these patients had RA. Pre-OR, the active TB rate in BIOBADASER patients was 20.9-fold higher than in the background Spanish population, while RA patients in the BIOBADASER had rates 22.6- and 6.2-fold higher than the background and EMECAR populations, respectively. Post-OR, 324 patients with a tuberculin skin test result > or =5 mm and/or chest radiograph findings suggestive of past TB were treated for 9 months with isoniazid (INH). Post-OR, active TB rates among the BIOBADASER patients decreased by 78% (incidence risk ratio [IRR] 0.22, 95% confidence interval [95% CI] 0.03-0.88; P = 0.008), while among RA patients in the BIOBADASER, the rate dropped by 83% and reached the EMECAR rate (IRR 1.0, 95% CI 0.02-8.2). There were no INH treatment-related hospitalizations or deaths. Strategies to treat latent TB infection that are tailored to the at-risk population can effectively and safely lessen the likelihood of active TB in patients treated with TNF antagonists.

Ethnic variation in the clinical manifestations of rheumatoid arthritis: role of HLA-DRB1 alleles.

To assess the extent of ethnic variation in the clinical expression of rheumatoid arthritis (RA) and the role of HLA-DRB1 alleles in this variation. We assessed consecutive RA patients for joint findings, subcutaneous nodules, laboratory and radiographic findings, and treatment. We typed HLA-DRB1 alleles to identify those that contain the shared epitope (SE). We adjusted ethnic comparisons for age and sex, and tested for ethnic heterogeneity in the effect of the SE. We studied 777 RA patients, 498 of whom were women (64%), 432 were Hispanic (56%), 272 were non-Hispanic white (NHW; 35%), 53 were African American (AA; 7%), and 20 were Asian (3%). Compared with NHW, Hispanics had significantly more tender joints (17 versus 11), more swollen joints (8 versus 7), more frequent rheumatoid factor (RF) positivity (93% versus 84%), higher erythrocyte sedimentation rate (ESR; 45 versus 36 mm/hr), and a lower number of lifetime disease-modifying antirheumatic drugs (1.9 versus 2.5). AA were older at onset (46 versus 44 years), had less frequent subcutaneous nodules (18% versus 28%), and higher ESR (42 versus 36 mm/hour) than did NHW. Hispanics and AA were more likely than NHW to be null for the SE (odds ratio [OR] = 4.59 for AA; and OR = 1.61 for Hispanics), and less likely to have 2 SE-carrying alleles (OR = 0.59 for Hispanics and OR = 0.25 for AA). The number of SE copies was associated with subcutaneous nodules, ESR, RF, and radiographic changes. Ethnic heterogeneity in the effect of the SE was modest. There is ethnic variation in the clinical expression of RA and in both the frequency and types of SE-carrying HLA-DRB1 alleles. Some ethnic variation in clinical findings is associated with differences in SE frequency. However, we found that the effect of the SE on the clinical features of RA varies little between ethnic groups.

Global Functional Status in Rheumatoid Arthritis: Disease Duration and Patient Age

With the aim of clarifying whether patient age could be an additional explanation for the differences in the clinical expression of rheumatoid arthritis (RA) found in different populations, we evaluated the possibility of patient age being a significant factor associated with global functional status, independent from disease duration. Our present results suggest that both disease duration and patient age are major factors in the global functional status of patients with RA, and that patient age is particularly important when a subgroup of patients with more than 60 years of age and more than 20 years of disease duration is considered. These data are relevant when comparing two different RA groups: not only should we have a similar mean age and mean disease duration, but also the subgroups of patients more than 60 years of age and with more than 20 years of disease duration should correspond to equivalent proportions in the populations studied.

Association of HLA-DR with susceptibility to and clinical expression of rheumatoid arthritis: re-evaluation by means of genomic tissue typing.

The clinical expression of rheumatoid arthritis (RA) varies considerably among individual patients. Genetic variations in human leucocyte antigen (HLA) may influence clinical expression. We re-examined the association of HLA-DR with susceptibility to and clinical expression of RA using genomic tissue typing, since most studies were based on (less reliable) serological techniques. Seventy-eight patients with recent-onset RA, all participating in a clinical trial on therapeutic strategies, were HLA-DR typed by means of low-resolution genomic typing. Cumulative disease activity within the first 3 yr of disease was measured. Of the RA patients, 54% expressed DR4 (DR4+) vs 26% of healthy controls. Rheumatoid factor (RF)-positive patients had a higher cumulative disease activity than RF-negative patients. Patients who were either DR1+ or DR4+ had a higher cumulative disease activity than those who expressed neither DR1 nor DR4. This association was less obvious after correction for RF status. The association of DR52+ (DR3, 5, 6) and a lower cumulative disease activity could also not be demonstrated after correction for RF status. Among RF-negative patients, DR51+ (or DR2+) was associated with a higher cumulative disease activity. Other HLA-DR types (including DR1 and DR4 separately) were not associated with the severity of RA. DR4 was associated with susceptibility to RA in our patients; HLA-DR low-resolution genomic tissue typing did not yield additional information to RF status for the clinical identification of individual patients with a poor prognosis.

The Effect of HLA-DRB1 Disease Susceptibility Markers on the Expression of RA

The study was designed to examine the effect on clinical expression of rheumatoid arthritis (RA) of HLA alleles, particularly DR4 and DR1 that contain susceptibility sequences for RA in the third hypervariable region (HVR3) of HLA-DRB1. We studied 114 consecutive Australian patients with RA attending a hospital outpatient clinic. The effects on indices of disease severity and activity of HLA DR4 and DR1, the DRB1*04 subtypes, and the polymorphism in the RA susceptibility sequence (QRRAA or QKRAA) were examined. The patients were initially divided into 6 groups, DR4,4; DR4,1; DR1.1; DR4/X; DR1,X, and DRX/X, and then further subdivided according to the actual HVR3 susceptibility sequence. The high risk conferred by the HVR3 susceptibility sequence, present in 76%, was confirmed, but 24% of the patients with long-standing seropositive erosive RA lacked this sequence. Among these those with DR2 had early-onset severe disease, and those with DR3 had late-onset milder disease. Differences in expression correlated with polymorphisms in the susceptibility sequence, in that active RA was associated more with QRRAA than QKRAA. There was no correlation of any HLA allele with disease severity. Our finding that the presence of the HVR3 sequence confers susceptibility and also influences the clinical expression and tempo of progression of RA suggests a role in pathogenesis for antigen presentation, whether of an autoantigenic molecule or a persisting infection.

Clinical expression of rheumatoid arthritis in Chilean patients

In populations such as Northern Europeans in which the HLA-DR4 subtypes Dw14 and Dw4 show strong association with rheumatoid arthritis (RA), these alleles and the double allelic dose of the shared epitope are considered severity markers. The clinical expression of RA varies in different populations, which may be determined by variation in the prevalence of these markers. In the present study we analyzed the expression of RA in 112 consecutive Chilean patients and its relation to the prevalence of genetic factors, prompted by our previous observation that DR4 is weakly associated to RA in this population. Mean age was 50 ± 14 years; 90% were seropositive and 87% were female, with a disease duration of 10 ± 8 years. Extra-articular manifestations were found in 38% of patients, rheumatoid nodules in 27%, vasculitis in 8%, and Sjögren's syndrome in 29%. Functional capacity (ACR, 1991) I or II: 82%. 15% of patients stopped working. Hand radiographs scored according to Steinbrocker in 89 patients: I, 21%; II, 15%; III, 43%; IV, 21%. In this series, patients with less formal education seemed to have more benign arthritis. In 97 controls and in 65 (56%) RA patients the presence of DRB1 alleles corresponding to DR1 and DR4 serotypes, to DR4-Dw subtypes, and homozygocity, were determined by polymerase chain reaction followed by specific oligonucleotide hybridization. The shared epitope was present in 53% of RA patients and in 30% of controls ( P = .0048, odds ratio [OR] = 2.64). A double allelic dose of the epitope was present in 15% of RA patients compared with 4% of controls ( P = .026, OR = 4.23). In a subgroup of 31 erosive RA patients we did not find a significant association of disease severity with the shared epitope in a single or double allelic dose. None of the DR4 subtypes that associate with RA in other populations was found significantly more prevalent in our patients. The severity of RA in our study compared with published series was intermediate between British patients with severe RA and Greek patients with milder disease. This may be due to the high prevalence of Dw13*0403 in our population.

Heterogeneity of disease phenotype in monozygotic twins concordant for rheumatoid arthritis.

The objective of the study was to investigate the genetic contribution to the clinical expression of rheumatoid arthritis (RA) by comparison of disease features in RA-concordant monozygotic (MZ) twin pairs. Fourteen RA-concordant MZ twin pairs recruited from a nation-wide study were examined to determine the degree of similarity in: (a) age of disease onset; (b) pattern of joint involvement; (c) pattern of extra-articular disease; (d) toxic reactions to drugs; (e) disease course; and (f) serology for rheumatoid factor (RF) and antinuclear antibody. There was considerable within-pair diversity in the variables studied. Some similarity within twin pairs was observed for the ages at disease onset (R = 0.63), presence of erosive changes (kappa = 0.61) and the presence of IgM RF (R = 0.87). No important similarity was seen, however, in the pattern of joint involvement, the occurrence of extra-articular disease, adverse drugs reactions, clinical disease course and reported disability level. There is heterogeneity in the genetic contribution to the clinical expression of RA. The overall lack of similarity for the majority of clinical variables indicates the importance of non-genetic factors on the expression of disease.

An Animal Model of Food Allergic Arthritis

Progress in understanding rheumatoid arthritis has been slow in large part because no widely accepted animal model exists that clearly reflects naturally occurring human disease, and because the clinical expression of rheumatoid arthritis may represent multiple etiologies with shared or subtly different immunopathogenic pathways. New insights about pathogenesis and causes are needed to understand this disease and ultimately to care for patients better.

Changes in immune function in patients with rheumatoid arthritis following treatment with sodium aurothiomalate.

The mitogenic response of peripheral blood lymphocytes from 21 patients with rheumatoid arthritis to concanavalin-A (con--A), phytohaemagglutinin (PHA), and pokeweed mitogen (PWM) was significantly lower than in 30 normal subjects. After 15--24 weeks' treatment with sodium aurothiomalate (GST) the response to these mitogens rose to within the normal range. Improvement over pretreatment values was significant for con-A and PWM measured as area under the dose response curve but only for con--A if response at optimal mitogen concentration is the sole criterion. The improvement in PHA response was not significant with either method of measurement. There was an improvement in disease activity by 15--24 weeks as measured by a fall in serum C-reactive protein (CRP), IgM rheumatoid factor (RF), Clq binding activity (ClqBA), and Ritchie articular index. Con--A lymphocyte responsiveness was inversely related to serum CRP levels, but measurements of disease activity were otherwise unrelated to lymphocyte mitogen responsiveness. The observed improvement in peripheral blood lymphocyte responsiveness during gold treatment contrasts with the suppressive effect of gold in vitro. We suggest that the improvement in lymphocyte function is due to the lessening of rheumatoid disease activity during gold treatment, and that the low serum gold levels in our patients were insufficient to mask this effect. Sera from some of our patients were capable of suppressing the function of normal lymphocytes, and this was less apparent after treatment. The suppressive effect of sera correlated with ClqBA. Suppressive factors in serum, including possibly immune complexes, may be one factor leading to suppression of lymphocyte function during rheumatoid arthritis. Such an inverse relationship between humoral and cellular immune mechanisms might influence the clinical expression of rheumatoid arthritis.