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Objective.Toll-like receptors (TLR) have been implicated in the pathogenesis of arthritis. We investigated the role of functional variants of TLR in the disease phenotype and severity of rheumatoid arthritis (RA).Methods.All patients from a longterm observational inception cohort (n = 319) were genotyped for 22 single-nucleotide polymorphisms (SNP) in TLR2, 3, 4, 5, 7, 8, and 9 using multiplex assays. Clinical characteristics including sex, age at disease onset, rheumatoid factor (RF), and shared epitope positivity and disease activity score and radiological progression were taken into account. Genotypes were analyzed for association with Disease Activity Scores (DAS28) and joint damage (Rau scores) at 3 and 6 years.Results.After Bonferroni correction, there was a moderate association between RF positivity and TLR8-rs5741883. No other TLR variant was significantly associated with any RA clinical characteristics.Conclusion.Using a large inception cohort and strict statistical evaluation, we could not identify an association between functional TLR variants and RA phenotype and disease severity. This suggests the functional TLR variants do not play a major role in RA phenotype and disease severity.

Objective.Rheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome were selected for a family trio-based association study.Methods.A total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies.Results.Four SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genesUBA1, TIMP1,andIL9R.These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA withTIMPLThe sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048).Conclusion.We provide evidence for an association of at least 2 X-chromosomal genes with RA:TIMP1(rs6520278) andIL9R(rs3093457).

Objective.To investigate whether the reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent influences the effect of a second TNF blocking agent.Methods.Data were used from 2 Dutch registries including patients with rheumatoid arthritis (RA) treated with TNF blocking agents. Patients were divided into 3 groups based on reason for discontinuation of the first: nonresponse, loss of response, or adverse events. The primary outcome was the change from baseline of the disease activity (by DAS28) at 6 months, corrected for the baseline DAS28 score. Secondary outcomes were the change from baseline at 3 months, EULAR response rates, and the percentages of patients who reached a DAS28 score ≤ 3.2 at 3 and at 6 months.Results.In total, 49 patients who failed due to nonresponse, 75 due to loss of response, and 73 due to adverse events were included. At 6 months, the change of DAS28 score from baseline did not differ significantly between the groups (−0.6 to −1.3; p ≥ 0.173) and similar good and moderate response rates were found (12% to 18%, p ≥ 0.523, and 34% to 55%, p ≥ 0.078, respectively). The secondary outcomes were also comparable between the 3 groups.Conclusion.The results of our observational study suggest that a second TNF blocking agent may be effective after failure of the first, regardless of the reason for discontinuation of the first TNF blocking agent.

Contains fulltext : 70771.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To investigate functional consequences of the Toll-like receptor 4 (TLR4) variant (Asp299Gly) in rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells from 28 patients with RA carrying or not carrying the TLR4 variant were incubated with lipopolysaccharide (LPS) and heat shock protein B8 (HSPB8). Concentrations of interleukin 6 (IL-6), tumor necrosis factor-alpha(TNF-alpha), and IL-10 were determined along with TLR4 and CD14 expression. RESULTS: TLR4 expression was similar in patients carrying or not carrying the variant. In contrast, both LPS and HSPB8 resulted in significantly lower secretion of IL-6, TNF-alpha, and IL-10 in those who carried the variant, whereas the frequency of CD14+ cells was higher in these individuals. CONCLUSION: TLR4 variant clearly reduces its potency to mediate signaling. Correction for CD14+ cells is necessary in comparable experiments.

Contains fulltext : 51672.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To identify risk factors for surgical site infection (SSI) in patients with rheumatoid arthritis (RA) with special attention for anti-tumor necrosis factor (anti-TNF) treatment. METHODS: All patients with RA who had undergone elective orthopedic surgery since introduction of anti-TNF were included in a retrospective parallel-cohort study with a one-year followup. Primary endpoint was a SSI according to the 1992 Centers for Disease Control and Prevention criteria and/or antibiotic use. Cohort 1 did not use anti-TNF, cohort 2 used anti-TNF but had either stopped (2A) or continued anti-TNF preoperatively (2B), the cutoff point being set at 4 times the half-life time of the drug. Infection rates were compared between cohorts, and logistic regression analysis was performed to examine risk factors. RESULTS: In total, 1219 (768 patients) procedures were included, and crude infection risks were 4.0% (41/1023), 5.8% (6/104), and 8.7% (8/92) in cohorts 1, 2A, and 2B, respectively. Elbow surgery (OR 4.1, 95% CI 1.6-10.1), foot/ankle surgery (OR 3.2, 95% CI 1.6-6.5), and prior skin or wound infection (OR 13.8, 95% CI 5.2-36.7) were associated with increased risk of SSI, whereas duration of surgery (OR 0.42, 95% CI 0.23-0.78) and sulfasalazine use (OR 0.21, 95% CI 0.05-0.89) were associated with decreased risk. Perioperative use of anti-TNF was not significantly associated with an increase in SSI rates (OR 1.5, 95% CI 0.43-5.2). CONCLUSION: The most important risk factor for SSI is history of SSI or skin infection. Although our study was not powered to detect small differences in infection rates, perioperative continuation of anti-TNF does not seem to be an important risk factor for SSI.

Contains fulltext : 50532.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To estimate a threshold for minimal clinically important radiological progression of joint damage using its longitudinal relation with functional disability in patients with rheumatoid arthritis (RA). To validate existing estimates of minimal clinically important difference (MCID) using this relation with functional disability. METHODS: We reanalyzed published data of 185 patients with early RA followed for a maximum of 9 years. Longitudinal regression (mixed models) was used, relating radiological damage (modified Sharp score) to functional disability (HAQ-DI), correcting for age (age at diagnosis and increasing disease duration), disease activity (DAS28), and demographic variables. Several shapes of the relation were investigated. Based on the observed relationship between radiological damage, functional disability, and the minimal clinically relevant increase in functional disability found in earlier studies, MCID for progression of joint damage was discussed. Existing estimates of MCID were evaluated for their influence on functional disability over the disease course. RESULTS: A longitudinal relation between the modified Sharp score and the HAQ-DI was found. Significant covariates were age, gender, and disease activity. The model indicated that the relation between the Sharp score and the HAQ-DI was dependent on the amount of damage (a threshold effect) and on patients' age. With lower age, no effect of joint damage on functional disability could be demonstrated and with higher age the effect of joint damage increased. With a typical patient from our cohort (age at diagnosis 55 yrs, some baseline damage, and an expected disease duration of 30 yrs), a (constant) progression of 6 points per year led to an increase of about 0.2 on the HAQ score, solely related to damage, over the disease course. This estimate of MCID was close to estimates based on expert opinion and equal or smaller than most estimates based on the smallest detectable difference. CONCLUSIONS: The MCID, defined using longitudinal effect on functional disability, is dependent on age and (progression of) joint damage. However, with a typical patient population this MCID was similar to thresholds based on expert opinion, adding to the validity of these estimates.

Contains fulltext : 52030.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Although nodulosis is a common extraarticular manifestation of rheumatoid arthritis, accelerated pulmonary nodulosis is a rare event. The etiology of rheumatoid nodules is still unknown. Nodulosis is not necessarily associated with active joint inflammation, suggesting different pathogenic mechanisms for nodule formation and synovial tissue inflammation. We describe a patient with extensive pulmonary nodulosis, probably related to etanercept treatment. Our case emphasizes the need for careful monitoring for adverse events during treatment with biologicals, especially since the differential diagnosis often includes a broad spectrum of diseases.

Objective.To compare the effectiveness of a third tumor necrosis factor-α (TNF-α)-blocking agent with rituximab after failure of 2 TNF-blocking agents in patients with rheumatoid arthritis (RA) in daily clinical practice.Methods.Patients receiving a third TNF-blocking agent or rituximab after failure of 2 TNF-blocking agents were selected from a Dutch biologic registry. The primary outcome was the results from the Disease Activity Score of 28 joints (DAS28) over the first 12 months after start of the third biologic using mixed-model analyses. Secondary outcomes included the course of the Health Assessment Questionnaire (HAQ) and the separate components of the DAS28 over the first 12 months and the change from baseline in DAS28 and HAQ at 3 and 6 months.Results.The overall course of the DAS28 over the first 12 months was significantly better for rituximab (p = 0.0044), as also observed for the HAQ, although the latter results were not statistically significant (p = 0.0537). The erythrocyte sedimentation rates, C-reactive protein, and swollen joint counts showed a better course for rituximab (p = 0.0008, p = 0.0287, p = 0.0547, respectively), but not the tender joint counts or visual analog scale for general health. DAS28 decreased significantly in both groups at 3 and 6 months (p ≤ 0.024), but the change in HAQ was significant for rituximab only at 3 months (p = 0.009).Conclusion.During the first 12 months of therapy, a larger improvement in disease activity and a trend toward a larger decrease in functional disability was observed in patients receiving rituximab. Switching to a biologic with another mechanism of action might be more effective after failure of 2 TNF-blocking agents in RA.

Objective.To determine the prevalence of and independent factors associated with joint involvement in a large population of patients with systemic sclerosis (SSc).Methods.This study was cross-sectional, based on data collected on patients included in the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) registry. We queried this database to extract data regarding global evaluation of patients with SSc and the presence of any clinical articular involvement: synovitis (tender and swollen joints), tendon friction rubs (rubbing sensation detected as the tendon was moved), and joint contracture (stiffness of the joints that decreased their range of motion). Overall joint involvement was defined by the occurrence of synovitis and/or joint contracture and/or tendon friction rubs.Results.We recruited 7286 patients with SSc; their mean age was 56 ± 14 years, disease duration 10 ± 9 years, and 4210 (58%) had a limited cutaneous disease subset. Frequencies of synovitis, tendon friction rubs, and joint contractures were 16%, 11%, and 31%, respectively. Synovitis, tendon friction rubs, and joint contracture were more prevalent in patients with the diffuse cutaneous subset and were associated together and with severe vascular, muscular, renal, and interstitial lung involvement. Moreover, synovitis had the highest strength of association with elevated acute-phase reactants taken as the dependent variable.Conclusion.Our results highlight the striking level of articular involvement in SSc, as evaluated by systematic examination in a large cohort of patients with SSc. Our data also show that synovitis, joint contracture, and tendon friction rubs are associated with a more severe disease and with systemic inflammation.

Contains fulltext : 70133.pdf (Publisher’s version ) (Closed access)