CD169+ Monocyte and Regulatory T Cell Subsets Are Associated with Disease Activity in Rheumatoid Arthritis.

Disease activity in rheumatoid arthritis (RA) is influenced by activation of circulating and synovial immune cells. Regulatory T cells (Tregs) and monocytes are key cells that drive inflammation in RA. This study investigated if a relationship exists between disease activity in RA and circulating Treg and monocyte numbers and phenotypes. A potential sialic acid (Sia) mediated link between Tregs and monocytes was also probed in vitro. Peripheral blood mononuclear cells (PBMCs) were isolated from RA patient (n = 62) and healthy control (n = 21) blood using density gradient separation. Flow cytometry was used to count and phenotype Treg and monocyte subsets, and to sort healthy control Tregs for Sia cell culture experiments. The effects of Sia on activated Treg FoxP3 and NFκB expression was assessed by flow cytometry and concentrations of secreted TNFα, IL-10 and IFNγ determined by ELISA. High disease activity RA patients who were unresponsive to disease modifying anti-rheumatic drugs (n = 31), have significantly lower relative numbers (percentages) of CD4+CD25+CD127− Tregs (p < 0.01) and memory CD45RA−FoxP3+ Tregs (p < 0.01), compared to low disease activity responders (n = 24). Relative numbers of non-classical CD169+ monocytes are associated with disease activity in RA (p = 0.012). Sia reduced Treg expression of FoxP3, NFκB and cytokines in vitro. A strong association has been identified between non-classical CD169+ monocytes and post-treatment disease activity in RA. This study also indicates that Sia can reduce Treg activation and cytokine release. We postulate that such a reduction could be mediated by interaction with sialyted proteins captured by CD169+ monocytes.

Anti-tumour necrosis factor-alpha response associated with combined CD226 and HLA-DRB1[*]0404 haplotype in rheumatoid arthritis.

OBJECTIVES: Predicting response to anti-tumour necrosis factor alpha (anti-TNFα) drugs at baseline remains an elusive goal in rheumatoid arthritis (RA) management. The purpose of this study was to determine if baseline genetic variants of PTPRC, AFF3, myD228, CHUK, MTHFR1, MTHFR2, CD226 and a number of KIR and HLA alleles could predict response to anti-TNF-α in rheumatoid arthritis patients. METHODS: Peripheral blood samples were collected from 238 RA patients treated with anti-TNFα drugs. Genotyping was performed using biochip array technology by Randox Laboratories Ltd. and sequence specific polymerase chain reaction. Linear regression analysis was performed to investigate the role of these genotypes in predicting response to treatment, as defined by European League Against Rheumatism (EULAR) response classification and absolute change in disease activity score (DAS28). RESULTS: Of 238 RA patients analysed, 50.4% received adalimumab, 29.7% received etanercept, 14.8% received infliximab, 3.4% certoluzimab and 1.7% golimumab. The MTHFR1 variant rs1801133 was significantly associated with the EULAR response, p=0.044. Patients with the HLA-DRB1*0404 allele displayed a significantly larger reduction in DAS28 compared to non-carriers (mean -2.22, -1.67 respectively, p=0.033). CD226 rs763361 was the only SNP variant significantly associated with ΔDAS28 (p=0.029). CONCLUSIONS: This study has investigated individual allele associations with reductions in DAS28 across a range of anti-TNFα treatments. A combined predictive model indicates that patients with the HLA-DRB1*0404 allele and without the CD226 rs763361 polymorphism exhibit the largest reduction in DAS28 after anti-TNF-α treatment.

Steroid injection for inferior heel pain: a randomised controlled trial.

BACKGROUND: Plantar fasciitis is a common cause of heel pain. The aim of this study was twofold: to compare steroid injection with placebo injection and to compare ultrasound guided with unguided steroid injection in the management of this condition. METHODS: 65 patients with inferior heel pain were recruited between November 2008 and June 2011. Heel pain was measured using a visual analogue scale (VAS) at baseline and follow-up 6 and 12 weeks after injection. RESULTS: 22 patients were randomised to ultrasound guided steroid injection, 21 patients to palpation guided steroid injection and 22 to ultrasound guided placebo injection. There was a significant difference in VAS scores between the groups at 6 and 12 weeks (p=0.018 and p=0.004, respectively). There was a 19.7 (95% CI 2.5 to 37.0) difference in mean VAS scores at 6 weeks between the ultrasound guided steroid group and the placebo group and a 24.0 (95% CI 6.6 to 41.3) difference between the unguided steroid group and the placebo group at 6 weeks. At 12 weeks, the mean difference was 25.1 (95% CI 6.5 to 43.6) and 28.4 (95% CI 11.1 to 45.7) respectively between both steroid injection groups and the placebo group. There was no difference in VAS scores following steroid injection between the ultrasound guided and the unguided groups at either time point. Plantar fascia thickness was significantly reduced after injection in both active treatment groups (p=0.00). CONCLUSIONS: In this study, steroid injection showed a clear benefit over placebo at 6 weeks and this difference was maintained at 12 weeks. Trial Registration No ISRCTN79628180 (www.controlled-trials.com).

Hypertrophic pulmonary osteoarthropathy (HPOA) (Pierre Marie-Bamberger syndrome): two cases presenting as acute inflammatory arthritis. Description and review of the literature.

We report the cases of two middle-aged male smokers who presented to the early synovitis clinic with an acute phase response, synovitis of the wrists and ankles and clubbing of the fingers, but no respiratory symptoms. Both proved to have primary lung tumours with hypertrophic pulmonary osteoarthropathy, in one case resolving promptly with treatment of the carcinoma. We review the literature, including theories on pathogenesis.

High-resolution ultrasonography of the first metatarsal phalangeal joint in gout: a controlled study.

OBJECTIVE: To compare high-resolution ultrasound (HRUS) with conventional radiography in the detection of erosions in the first metatarsophalangeal joints (1st MTPJs) of patients with gout and to identify the characteristic sonographic features of gout. METHODS: HRUS examination of the 1st MTPJs of both feet was performed by two independent sonographers. The presence of joint and soft-tissue pathology was recorded. x Ray examination of the feet was performed on the same day and reported by the same radiologist. RESULTS: 39 male patients with gout and 22 age-matched control subjects (14 with an inflammatory arthropathy and 8 disease free) were studied. The agreement on erosion between HRUS and x ray was poor, kappa = 0.229 (non-weighted), with McNemar's test being significant (p<0.001) indicating a large number of false negative x rays. 22 MTPJs in patients with gout had never been subjected to a clinical attack of acute gout. In these MTPJs, there were 10 erosions detected by HRUS and 3 erosions on x ray. HRUS features significantly more prevalent in the patients with gout were hard and soft tophus-like lesions (p<0.01) and the double contour sign (p<0.01). CONCLUSIONS: These data show that HRUS may assist in the management of gout in two ways: first, by aiding in the diagnosis by identifying the sonographic features that may be representative of the disease, and, second, by allowing the early detection of erosive joint damage and/or tophaceous deposits even in clinically silent joints.

Lack of support for the presence of an osteoarthritis susceptibility locus on chromosome 6p.

OBJECTIVE: To replicate, in a Northern Irish population, the previously reported association between a locus on chromosome 6 and hip osteoarthritis (OA). METHODS: Patients with hip OA were identified from a registry of patients who had undergone total hip replacement surgery over an 8-year period at a single large orthopedic unit in Northern Ireland. Patients identified as index cases were contacted by mail and asked to reply only if another family member also had undergone total hip replacement surgery. Using this approach, we identified 288 sibling pairs concordant for primary hip OA. DNA was extracted from peripheral blood, and microsatellite markers were amplified by polymerase chain reaction and subsequently genotyped. RESULTS: No evidence of linkage to this region was demonstrated by either 2-point analysis or multipoint analysis of 17 microsatellites. CONCLUSION: The reported association between a locus on chromosome 6 and hip OA could not be confirmed in this population. Different methods of ascertainment and phenotyping of OA may contribute to the current inability to replicate genetic associations for hip OA.