Rheumatoid Arthritis: Clark P

Clark P, Tugwell P, Bennet K, Bombardier C, Shea B, Wells G, Suarez-Almazor ME. · Health Services Research, Veterans Affairs Medical Center, Mailbox Station 152, 2002 Holcombe Blvd, Houston, Texas 77024, USA. · Cochrane Database Syst Rev. · Pubmed #10796386 No free full text.

Abstract: OBJECTIVES: To estimate the short-term benefit and risk of side-effects of injectable gold for rheumatoid arthritis. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group trials register, and Medline, up to July 1997, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). The search was complemented with bibliography searching of the reference list of the trials retrieved from the electronic search. Key experts in the area were contacted for further published and unpublished articles. SELECTION CRITERIA: Randomized clinical trials (RCT) comparing injectable gold against placebo in patients with rheumatoid arthritis were included. DATA COLLECTION AND ANALYSIS: Methodological quality of the RCTs was asessed by two reviewers (MS, BS) (kappa=1.0). Rheumatoid arthritis outcome measures were extracted by two reviewers from the publications for the 6 month endpoint. Sufficient data was obtained to conduct a pooled analysis of the number of swollen joints, physician global assessment, patient global assessment and erythrocyte sedimentation rate (ESR). Results were analyzed as standardized weighted mean differences for swollen joints and global assessments and weighted mean differences for ESR. Toxicity was evaluated with pooled odds ratios for withdrawals. Heterogeneity was estimated using a chi-square test. Fixed effects models were used throughout. MAIN RESULTS: Four trials and 415 patients were included. A statistically significant benefit was observed for injectable gold when compared to placebo. The standardized weighted difference (effect size) between gold and placebo for the number of swollen joints was -0.5, translating into a percentage change of 30% in favour of gold adjusted for placebo. Statistically significant differences were also observed for ESR and patient and physician assessments. Twenty two percent of the treated patients withdrew from toxicity compared to 4% of controls (OR=3.9 - 95%Cl: 2.1 - 7.2). REVIEWER'S CONCLUSIONS: Although its use can be limited by the incidence of serious toxicity, injectable gold has an important clinically and statistically significant benefit in the short term treatment of patients with rheumatoid arthritis.

Mathieu MC, Lord-Dufour S, Bernier V, Boie Y, Burch JD, Clark P, Denis D, Han Y, Mortimer JR, Therien AG. · Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Kirkland, Canada. · Eur J Immunol. · Pubmed #18506884 No free full text.

Abstract: Prostaglandin E(2) (PGE(2)) is a major mediator of inflammation and is present at high concentrations in the synovial fluid of rheumatoid arthritis (RA) patients. PGE(2), acting through the EP4 receptor, has both pro- and anti-inflammatory roles in vivo. To shed light on this dual role of PGE(2), we investigated its effects in whole blood and in primary human fibroblast-like synoviocytes (FLS). Gene expression analysis in human leukocytes, confirmed at the protein level, revealed an EP4-dependent inhibition of the expression of genes involved in the IFN-gamma-activation pathway, including IFN-gamma itself. This effect of the PGE(2)/EP4 axis on IFN-gamma is a reciprocal phenomenon since IFN-gamma blocks PGE(2) release and blocks EP receptor expression. The mutually antagonistic relationship between IFN-gamma and PGE(2) extends to downstream cytokine and chemokine release; PGE(2) counters the effects of IFN-gamma, on the release of IP-10, IL-8, TNF-alpha and IL-1beta. To gain further insight into IFN-gamma-mediated cellular events in RA, we assessed the effects of IFN-gamma on gene expression in FLS. We observed an IFN-gamma-dependent up-regulation of macrophage-attracting chemokines, and down-regulation of metalloprotease expression. These results suggest the existence of a mutually antagonistic relationship between PGE(2) and IFN-gamma, which may represent a fundamental mechanism of immune control in diseases such as RA.

Chen M, Boilard E, Nigrovic PA, Clark P, Xu D, Fitzgerald GA, Audoly LP, Lee DM. · Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #18438856 links to  free full text

Abstract: OBJECTIVE: Prostaglandins (PGs) are found in high levels in the synovial fluid of patients with rheumatoid arthritis, and nonsteroidal blockade of these bioactive lipids plays a role in patient care. The aim of this study was to explore the relative contribution of cyclooxygenase (COX) isoforms and PG species in the autoantibody-driven K/BxN serum-transfer arthritis. METHODS: The prostanoid content of arthritic ankles was assessed in ankle homogenates, and the importance of this pathway was confirmed with pharmacologic blockade. The presence of COX isoforms was assessed by Western blotting and their functional contribution was compared using COX-1-/- and COX-2-/- mice as well as isoform-specific inhibitors. The relative importance of PGE2 and PGI2 (prostacyclin) was determined using mice deficient in microsomal PGE synthase 1 (mPGES-1) and in the receptors for PGI2. RESULTS: High levels of PGE2 and 6-keto-PGF1alpha (a stable metabolite of PGI2) were detected in arthritic joint tissues, correlating strongly with the intensity of synovitis. Pharmacologic inhibition of PG synthesis prevented arthritis and ameliorated active disease. While both COX isoforms were found in inflamed joint tissues, only COX-1 contributed substantially to clinical disease; COX-1-/- mice were fully resistant to disease, whereas COX-2-/- mice remained susceptible. These findings were confirmed by isoform-specific pharmacologic inhibition. Mice lacking mPGES-1 (and therefore PGE2) developed arthritis normally, whereas mice incapable of responding to PGI2 exhibited a significantly attenuated arthritis course, confirming a role of PGI2 in this arthritis model. CONCLUSION: These findings challenge previous paradigms of distinct "housekeeping" versus inflammatory functions of the COX isoforms and highlight the potential pathogenic contribution of prostanoids synthesized via COX-1, in particular PGI2, to inflammatory arthritis.

Clark P, Rowland SE, Denis D, Mathieu MC, Stocco R, Poirier H, Burch J, Han Y, Audoly L, Therien AG, Xu D. · Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, QC H9H 3L1, Canada. · J Pharmacol Exp Ther. · Pubmed #18287210 links to  free full text

Abstract: Previous evidence has implicated E prostanoid receptor 4 (EP4) in mechanical hyperalgesia induced by subplantar inflammation. However, its role in chronic arthritis remains to be further defined because previous attempts have generated two conflicting lines of evidence, with one showing a marked reduction of arthritis induced by a collagen antibody in mice lacking EP4, but not EP1-EP3, and the other showing no impact of EP4 antagonism on arthritis induced by collagen. Here, we assessed the effect of a novel and selective EP4 antagonist MF498 [N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide] on inflammation in adjuvant-induced arthritis (AIA), a rat model for rheumatoid arthritis (RA), and joint pain in a guinea pig model of iodoacetate-induced osteoarthritis (OA). In the AIA model, MF498, but not the antagonist for EP1, MF266-1 [1-(5-{3-[2-(benzyloxy)-5-chlorophenyl]-2-thienyl}pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol] or EP3 MF266-3 [(2E)-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide], inhibited inflammation, with a similar efficacy as a selective cyclooxygenase 2 (COX-2) inhibitor MF-tricyclic. In addition, MF498 was as effective as an nonsteroidal anti-inflammatory drug, diclofenac, or a selective microsomal prostaglandin E synthase-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile], in relieving OA-like pain in guinea pigs. When tested in rat models of gastrointestinal toxicity, the EP4 antagonist was well tolerated, causing no mucosal leakage or erosions. Lastly, we evaluated the renal effect of MF498 in a furosemide-induced diuresis model and demonstrated that the compound displayed a similar renal effect as MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone], reducing furosemide-induced natriuresis by approximately 50%. These results not only suggest that EP4 is the major EP receptor in both RA and OA but also provide a proof of principle to the concept that antagonism of EP4 may be useful for treatment of arthritis.

Pulichino AM, Rowland S, Wu T, Clark P, Xu D, Mathieu MC, Riendeau D, Audoly LP. · Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada. · J Pharmacol Exp Ther. · Pubmed #16973887 links to  free full text

Abstract: The inhibition of prostaglandin (PG) synthesis is at the center of current anti-inflammatory therapies. Because cyclooxygenase-2 (COX-2) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of multiple PGs, there is currently a strong focus on characterizing the role of the different PGs in the inflammation process and development of arthritis. Evidence to date suggests that both PGE(2) and PGI(2) act as mediators of pain and inflammation. Most of the data indicating a role for PGI(2) in this context have been generated in animal models of acute pain. Herein, we describe the role of PGI(2) in models of osteoarthritis (OA) and rheumatoid arthritis using a highly selective PGI(2) receptor (IP, Ptgir) antagonist and IP receptor-deficient mice. In the rat OA model using monoiodoacetate injection into the knee joint, the IP antagonist reduced pain with an efficacy approaching that of the NSAID diclofenac. In a chronic model of inflammatory arthritis, collagen-antibody induced arthritis model in mice, IP receptor-deficient mice displayed a 91% reduction in arthritis score. Interestingly, pretreatment with the IP [N-[4-(imidazolidin-2-ylideneamino)-benzyl]-4-methoxy-benzamide] antagonist in this model also caused a significant reduction of the symptoms, whereas administration of the compound after the initiation of arthritis had no detectable effect. Our data indicate that, in addition to its role in acute inflammation, PGI(2) is involved in the development of chronic inflammation. The results also suggest that the inhibition of PGI(2) synthesis by NSAIDs and COX-2 inhibitors, in addition to that of PGE(2), contributes to their efficacy in treating the signs of arthritis.

Clark P, Lavielle P, Martínez H. · Clinical Epidemiology Unit, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Hospital General de México, OD, Mexico City, Mexico. · J Rheumatol. · Pubmed #12858463 No free full text.

Abstract: OBJECTIVE: Rheumatologists often deal with patients' pain, as commonly measured by clinical scales. However, no published study in the last 25 years has explored patient preferences for the 2 most frequently used clinical scales the verbal rating scale (VRS) and the visual analog scale (VAS). We (1) evaluated patient preferences for the 10 cm horizontal VAS versus the 5 point VRS and identified associated reasons for their preferences; and (2) validated the test-retest reliability and construct validity of these scales. METHODS: Patients with painful rheumatological conditions rated the VAS and the VRS to assess pain intensity and stated which scale they preferred and why. Exploration of tender points and dolorimetry was performed in all cases. RESULTS: Of 113 patients in the sample, 93% were women, 85% of whom had rheumatoid arthritis. In this sample, 52.8% preferred the VRS, 28.3% the VAS, and 18.9% expressed no preference. Patients who preferred the VRS said it was easier than the VAS to understand and rate. They also reported being more comfortable using words than numbers. Patients who preferred the VAS said that numbers classified pain better and that this allowed them to be objective and precise. Patients with 0-6 years of schooling preferred the VRS, while those with > 6 years preferred the VAS. There was a significant association between the number of tender points and pain intensity with both scales, as well as between threshold and tolerance with the VAS. High correlations were found between the VAS and the VRS (r = 0.79) and between tolerance and threshold (r = 0.96). Test-retest showed a high correlation for both scales: VAS = 0.97 and VRS = 0.89. CONCLUSION: Both scales are valid measures of pain intensity. The choice should depend on the setting, the clinician's goal, and the patient's level of education. Patient preference is central to better physician-patient communication.