ObjectiveThe Disease Activity Score in 28 joints (DAS28), used to assess disease activity in rheumatoid arthritis (RA), is a composite score comprising clinical, biochemical, and patient self-report measures. We hypothesized that psychological factors (cognitions and mood) would be more strongly associated with patient-reported components of the DAS28 than clinical or biochemical components.MethodsA cross-sectional, observational study of 322 RA patients with active disease (mean DAS28 6.0) awaiting therapy with a biologic agent was undertaken. Patients' illness beliefs, treatment beliefs, and mood were measured using the Brief Illness Perception Questionnaire (IPQ), the Beliefs about Medicines Questionnaire (BMQ), and the Hospital Anxiety and Depression Scale (HADS), respectively. Relationships between psychological factors and 1) total DAS28 and 2) individual components of the DAS28 were analyzed using linear regression.ResultsTotal DAS28 produced significant but weak associations with 2 of the Brief IPQ items, but no associations with BMQ or HADS scores. There were larger significant associations between the patient-reported visual analog scale (VAS) with 5 items of the Brief IPQ and with HADS depression. Low illness coherence was associated with higher tender joint count. Three Brief IPQ items and HADS anxiety scores were significantly associated with C-reactive protein level or erythrocyte sedimentation rate. No psychological factors were associated with the swollen joint count.ConclusionOne of the subjective components of the DAS28, patient VAS, was highly correlated with cognitive factors and depression in those with severe RA. By reporting individual DAS28 components, clinicians may be better able to assess the impact of therapies on each component, adjusting approaches according to patients' needs.

ObjectiveSeveral rheumatoid arthritis (RA) susceptibility variants map close to genes involved in the tumor necrosis factor (TNF) signaling pathway, prompting the investigation of RA susceptibility variants in studies of predictors of response to TNF blockade. Based on a previously reported association of RA with the PTPRC genetic locus, the present study was undertaken to test established RA susceptibility variants, including PTPRC, in the prediction of response to TNF blockade in a large cohort of patients from the UK.MethodsDNA was extracted from the blood of 1,115 UK patients with RA who were receiving anti-TNF biologic therapy. Samples were analyzed for 29 single-nucleotide polymorphisms (SNPs) previously established as RA susceptibility variants. In the primary analysis, the effect of each SNP on treatment response was assessed by linear regression, using an additive model, in which absolute change in the Disease Activity Score in 28 joints at 6 months of followup was the outcome measure. In a secondary analysis, logistic regression models were used to compare patients with a good treatment response (n = 274) to those with a poor response (n = 195), as defined using the European League Against Rheumatism response criteria. Results were combined with those from previous studies to confirm the findings by meta-analysis.ResultsThe PTPRC rs10919563 SNP was associated with improved treatment response in both the primary analysis (regression coefficient 0.19, 95% confidence interval [95% CI] 0.09, 0.37; P = 0.04) and secondary analysis (odds ratio 0.62, 95% CI 0.40, 0.95; P = 0.03). A meta-analysis combining these data with the results from a previous study strengthened the evidence for association with the PTPRC SNP (P = 5.13 × 10−5). No convincing association of the treatment response with other candidate loci was detected.ConclusionPresence of the rs10919563 RA susceptibility variant at the PTPRC gene locus predicts improved response to anti-TNF biologic therapy. Fine-mapping studies are required to determine whether this SNP or another variant at the locus provides the greatest predictive accuracy for treatment response.

The introduction of anti-TNF therapy has dramatically improved the outlook for patients suffering from a number of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease. Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment response is likely to be multifactorial; however, variation in genes or their expression may identify those most likely to respond. By targeted testing of variants within candidate genes, potential predictors of anti-TNF response have been reported; however, very few markers have replicated consistently between studies. Emerging genome-wide association studies suggest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect. Other potential serum biomarkers of response have also been explored including cytokines and autoantibodies, with antibodies developing to the anti-TNF drugs themselves being correlated with treatment failure.

In this CTA model, combined protocol of alphabeta-TCR monoclonal antibody and CsA resulted in induction of donor-specific tolerance across the MHC barrier without recipient conditioning. We believe that our findings will foster development of new therapeutic strategies and expand clinical applications for composite-tissue transplantation.