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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.To investigate the possible role ofFCGR2A519A>G andFCGR3A559A>C functional polymorphisms in the genetic predisposition to susceptibility to systemic sclerosis (SSc) or clinical phenotype.Methods.A total of 1566 patients with SSc and 2271 geographically matched controls were included in our study. We analyzed the genotype and allele frequencies of theFCGR2A519A>G andFCGR3A559A>C functional variants in 6 independent European cohorts of white patients with SSc, and white controls. The cohorts comprised 165 Dutch patients with SSc and 1326 controls, 236 Spanish patients with SSc and 257 controls, 267 German patients with SSc and 270 controls, 202 Swedish patients with SSc and 261 controls, 416 Italian patients with SSc and 157 controls, and additionally 280 English patients with SSc. Genotyping was performed using Taqman 5′ allelic discrimination assay. The study reached a 99% power to detect the effect of a polymorphism at an OR of 1.3.Results.NeitherFCGR2A519A>G norFCGR3A559A>C was significantly associated with susceptibility to SSc. We did not find an association with specific disease phenotypes, limited or diffuse cutaneous involvement, autoantibody profiles, or pulmonary involvement.Conclusion.Our study strongly suggests the lack of a role for theFCGR2A519A>G andFCGR3A559A>C polymorphisms in SSc susceptibility or clinical phenotype in 6 independent European cohorts.

Objective.C-C chemokine receptor 5 (CCR5) plays an important role in inflammation. A 32 base-pair (Δ32) deletion in the CCR5 gene leads to a nonfunctional receptor. This deletion has been reported to have a protective effect on the development and progression of several autoimmune diseases. We investigated whether the Δ32 deletion is associated with disease susceptibility in a population of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and lupus nephritis (LN); and whether it is associated with disease severity.MethodsDNA samples from 405 RA patients, 97 SLE patients, 113 LN patients, and 431 healthy controls were genotyped for the CCR5 Δ32 deletion. Differences in genotype frequencies were tested between patients and controls. Association of genotypes with disease severity was analyzed.ResultsGenotype frequencies of each group were in Hardy-Weinberg equilibrium. The genotype frequencies of patients did not differ significantly from controls (CCR5/Δ32, Δ32/Δ32: RA 18.3% and 1.2%, respectively; SLE 17.5% and 2.1%; LN 13.3% and 1.8%; controls 20.0% and 2.8%). However, there was a trend for lower Δ32 deletion allele frequency in LN patients compared to controls (p = 0.08). There was no significant association between the CCR5 status and disease severity in RA, SLE, or LN.Conclusion.Although an association with LN cannot be excluded, the CCR5 Δ32 deletion does not seem to be a disease susceptibility genotype for RA, SLE, or LN. No significant effect of the Δ32 deletion on disease severity was demonstrated.

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 : 53375.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To explore the relation of changes in measures of bone turnover and changes in bone mineral density (BMD) of the lumbar spine and total hip over 18 months in a double-blinded, randomized trial, comparing the effect of alfacalcidol (101 patients) versus alendronate (100 patients) on BMD in patients who recently started treatment with glucocorticoids for various rheumatic diseases. METHODS: Associations between changes in serum procollagen type I C-propeptide (P1CP), fasting urine N-terminal telopeptide of type I collagen (NTx), serum calcium, parathyroid hormone (PTH), osteocalcin, and change from baseline in BMD over 18 months were explored with regression and correlation analyses. RESULTS: In both treatment groups, there was a statistically significant decrease in NTx. In the alfacalcidol group there was also a significant increase in P1CP and osteocalcin, in contrast to the alendronate group, but BMD in the alfacalcidol decreased versus an increase in the alendronate group (p < 0.001). In neither treatment group were changes in biochemical measures correlated with the change in BMD, with the exception of a negative correlation in the alendronate group between changes in total hip BMD and NTx. Use of alendronate resulted in an increased PTH in 27 patients, but the increase in BMD of these patients was not statistically significantly different compared to patients taking alendronate with normal PTH levels. CONCLUSION: Changes in BMD were not associated with changes in bone measures, with the exception of NTx in the alendronate group. For the patient taking glucocorticoids in clinical practice, the value of serial assessment of bone markers is low; changes in markers are no substitute for changes in BMD. ClinicalTrials.gov number: NCT00138983.

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 : 53450.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To study prospectively the effect of treatment with cyclophosphamide pulses (CYC) or azathioprine with methylprednisolone (AZA), both for 24-month periods, on health-related quality of life (HRQOL) in patients with proliferative lupus nephritis (LN) in a randomized controlled trial. We expected better HRQOL during AZA treatment. METHODS: HRQOL and disease activity were measured at start and after 12 and 24 months. Generic questionnaires [patient's visual analog scale (VAS), Medical Outcomes Study Short Form-36 Health Survey (SF-36), Profile of Mood States] and a disease-specific measure [Systemic Lupus Erythematosus (SLE) Symptom Checklist] were used. Treatment burden was assessed at 24 months. Disease activity was measured with the SLE Disease Activity Index (SLEDAI) and physician's VAS. RESULTS: Complete questionnaire data were available from 47 of the 87 patients included in the trial. These patients were representative of the whole group, except that completers were more often Caucasian. HRQOL scores improved significantly during treatment, particularly during the first year, on both generic and disease-specific outcomes. No statistically significant differences were found in HRQOL between the CYC and AZA groups, except for the SF-36 mental component summary scale, which showed more favorable scores in the AZA group. The mean reported treatment burden at 24 months was significantly higher in the CYC group. HRQOL scores did not correlate with the SLEDAI and physician's VAS. The disease activity measures correlated positively with each other. CONCLUSION: Treatment of patients with proliferative LN with immunosuppressive drugs and corticosteroids improves HRQOL, particularly in the first year. Due to the small groups studied, the absence of differences between AZA and CYC for most HRQOL scales should be interpreted cautiously: our data suggest that there may be no significant differences. Differences were a higher perceived treatment burden and worse mental HRQOL in the CYC group.

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.

Contains fulltext : 47486.pdf (Publisher’s version ) (Closed access) Animal models of arthritis can be used to understand elements of the arthritic process in patients. Recent therapeutic approaches in patients with rheumatoid arthritis (RA) with biologics are based on initial findings in murine models of experimental arthritis, although final proof of concept must come from clinical studies. Animal models are powerful tools for studying pathologic changes in articular cartilage and bone in great detail, and can be used to evaluate mechanisms of erosive processes. Although in general more inflammation drives more destruction, the uncoupling of inflammation and erosion can be seen as well, and different mediators are involved in these processes.

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)