Rheumatoid Arthritis: Brown C

Quinn MA, Conaghan PG, O'Connor PJ, Karim Z, Greenstein A, Brown A, Brown C, Fraser A, Jarret S, Emery P. · Academic Unit of Musculoskeletal Disease, First Floor, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. · Arthritis Rheum. · Pubmed #15641102 links to  free full text

Abstract: OBJECTIVE: Anti-tumor necrosis factor alpha agents are among the most effective therapies for rheumatoid arthritis (RA). However, their optimal use is yet to be determined. This 12-month double-blind study attempted remission induction using standard therapy with or without infliximab in patients with early, poor-prognosis RA. The primary end point was synovitis (measured by magnetic resonance imaging [MRI]). Clinical observations continued to 24 months. METHODS: All patients had fewer than 12 months of symptoms. Assessments included full metrologic evaluation, laboratory tests, radiographs, functional evaluation using the Health Assessment Questionnaire (HAQ), and quality of life measurement using the RA Quality of Life (RAQoL) questionnaire. MRI was performed at 0, 4, 14, and 54 weeks; MR images were scored blindly. Patients received methotrexate (MTX) and were randomized to receive either infliximab or placebo for 12 months. RESULTS: Twenty patients were recruited (mean age 52 years, mean symptom duration 6 months, mean C-reactive protein level 42 mg/liter, and 65% rheumatoid factor positive). At 1 year, all MRI scores were significantly better, with no new erosions in the infliximab plus MTX group; a greater percentage of infliximab plus MTX-treated patients fulfilled the American College of Rheumatology (ACR) 50% and 70% improvement criteria (78% versus 40% in the placebo plus MTX group and 67% versus 30%, respectively) and had a greater functional benefit (P < 0.05 for all comparisons). Importantly, at 1 year after stopping induction therapy, response was sustained in 70% of the patients in the infliximab plus MTX group, with a median Disease Activity Score in 28 joints (DAS28) of 2.05 (remission range). At 2 years, there were no significant between-group differences in the DAS28, ACR response, or radiographic scores, but differences in the HAQ and RAQoL scores were maintained (P < 0.05). CONCLUSION: Remission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year. At 2 years, functional and quality of life benefits were sustained, despite withdrawal of infliximab therapy. These data may have significant implications for the optimal use of expensive biologic therapies.

Wakefield RJ, O'Connor PJ, Conaghan PG, McGonagle D, Hensor EM, Gibbon WW, Brown C, Emery P. · Chapel Allerton Hospital, Leeds, UK. · Arthritis Rheum. · Pubmed #17907233 links to  free full text

Abstract: OBJECTIVE: To investigate the frequency and distribution of finger tenosynovitis in patients with early, untreated rheumatoid arthritis (RA) using gray-scale ultrasound (US) and magnetic resonance imaging (MRI). METHODS: Fifty patients underwent US and MRI of metacarpophalangeal (MCP) joints 2-5. Twenty healthy controls underwent US only. Flexor and extensor involvement was documented for each joint. Intrareader reliability (IRR) was calculated by rereading static images. RESULTS: Flexor tenosynovitis was found in 57 (28.5%) of 200 joints in 24 (48%) of 50 patients on US compared with 128 (64%) of 200 joints in 41 (82%) of 50 patients on MRI. Periextensor tenosynovitis was found in 14 (7%) joints in 9 (18%) patients on US compared with 80 (40%) joints in 36 (72%) patients on MRI. No controls had imaging tenosynovitis. Using MRI as the gold standard, the sensitivity, specificity, and negative and positive predictive values for US were 0.44, 0.99, 0.49, and 0.98, respectively, for flexor tenosynovitis and 0.15, 0.98, 0.63, and 0.86 for extensor tenosynovitis, respectively. The IRR was 0.85 and 0.8 for US and MRI, respectively. The most frequently involved joints on US and MRI were the second and third MCP joints. CONCLUSION: This is the first study to compare US and MRI for the detection of tenosynovitis in the fingers of patients with early untreated RA. Tenosynovitis was found to be common using both modalities, with MRI being more sensitive. A negative US scan does not exclude inflammation and an MRI should be considered. Further work is recommended to standardize definitions and image acquisition for both US and MRI images.

Brown C, Gaspar J, Pettit A, Lee R, Gu X, Wang H, Manning C, Voland C, Goldring SR, Goldring MB, Libermann TA, Gravallese EM, Oettgen P. · Beth Israel Deaconess Medical Center, Department of Medicine, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA. · J Biol Chem. · Pubmed #14715662 links to  free full text

Abstract: Angiogenesis is a critical component of the inflammatory response associated with a number of conditions. Angiopoietin-1 (Ang-1) is an angiogenic growth factor that promotes the chemotaxis of endothelial cells and facilitates the maturation of new blood vessels. Ang-1 expression is up-regulated in response to tumor necrosis factor-alpha (TNF-alpha). To begin to elucidate the underlying molecular mechanisms by which Ang-1 gene expression is regulated during inflammation, we isolated 3.2 kb of the Ang-1 promoter that contain regulatory elements sufficient to mediate induction of the promoter in response to TNF-alpha, interleukin-1beta, and endotoxin. Surprisingly, sequence analysis of this promoter failed to reveal binding sites for transcription factors that are frequently associated with mediating inflammatory responses, such as NF-kappaB, STAT, NFAT, or C/EBP. However, putative binding sites for ETS and AP-1 transcription factor family members were identified. Interestingly, among a panel of ETS factors tested in a transient transfection assay, only the ETS factor ESE-1 was capable of transactivating the Ang-1 promoter. ESE-1 binds to specific ETS sites within the Ang-1 promoter that are functionally important for transactivation by ESE-1. ESE-1 and Ang-1 are induced in synovial fibroblasts in response to inflammatory cytokines, with ESE-1 induction slightly preceding that of Ang-1. Mutation of a high-affinity ESE-1 binding site leads to a marked reduction in Ang-1 transactivation by ESE-1, inducibility by inflammatory cytokines, and DNA binding to the ESE-1 protein. Transcriptional profiling of cells transiently transfected with an ESE-1 expression vector demonstrates that the endogenous Ang-1 gene is directly inducible by ESE-1. Finally, Ang-1 and ESE-1 exhibit a similar and strong expression pattern in the synovium of patients with rheumatoid arthritis. Our results support a novel paradigm for the ETS factor ESE-1 as a transcriptional mediator of angiogenesis in the setting of inflammation.