Rheumatoid Arthritis: Williams R

Feldmann M, Brennan FM, Paleolog E, Cope A, Taylor P, Williams R, Woody J, Maini RN. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, London W6 8LH, UK. · Novartis Found Symp. · Pubmed #15027483 No free full text.

Abstract: The importance of tumour necrosis factor (TNF)alpha in rheumatoid arthritis (RA) was initially proposed on the basis of analysis of cytokine gene regulation at the local site of the disease, the synovium. This was then verified in animal models and established in an extensive series of clinical trials, culminating in now 250000 treated patients with either of two approved TNF inhibitors, antibody or fusion protein. The degree and magnitude of clinical benefit has enabled analyses of the mechanism by which anti-TNF benefits, and hence insights into important steps in the disease process. It was found that essentially all aspects of RA were ameliorated, and important mechanisms of benefit involved diminution of multiple pro-inflammatory cytokines, adhesion molecules and chemokines, leading to reduced cell trafficking, reduced angiogenesis and most importantly halting of joint destruction. What of the problems? Safety is better than prior drugs, but there is a small increase in severe infections, smaller than might have been anticipated. Cost is the major drawback limiting greater use. In view of the central pathological processes down-regulated, and their role in many diseases, the early clinical success of anti-TNF in RA led to subsequent successful trials and registration in Crohn's disease and juvenile rheumatoid arthritis, and successful trials in ankylosing spondylitis, psoriasis and psoriatic arthritis. The era of anti-cytokine therapeutics is just dawning.

Feldmann M, Miotla J, Paleolog E, Williams R, Malfait AM, Taylor P, Brennan FM, Maini RN. · Kennedy Institute of Rheumatology, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK. · Ann Rheum Dis. · Pubmed #11053102 links to  free full text

Abstract: The era of anti-cytokine treatment in rheumatology has just begun. The first generation therapeutic agents, biological agents that block tumour necrosis factor alpha such as monoclonal antibodies or receptor Ig fusion proteins are safe and effective, and so this has generated much interest in how to increase the benefit or deliver it more cost effectively. This article provides a personal view of the coming trends in anti-cytokine treatment. Which of these will be realised in the future will be of interest.

Kiely P, Williams R, Walsh D, Young A, Anonymous00023. · Department of Rheumatology, St George's Healthcare NHS Trust, London, UK. · Rheumatology (Oxford). · Pubmed #18984608 No free full text.

Abstract: OBJECTIVES: To report from the Early Rheumatoid Arthritis Network (ERAN), time from symptom onset to start of therapy, treatment choices and disease outcome in early RA. METHODS: Patients with newly diagnosed RA were prospectively enrolled from 19 centres in the UK and Eire. Standardized information was collected on case report forms at first presentation, 3-6 months, 1 yr and annually thereafter. The choice and intensity of drug treatment was left to the discretion of individual centres. RESULTS: A total of 808 patients were recruited between 2002 and 2007, with a mean follow-up of 16 (0-60) months. Of them, 62% fulfilled four or more ACR criteria for RA at first visit. The median time from onset of symptoms to referral to secondary care was 4 months [interquartile range (IQR) 2-9, n = 655] and to start of first DMARD 8 months (IQR 4-13, n = 638). DMARDs were prescribed in 97% of the patients, initially as monotherapy in 91%, and as combination therapy in 9%. The second DMARD (n = 220) was a switch to another as monotherapy in 52% and step-up to combination therapy in 48%. The proportions with a 28-joint disease activity score >5.1 at baseline and 3 yrs were 46 and 19%, >3.2 were 84 and 54% and <2.6 were 6 and 33%, respectively. CONCLUSIONS: Patients presenting with RA in ERAN do not receive DMARDs promptly, largely due to delays in referral to secondary care. Contemporary treatment practice is to start with DMARD monotherapy, and to use combination DMARDs as second-line therapy in approximately half of them. Over 3 yrs the proportion of patients continuing to have active disease remains high.

Inglis JJ, Notley CA, Essex D, Wilson AW, Feldmann M, Anand P, Williams R. · Kennedy Institute of Rheumatology, Imperial College London, London, UK. · Arthritis Rheum. · Pubmed #18050216 links to  free full text

Abstract: OBJECTIVE: There is a disparity in the animal models used to study pain in rheumatoid arthritis (RA), which tends to be acute in nature, and models used to assess the pathogenesis of RA. The latter models, like human RA, are lymphocyte-driven and polyarthritic. We assessed pain behavior and mechanisms in collagen-induced arthritis (CIA), the model of preclinical arthritis used most commonly in the field of immunology. We then validated the model using anti-tumor necrosis factor (anti-TNF) therapy, which has analgesic effects in models of inflammation as well as in human RA. METHODS: CIA was induced in DBA/1 mice by immunization with type II collagen at the base of the tail. Swelling and mechanical and thermal hyperalgesia were assessed before and for 28 days after the onset of arthritis. Spontaneous behavior was assessed using an automated activity monitor. Glial activity was assessed by glial fibrillary acidic protein expression, and nerve damage was evaluated by activating transcription factor 3 expression. The actions of anti-TNF therapy on nociception were then evaluated. RESULTS: Arthritis resulted in a decrease in the threshold for thermal and mechanical stimuli, beginning on the day of onset. Decreased spontaneous activity was also observed. A significant increase in the number of hyperplasic spinal cord astrocytes was observed beginning 10 days after the onset of arthritis. Anti-TNF therapy was profoundly analgesic, with an efficacy similar to that of cyclooxygenase 2 inhibition, and reduced astrocyte activity in CIA. CONCLUSION: This study shows that the CIA model is suitable for testing not only antiinflammatory but also analgesic drugs for potential use in RA, and highlights the importance of using appropriate disease models to assess relevant pain pathways.

Wolfe F, Michaud K, Choi HK, Williams R. · Arthritis Research Center Foundation, University of Kansas School of Medicine, Wichita, KS 67214, USA. · J Rheumatol. · Pubmed #16206340 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) causes disability and reduced productivity. There are no large quantitative studies of earnings and productivity losses in patients with clinical RA, and no studies of household income losses. We describe methods for obtaining earnings and household income losses that are applicable to working as well as nonworking RA patients, and we perform such studies using these methods. METHODS: We estimated cross-sectional expected annual earnings and household income losses in 6,649 persons with RA from Current Populations Survey (CPS) and O*NET (Occupational Information Network) data, and we estimated expected household income and earnings losses based on demographic characteristics after adjustment to Medical Outcomes Study Short-Form 36 (SF-36) population norms (internal method). Workplace productivity was measured by the Work Limitations Questionnaire (WLQ). RESULTS: 27.9% of patients aged < or = 65 years considered themselves disabled after 14.6 years of RA, and 8.8% received disability benefits. Annual earnings losses ranged between USD 2,319 and USD 3,407 by the CPS and internal method (preferred), with losses of 9.3% and 10.9%. A 0.25 difference in Health Assessment Questionnaire (HAQ) score was associated with a $1,095 difference in annual earnings. Productivity losses were 6% based on work limitations identified by the WLQ. Household income loss (percentage loss) including transfer payments was USD 6,287 (11.8%) for all patients, USD 4,247 (6.9%) for employed patients, and USD 7,374 (14.8%) for nonworking patients. Among nonworking nondisabled patients aged < or = 65 years, income loss was 14.1%. CONCLUSION: As measured by annual household income loss, the overall impact of RA is USD 6,287 (11.8%). Earnings and household income are dependent on functional status, education, age, ethnicity, and marital status. Income loss is predicted by the HAQ, HAQ-II, Modified HAQ, and SF-36.

Foey AD, Field S, Ahmed S, Jain A, Feldmann M, Brennan FM, Williams R. · Kennedy Institute of Rheumatology Division, Charing Cross Hospital Campus, Imperial College School of Medicine, London, UK. · Arthritis Res Ther. · Pubmed #14680506 links to  free full text

Abstract: Vasoactive intestinal peptide (VIP) is an anti-inflammatory immunomodulatory neuropeptide with therapeutic potential demonstrated for collagen-induced arthritis. The aim of this study was to characterise its potential anti-arthritic effect on human monocytes, macrophages, T cells, and rheumatoid arthritis synovial membrane cells. Monocytes, macrophages, and T cells derived from human peripheral blood were treated with VIP and compared with other cAMP-elevating drugs for a range of activating stimuli. Cytokine production was assessed for cell cultures and, in addition, the ability of VIPs to activate cAMP response element binding protein. VIP partially suppressed monocyte- and macrophage-derived tumour necrosis factor alpha (TNF-alpha) with no effect on IL-10, whereas VIP fails to regulate IL-10 and TNF-alpha production by T lymphocytes. No such modulation of cytokine profile was observed for rheumatoid arthritis synovial membrane cells. Elevation of intracellular cAMP, on the other hand, potently suppressed macrophage TNF-alpha production and modulated T-cell response by inhibiting TNF-alpha and IFN-gamma. VIP's lack of effect on IL-10 and its slight effect on TNF-alpha results from cAMP being rapidly degraded as the phosphodiesterase IV inhibitor, rolipram, rescues cAMP-dependent activation of cAMP response element binding protein. Interestingly, macrophages stimulated with phorbol 12-myristate 13-acetate/ionomycin displayed an augmented IL-10 response upon addition of dibutyryl cAMP, with corresponding downregulation in TNF-alpha, suggesting a complex interaction between protein kinase C and protein kinase A in cytokine regulation. In conclusion, VIP may represent an efficaceous anti-arthritic treatment modulating macrophage and T-cell cytokine profiles when used alongside a phosphodiesterase inhibitor.