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OBJECTIVE: A recent high-density fine-mapping (ImmunoChip) study of genetic associations in rheumatoid arthritis (RA) identified 14 risk loci with validated genome-wide significance, as well as a number of loci showing associations suggestive of significance (P = 5 × 10(-5) < 5 × 10(-8)), but these have yet to be replicated. The aim of this study was to determine whether these potentially significant loci are involved in the pathogenesis of RA, and to explore whether any of the loci are associated with a specific RA serotype. METHODS: A total of 16 single-nucleotide polymorphisms (SNPs) were selected for genotyping and association analyses in 2 independent validation cohorts, comprising 6,106 RA cases and 4,290 controls. A meta-analysis of the data from the original ImmunoChip discovery cohort and from both validation cohorts was carried out, for a combined total of 17,581 RA cases and 20,160 controls. In addition, stratified analysis of patient subsets, defined according to their anti-cyclic citrullinated peptide (anti-CCP) antibody status, was performed. RESULTS: A significant association with RA risk (P < 0.05) was replicated for 6 of the SNPs assessed in the validation cohorts. All SNPs in the validation study had odds ratios (ORs) for RA susceptibility in the same direction as those in the ImmunoChip discovery study. One SNP, rs72928038, mapping to an intron of BACH2, achieved genome-wide significance in the meta-analysis (P = 1.2 × 10(-8), OR 1.12), and a second SNP, rs911263, mapping to an intron of RAD51B, was significantly associated in the anti-CCP-positive RA subgroup (P = 4 × 10(-8), OR 0.89), confirming that both are RA susceptibility loci. CONCLUSION: This study provides robust evidence for an association of RA susceptibility with genes involved in B cell differentiation (BACH2) and DNA repair (RAD51B). The finding that the RAD51B gene exhibited different associations based on serologic subtype adds to the expanding knowledge base in defining subgroups of RA.

Multiple epiphyseal dysplasia (MED) is a dominantly inherited chondrodysplasia characterized by mild short stature and early-onset osteoarthrosis. Some forms of MED clinically resemble another chondrodysplasia phenotype, the mild form of pseudoachondroplasia (PSACH). On the basis of their clinical similarities as well as similar ultrastructural and biochemical features in cartilage from some patients, it has been proposed that MED and PSACH belong to a single bone-dysplasia family. Recently, both mild and severe PSACH as well as a form of MED have been linked to the same interval on chromosome 19, suggesting that they may be allelic disorders. Linkage studies with the chromosome 19 markers were carried out in a large family with MED and excluded the previously identified interval. Using this family, we have identified an MED locus on the short arm of chromosome 1, in a region containing the gene (COL9A2) that encodes the alpha 2 chain of type IX collagen, a structural component of the cartilage extracellular matrix.

Enteropathic arthritis is a form of arthritis associated with the chronic inflammatory bowel diseases, ulcerative colitis, and Crohn's disease. This form of arthritis is classified as one of the group of seronegative spondyloarthropathies, which also includes psoriatic arthritis, reactive arthritis, and idiopathic ankylosing spondylitis. Joint involvement also occurs with other gastrointestinal diseases such as Whipple's disease, celiac disease, and following intestinal bypass surgery for morbid obesity. In these conditions, abnormal bowel permeability and immunologic and genetic influences are probably involved in the pathogenesis of the joint disease, although the exact mechanisms remain uncertain.

Aim of Investigation: To examine the mechanisms involved in chronic pain and its relief using functional magnetic resonance imaging (fMRI). We were interested in how evoked clinical joint pain processing in rheumatoid arthritis (RA) patients changes after anti-TNF-alpha treatment. Anti-TNF treatment blocks the action of TNF-alpha, a key factor in joint inflammation, suppressing disease activity in severe RA reducing both joint pain and inflammation. Methods: Twenty-one patients with severe RA and due to begin anti-TNF treatment have so far been recruited to the study with full informed consent. We used fMRI to investigate changes in brain activation in response to joint pressure pain and thermal stimulation at a fixed temperature to elicit moderate pain over the course of treatment (i) before the treatment, (ii) 1 month, (iii) 8 months after treatment began. Clinical, psychological and psychophysical data was collected at each time point. Results: Up to now, 10 patients have responded positively to treatment and completed all 3 time points (TP). Clinical and psychobehavioural results Between TP-1 and TP-2 there was a significant decrease in pain ratings, on 11-point numerical rating scale for both pressure (5.1 vs. 3.3 p=0.002) and heat (6.2 vs. 5.1 p=0.004), as well as for daily pain (5.9 vs. 4.3 p=0.004). The difference between the TP-1 and TP-3 was even more significant: for pressure pain ( and daily pain but not more sp for heat pain. There was a significant reduction in disease activity score in 28 joints (DAS 28) and blood inflammatory markers. There was no significant difference in the depression and catastrophising scores for TP-1 vs. TP-2, but they both significantly decreased at TP-3 vs. TP-1. Imaging results: We observed a robust activation in response to both types of painful stimuli. In the pressure pain condition there was a decrease in activation, at TP-2 vs. TP-1 in the left primary sensorimotor cortex, secondary sensory cortex bilaterally and right insula. For TP-3 vs. TP-1 there was a decrease of activation bilaterally in insula and somatosensory cortex. For heat stimulation, there was a bilateral decrease in activation in cingulate, thalamus and striatum for the TP-2 vs. TP-1 but not for the TP-3 vs. TP-1, reflecting perhaps modulation of nociceptive processing as patients recover. Conclusions: We observed a notable reduction in disease activity after 1 month of treatment in clinical, psychological and fMRI data. The observed imaging changes correlated with a reduced noxious input and decreased perceived pain intensity. Acknowledgments: The study was funded by GlaxoSmithKline as a part of an ongoing academic collaboration.

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Introduction: Anti-TNF treatment blocks the action of proinflammatory cytokine, tumor necrosis factor, and reduces pain and disease activity in rheumatoid arthritis (RA). We were interested in changes in processing of evoked pain in RA patients after successful anti-TNF treatment. Methods: Ten patients with severe RA were scanned before the beginning of treatment and after 6 months of successful therapy. 22 healthy volunteers were recruited as a control group and were scanned only once. We used fMRI to investigate brain activation changes in response to joint pressure pain and thermal stimulation at a fixed temperature to elicit moderate pain. Results: At the baseline, the comparison of moderately painful pressure pain in patients vs. non-painful pressure stimulation in controls revealed more extensive activation in the anterior cingulate cortex, the brainstem and bilaterally in the thalamus and insula. As for the thermal stimulation, patients and controls rated it as moderately painful, however, there was less activation in the thalamus and insula in patients than in controls. Patients were scanned again after six months of the treatment and the same stimulation intensity was used as at the baseline. Joint pressure pain was rated significantly lower, whereas thermal pain ratings remained the same. In comparison to the control group imaging data, patients showed more activation in response to pressure stimulation in the cingulate cortex and brainstem; patients’ brain activation in response to thermal stimulation was not different from controls. Conclusions: We observed a normalization of pain processing after successful anti-TNF treatment.