Impact of Dual Rheumatoid Factor and Anticitrullinated Protein Antibody Seropositive, Single Seropositive, and Seronegative Rheumatoid Arthritis on Outcomes.

BackgroundPatients with seropositive rheumatoid arthritis (RA) (positive Rheumatoid Factor (RF)) are more susceptible to extra-articular manifestations [1]. The role of RF in the occurrence of comorbidity is not clear.ObjectivesWe aimed...

BackgroundPrevalence of rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibody (ACPA) positivity in US patients with rheumatoid arthritis (RA) is around 70% [1]. Seropositive RA status, defined by positivity for...

Background:Previous studies have shown an increased mortality in persons with rheumatoid arthritis (RA) compared to the general population. Chronic systemic inflammation and excess comorbidity burden contribute to increased mortality in...

To compare the frequencies and responsiveness of rheumatoid factor (RF)-producing B cells in the peripheral blood of patients with seronegative and seropositive rheumatoid arthritis (RA). Frequencies of IgM+, IgG+, and RF+ B cells were determined by limiting-dilution analysis of purified peripheral blood B cells from 6 patients with seropositive RA, 8 patients with seronegative RA, and 7 normal controls. B cell help was provided by cloned T helper cells, which were stimulated by either anti-CD3 or the bacterial superantigen staphylococcal enterotoxin D (SED). IgM and IgG antibodies and RF in culture supernatants were detected by enzyme-linked immunosorbent assay. In the presence of anti-CD3-stimulated T helper cells, 2-10% of B cells from normal individuals secreted IgM and IgG antibodies. The frequency of RF+ B cells was low and ranged from 1:182 to 1:885 (RF+: IgM+) B cells. In patients with seropositive RA, the numbers of Ig-producing B cells were reduced by a factor of 2, while the fraction of RF+ B cell precursors was expanded by more than 50-fold (7-20% of IgM+ B cells; P = 0.004). Patients with seronegative RA had higher frequencies of RF-producing B cells (1.5-6% of IgM+ B cells) than normal individuals (P = 0.002), but not to the same extent as seropositive patients (P = 0.002). Stimulation of B cells using SED preferentially induced RF+ B cells in normal controls and in patients with seronegative and seropositive RA. B cell precursors with the potential to secrete RF were detectable in high frequencies in normal individuals and in patients with seropositive and seronegative RA. In all donors, these B cells could be stimulated with the bacterial superantigen SED. In normal individuals, RF+ B cells remained nonresponsive to help provided by anti-CD3-activated T cells, but were responsive in RA patients. Seronegative and seropositive RA form a continuous spectrum of disease, with a higher number of RF-secreting B cells in the seropositive patients.

BackgroundThe most common extraarticular manifestation of rheumatoid arthritis (RA) is the rheumatoid nodule, which is reported to affect about 30% of patients with RA.[1] The development of rheumatoid nodules has...

The existence of a subpopulation of patients with rheumatoid arthritis (RA) who lack detectable rheumatoid factor (RF) is well documented. The cellular basis for nonexpression of RF in seronegative RA is not understood. In order to approach this problem, we compared mononuclear leukocytes (MNL) from 20 healthy adult controls, 20 seropositive RA and 22 seronegative RA patients to assess their capacity to synthesize IgM and IgM RF in vitro in the presence and absence of pokeweed mitogen (PWM). MNL from 10 of 20 seropositive RA patients spontaneously elaborated IgM RF (mean = 16.7 ng/106 cells), whereas this was not observed with MNL from either controls or seronegative patients. Small quantities of IgM were spontaneously released by MNL from the seropositive (68.1 ng/106 cells), seronegative (43.1 ng/106 cells), and control (142.3 ng/106 cells) groups. PWM induced IgM RF production by MNL from 10 of 20 controls (18.5 ng/106 cells) and 8 of 22 seronegative RA patients (13.5 ng/106 cells); however, this was significantly less than the production observed with seropositive RA MNL (13 of 20; 37.5 ng/106 cells). In contrast, IgM production in response to PWM was significantly less in both the seronegative (999.7 ng/106 cells) and seropositive RA groups (471.7 ng/106 cells) than in the control group (2,678 ng/106 cells). IgM RF constituted a significantly higher proportion of total IgM synthesized by seropositive RA MNL (10.7%) than either seronegative RA MNL (2.5%) or control MNL (1.2%). Differences in IgM RF production in vitro could not be explained by HLA—DR4 status. Hidden RF was not detected in seronegative MNL supernatants. The results indicate clear differences in the pattern of in vitro release of IgM and IgM RF by MNL from seronegative RA patients as compared to either seropositive RA MNL or control MNL. The similarity of seronegative RA MNL to control MNL with regard to in vitro expression of IgM RF suggests that regulatory mechanisms governing RF synthesis are relatively intact in patients who have seronegative RA.

Background:Several studies show increased risk of dementia among individuals with rheumatoid arthritis (RA), while others show no association. One reason for this discrepancy might be differential association by serostatus. No...

Work disability (WD) in early rheumatoid arthritis (RA) has not been extensively evaluated in Germany. Therefore, the occurrence of WD pension within the first seven years of RA and prognostic indicators of the first year including the duration of sick leave (SL) were analyzed. Within the first year of RA according to the ACR 1987 criteria, 141 gainfully employed patients were entered into a prospective multicenter study (61% females, mean age 47 +/- 9 years, mean disease duration 6 +/- 3.5 months). One hundred and ten patients (78%) participated in a reevaluation (postal questionnaire) after a mean follow-up of 6.1 +/- 0.4 years. Predictors of WD pension were identified in univariate analyses and in backward multivariate Cox regression analyses (p < 0.05) with Hazard-ratios [H-R] as measures of WD risk. Of 110 patients 53 (48%) were still employed at reexamination. WD due to RA occurred in 5% after one year disease duration, in 15% after 2 years, in 20% after 3 years, and in 28% after 6.5 years. Other reasons for leaving the labor force were found in 24%. High pain intensity, radiographic erosions, comorbidity and the pain behavior of avoidance were associated with WD only in univariate analyses. Age > 45 years [H-R 6.3] and the following job-related prognostic indicators were identified in the multivariate analyses: working under pressure of time [H-R 9.0], limited joint motion interferring with job tasks [H-R 5.9], feeling overworked [H-R 3.8] and work status (unskilled blue-collar workers vs white-collar professionals and self-employed persons) [H-R 3.4]. In an alternative final Cox-regression model the variables feeling overworked and work status were replaced by SL duration > 8 weeks within the first year of RA [H-R 7.1]. Since WD frequently occurs already within the first 3 years (20%) adequate interventions resulting from the prognostic indicators have to begin early in the course of RA. Apart from the rheumatological treatment and rehabilitation focusing on the reduction of pain, improved coping with pain, reduced joint destruction and improved mobility particularly working under pressure of time should be avoided and the work place has to be adjusted in case of limited joint motion interferring with job tasks. SL of several weeks duration already within the first year of RA is a red flag for impending WD.

Toll-like receptors (TLRs) are known to have an important role in triggering the innate immune response and in priming antigen-specific adaptive immunity and inflammation. The differences in synovial tissue expression of the TLRs between seronegative and seropositive rheumatoid arthritis (RA) were examined from 9 seropositive RA, 5 seronegative RA and 4 osteoarthritis (OA) patients. Synovitis status was assessed using Krenn’s scoring and TLR 1–9 expression by immunohistochemistry. Tissue citrulline content was analysed by HPLC method. In RA TLR expression was generally higher than in OA. TLR2 expression was higher in both seronegative and seropositive RA compared to OA. TLR 1, 4 and 8 expressions were higher in seropositive RA than in seronegative RA or in OA. For TLRs 3, 5, 6, 7 and 9 local differences of expression were found between groups. TLR 1–9 expression correlated with the synovitis grade. No statistical difference was found in synovial tissue citrulline content between the groups. In seropositive RA, the TLR repertoire in the synovial tissue differs from seronegative RA and could explain differences in disease outcomes. The high expression of protein sensing (TLR1, TLR2 and TLR4) and nucleic acid sensing TLRs (TLR7, TLR8 and TLR9) in the seropositive RA could make the synovium primed for reacting to citrullinated proteins and nucleic acids that could be released to extracellular space in formation of neutrophil extracellular traps. This reactivity could be augmented by Fc receptor activation by anti-citrullinated protein antibody immunocomplexes associated with seropositive RA.

The differences between seronegative and seropositive rheumatoid arthritis (RA) have not been widely reported. We performed electronic health record (EHR)-based phenome-wide association studies (PheWAS) to identify disease associations in seropositive and seronegative RA. A validated algorithm identified RA subjects from the de-identified version of the Vanderbilt University Medical Center EHR. Serotypes were determined by rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) values. We tested EHR-derived phenotypes using PheWAS comparing seropositive RA and seronegative RA, yielding disease associations. PheWAS was also performed in RF-positive versus RF-negative subjects and ACPA-positive versus ACPA-negative subjects. Following PheWAS, select phenotypes were then manually reviewed, and fibromyalgia was specifically evaluated using a validated algorithm. A total of 2,199 RA individuals with either RF or ACPA testing were identified. Of these, 1,382 patients (63%) were classified as seropositive. Seronegative RA was associated with myalgia and myositis (odds ratio [OR] 2.1, P = 3.7 × 10-10 ) and back pain. A manual review of the health record showed that among subjects coded for Myalgia and Myositis, ∼80% had fibromyalgia. Follow-up with a specific EHR algorithm for fibromyalgia confirmed that seronegative RA was associated with fibromyalgia (OR 1.8, P = 4.0 × 10-6 ). Seropositive RA was associated with chronic airway obstruction (OR 2.2, P = 1.4 × 10-4 ) and tobacco use (OR 2.2, P = 7.0 × 10-4 ). This PheWAS of RA patients identifies a strong association between seronegativity and fibromyalgia. It also affirms relationships between seropositivity and chronic airway obstruction and between seropositivity and tobacco use. These findings demonstrate the utility of the PheWAS approach to discover novel phenotype associations within different subgroups of a disease.

BackgroundIn patients with seronegative rheumatoid arthritis (RA) there is a difficulty to make the differential diagnosis with the spondyloarthropathies.ObjectivesTo assess the presence of enthesitis in patients with seronegative RA in...

OP0111 RHEUMATOID ARTHRITIS SEROLOGIC PHENOTYPE AT DIAGNOSIS AND SUBSEQUENT RISK FOR PNEUMONIA IDENTIFIED USING MACHINE LEARNING APPROACHES

IntroductionTo investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years.MethodsIn 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years.Results68% of the patients had accelerated hand BMD loss (>-0.003 g/cm2) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage.ConclusionsIn the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year.

A5.8 B Cell Depletion Therapy in a Cohort of Patients with Seropositive and Seronegative Rheumatoid Arthritis

THU0107 BARIATRIC SURGERY DOES NOT PREVENT THE DEVELOPMENT OF RHEUMATOID ARTHRITIS IN OBESE SUBJECTS