Rheumatoid Arthritis: Smith SJ

Giembycz MA, Smith SJ. · Department of Pharmacology and Therapeutics, Respiratory Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. · Curr Pharm Des. · Pubmed #17020529 No free full text.

Abstract: Over the last fifteen years there has been much excitement in the idea that targeting phosphodiesterase (PDE) 4 with small molecule inhibitors could lead to the discovery of novel, steroid-sparing compounds with utility in treating a multitude of diseases associated with chronic inflammation. However, dose-limiting side effects, of which nausea and vomiting are the most common are worrisome, have hampered their clinical development. Indeed, a fundamental obstacle that still is to be overcome by the pharmaceutical industry is to make compounds that dissociate beneficial from the adverse events. Unfortunately, both of these activities of PDE4 inhibitors represents an extension of their pharmacology and improving the therapeutic ratio has proved to be a major challenge. Several strategies have been considered, with some degree of success, but compounds with an optimal pharmacophore still have not been reported. An alternative approach to targeting PDE4 is to inhibit other cAMP PDE families that are also expressed in immune and pro-inflammatory cells in the hope that the beneficial activity can be retained at the expense of side effects. One such candidate is PDE7A. In this article we review the literature on PDE7A and explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, lupus, rheumatoid arthritis and multiple sclerosis.

Keefe FJ, Smith SJ, Buffington AL, Gibson J, Studts JL, Caldwell DS. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA. · J Consult Clin Psychol. · Pubmed #12090374 No free full text.

Abstract: This article provides an overview of the emerging literature on biopsychosocial assessment and treatment for two of the most common forms of arthritis: osteoarthritis and rheumatoid arthritis. The article is divided into 3 parts. In the 1st part, the basic elements of the biopsychosocial approach to assessing and treating persons having arthritis is described. In the 2nd part, the authors evaluate studies of biopsychosocial approaches to the assessment of arthritis pain and disability. Six research areas are reviewed: learned helplessness, depression, stress, pain coping, self-efficacy, and the social context of arthritis. The 3rd part of the article reviews studies that testing the efficacy of biopsychosocial treatment approaches for persons having osteoarthritis and rheumatoid arthritis.

Tetlow LC, Smith SJ, Mawer EB, Woolley DE. · University Department of Medicine, Manchester Royal Infirmary. · Ann Rheum Dis. · Pubmed #10343528 links to  free full text

Abstract: OBJECTIVES: The active form of vitamin D3, 1 alpha,25 dihydroxyvitamin D3 (1,25D3), through its interaction with vitamin D receptors (VDR), is reported to effect a variety of anabolic and catabolic events, especially in bone and cartilage tissues. As cartilage degradation and tissue remodelling are characteristic features of the rheumatoid lesion, the distribution and expression of VDR at sites of cartilage erosion was examined. METHODS: Immunolocalisation techniques using a rat monoclonal antibody to VDR and an alkaline phosphatase conjugated avidin/biotin detection system were used to examine VDR in 18 specimens of cartilage-pannus junction, 10 specimens of rheumatoid synovium or cartilage tissue, and four primary cultures of adherent rheumatoid synovial cells (RSC). For comparison, VDR expression was examined in 10 specimens of normal, healthy age matched articular cartilage. RESULTS: VDR was demonstrated in 15 of 18 cartilage-pannus junctions either at the interface (8 of 18), within the pannus tissue (12 of 18), and by chondrocytes often close to the erosive lesion (10 of 18). All the rheumatoid synovial tissue and 5 of 10 cartilage specimens showed cells with positive staining, but the extent of this was variable. Negligible VDR staining was observed for normal cartilage. Primary cultures of RSC also showed variability in both the numbers and proportions of macrophages or synovial fibroblasts stained for VDR (range 10-50%), this being more common in cultures with a high proportion of macrophages. CONCLUSIONS: VDR expression has been demonstrated by most specimens of cartilage-pannus junction; was associated with various cell types, including chondrocytes, but not exclusively with CD68+ macrophages. The focal nature of VDR expression within the rheumatoid lesion suggests a contributory role for 1 alpha,25D3 in the pathophysiological processes of rheumatoid arthritis.

Smith SJ, Hayes ME, Selby PL, Mawer EB. · University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL. · Ann Rheum Dis. · Pubmed #10340962 links to  free full text

Abstract: OBJECTIVE: This study was designed to investigate whether 1, 25-dihydroxyvitamin D3 (1,25-(OH)2D3), produced by activated synovial fluid macrophages, promotes its own catabolism by upregulating vitamin D-24-hydroxylase (24-OHase) in synovial fibroblasts through a vitamin D receptor (VDR) mediated mechanism. METHODS: Synovial macrophages and fibroblasts were derived from patients with rheumatoid arthritis. Expression of VDR and 24-OHase mRNAs was determined using in situ hybridisation. Vitamin D hydroxylase activity was determined by incubating cells with [3H]-25-(OH)D3, or [3H]-1,25-(OH)2D3, and metabolite synthesis quantified using high performance liquid chromatography. RESULTS: 1, 25-(OH)2D3 increased expression of mRNA for both VDR and 24-OHase in fibroblasts by approximately threefold over 24 hours. 1,25-(OH)2D3 increased fibroblast 24-OHase activity, yielding 24-hydroxylated, and more polar, metabolites. In co-culture, fibroblasts were able to catabolise macrophage derived 1,25-(OH)2D3. CONCLUSIONS: 1, 25-(OH)2D3 is produced by macrophages in vitro at biologically relevant concentrations and can increase its own catabolism by synovial fibroblasts; this effect is probably mediated via upregulation of both synovial fibroblast VDR and 24-OHase.