Rheumatoid Arthritis: Simon LS

Lipsky PE, Abramson SB, Breedveld FC, Brook P, Burmester R, Buttgereit F, Cannon GW, Catella-Lawson F, Crofford LJ, Doherty M, Dougados M, DuBois RN, Froelich J, Garcia Rodriguez LA, Gibofsky A, Hernandez-Diaz S, Hochberg MC, Krause A, Liang MH, Machold K, Peloso PM, Raisz LG, Schayes B, Scheiman JM, Simon LS, Smolen J. · No affiliation provided · J Rheumatol. · Pubmed #10852251 No free full text.

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Simon LS. · Harvard Medical School, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. · Bull NYU Hosp Jt Dis. · Pubmed #17922675 links to  free full text

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Strand V, Simon LS. · Division of Immunology and Rheumatology, Stanford University School of Medicine, 306 Ramona Road, Portola Valley, CA 94028, USA. · Clin Exp Rheumatol. · Pubmed #14969074 No free full text.

Abstract: The use of glucocorticoid therapy in the treatment of rheumatoid arthritis [RA] remains controversial. There has been much data accumulated over the years describing both the risks and benefits of acute and chronic glucocorticoid therapy. Initially there was significant enthusiasm for this type of therapy given the extent of the anti-inflammatory effects. However, use was then modified as chronic therapy with higher doses was associated with frequent reports of important safety concerns. More recently low dose glucocorticoid therapy (e.g. < or = 5 mg prednisone per day) is being reconsidered in particular for patients with early disease. This paper will review the historical experience with higher dose therapy along with the evolving evidence of an improved benefit to risk ratio with the advent of concomitant therapies to minimize some of the more problematic adverse events associated with chronic use of even low dose glucocorticoid therapy. It is suggested that with appropriate monitoring and careful concomitant prophylactic therapy to prevent osteoporosis, adjunctive therapy using low dose glucocorticoids along with the appropriate disease modifying anti-rheumatic drug may be a reasonable treatment plan for select patients.

Simon LS, Smolen JS, Abramson SB, Appel G, Bombardier C, Brater DC, Breedveld FC, Brune K, Burmester GR, Crofford LJ, Dougados M, DuBois RN, Fitzgerald GA, Frishman W, García Rodríguez LA, Hochberg MC, Kalden JR, Laine L, Langman MJ, Prescott SM, van de Putte LB, Whelton A, White WB, Willaims GH. · Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. · J Rheumatol. · Pubmed #12136912 No free full text.

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Simon LS, Yocum D. · Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. · Rheumatology (Oxford). · Pubmed #11001378 links to  free full text

Abstract: Several new drugs have recently been introduced for the treatment of rheumatoid arthritis (RA). These include the cyclooxygenase-2 inhibitor, celecoxib, the anti-tumour necrosis factor agents, etanercept and infliximab, and the new disease-modifying anti-rheumatic drug (DMARD), leflunomide. In clinical trials, celecoxib has been shown to be effective for palliation of the signs and symptoms of RA and to have fewer gastrointestinal side-effects than conventional non-steroidal anti-inflammatory drugs. Etanercept and infliximab are indicated for reduction of the signs and symptoms of RA in patients who have failed to respond adequately to previous DMARDs. The clinical success rate in etanercept-treated patients is significantly better than in placebo-treated patients for up to 18 months. Leflunomide is a DMARD with a novel mechanism of action that has been approved as a first-line treatment for RA. Treatment with leflunomide results in significantly greater improvement of the signs and symptoms of RA than placebo for up to 2 yr and slows radiographically assessed disease progression. Agents are currently in development that will be targeted against components of the immune activation and co-stimulatory pathways. These include antibodies directed against the interleukin-2 receptor and blockers of the CD28 and CD40 co-stimulatory pathways. Continuing research into the pathogenesis of RA will undoubtedly identify even more effective therapeutic approaches for the management of this disease in the future.

Simon LS. · Harvard Medical School, Boston, Massachusetts, USA. · Int J Clin Pract. · Pubmed #10912314 No free full text.

Abstract: The purpose of this paper is to review the benefits and limitations of current disease-modifying antirheumatic drugs (DMARDs) used for the treatment of rheumatoid arthritis (RA). Literature about DMARD use in RA, both as monotherapy and in combination therapy, is reviewed. The efficacy and safety of methotrexate, antimalarials, gold-containing compounds, sulphasalazine, D-penicillamine, azathioprine and cyclosporin, as well as several new antirheumatic agents are considered. Controlled short-term clinical studies demonstrate that DMARDs are superior to placebo. Early and continuous use of DMARDs is necessary to slow joint damage and improve long-term outcomes. Unfortunately, long-term treatment with these drugs is frequently limited by loss of response and/or onset of serious adverse events. The efficacy of combination DMARD therapy has also been tested, but with mixed success, and the goals of combination DMARD therapy have yet to be fully realised. New DMARDs that have recently been introduced offer promise for future RA management.

Simon LS. · Department of Medicine, Harvard Medical School of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. · Am J Med. · Pubmed #10390126 No free full text.

Abstract: Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase (COX) and subsequent downstream synthetases. Recently, it has been found that there are two closely related forms of COX, which are now known as COX-1 and COX-2. Although both isoforms of this enzyme convert arachidonate to prostaglandins, there are significant differences in their distribution in the body and their roles in health and disease. The basis for these important differences lies in the genes for COX-1 and COX-2 and the regulation of these genes. COX-1, the predominantly constitutive form of the enzyme, is expressed throughout the body and provides certain homeostatic functions, such as maintaining normal gastric mucosa, influencing renal blood flow, and aiding in blood clotting by abetting platelet aggregation. In contrast, COX-2, the inducible form, is expressed in response to inflammatory and other physiologic stimuli and growth factors and is involved in the production of those prostaglandins that mediate pain and support the inflammatory process. All conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit both COX-1 and COX-2 at standard anti-inflammatory doses. The beneficial anti-inflammatory and analgesic effects occur through the inhibition of COX-2, but the gastrointestinal toxicities and the mild bleeding diathesis occur as a result of concurrent inhibition of COX-1. It is important that physicians fully understand the pharmacologic basis for the differential actions of NSAIDs when prescribing them for pain and inflammation. This understanding is also important so that physicians can critically evaluate the basis for, and the emerging data on, COX-2-specific inhibitors and their potential role in clinical medicine. Agents that would inhibit COX-2 while sparing COX-1 represent an attractive therapeutic development and could represent a major advance in the treatment of rheumatoid arthritis and osteoarthritis, as well as a diverse array of other conditions.

Simon LS. · Harvard Medical School, USA. · Geriatrics. · Pubmed #10377916 No free full text.

Abstract: For physicians and patients alike, managing the symptoms of rheumatoid and osteoarthritis is an ongoing challenge. Myriad therapies are available, although virtually all provide only temporary relief and produce side effects that interrupt long-term use. New disease-modifying antirheumatic drugs, biologic response modifiers, and cyclooxygenase inhibitors offer the promise of more effective, longer lasting symptom management and, in some cases, reduced side effects. The population of older persons affected by arthritis continues to grow. Increased familiarity with these new treatments will aid primary care physicians in helping older patients better manage their arthritis during the next decade.

Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. · Pharmacia Clinical Research and Development, 4901 Searle Pkwy, Bldg A3E, Skokie, IL 60077, USA. · JAMA. · Pubmed #10979111 links to  free full text

Abstract: CONTEXT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE: To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. DESIGN: The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. SETTING: Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS: A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. INTERVENTIONS: Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (</=325 mg/d) was permitted. MAIN OUTCOME MEASURES: Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period. RESULTS: For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P =.09) and 2. 08% vs 3.54% (P =.02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P =.04) and 1.40% vs 2.91% (P =.02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P =.92) and 4.70% vs 6.00% (P =.49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use. CONCLUSIONS: In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. JAMA. 2000;284:1247-1255

Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, Isakson PC, Verburg KM, Yu SS, Zhao WW, Geis GS. · Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass 02215, USA. · JAMA. · Pubmed #10580457 links to  free full text

Abstract: CONTEXT: In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal (GI) tract effects that result from COX-1 inhibition. OBJECTIVE: To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis. DESIGN: Randomized, multicenter, placebo-controlled, double-blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh February 1998. SETTING: Seventy-nine clinical sites in the United States and Canada. PATIENTS: A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were randomized; 688 (60%) of these completed the study. INTERVENTIONS: Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or placebo (n = 231). MAIN OUTCOME MEASURES: Improvement in signs and symptoms of rheumatoid arthritis as assessed using standard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment, compared among treatment groups. RESULTS: All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo. Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks. The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of 99, and the incidences across all dosages of celecoxib were not significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice per day, respectively; and 31 % for naproxen. CONCLUSION: In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.

Cohen SB, Cohen MD, Cush JJ, Fleischmann RM, Mease PJ, Schiff MH, Simon LS, Weaver AL. · The University of Texas Southwestern Medical Center, Office of Continuing Education, 5323 Harry Hines Blvd., Dallas, TX 75390-9059. · J Rheumatol Suppl. · Pubmed #19193621 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic, multisystem, inflammatory disorder of the joints that affects about 1% of the world population. The ultimate goals of therapy include remission of disease and prevention of joint damage. Reaching these goals has become a realistic outcome for an increasing number of patients as treatment options have expanded over the past 3 decades. In addition to older therapies, such as methotrexate (MTX), other disease modifying drugs (DMARD), and tumor necrosis factor (TNF) inhibitors, newer biologic treatments have become available. For the substantial number of patients who experience an inadequate response to standard medications, biologic response modifiers (BRM) provide an important therapeutic alternative. The availability of multiple treatment options in the absence of clear definitions or criteria for remission and inadequate response, however, makes clinical decisions about measuring outcomes, predicting response to treatment, and prescribing pharmacologic therapies challenging. In this program, distinguished rheumatologists weigh the evolving body of clinical evidence to draw sound conclusions and resolve key issues in managing inadequate response to treatment and in achieving optimal outcomes in RA.

Crofford LJ, Breyer MD, Strand CV, Rushitzka F, Brune K, Farkouh ME, Simon LS. · Center for the Advancement of Women's Health, University of Kentucky, Lexington, Kentucky, USA. · J Rheumatol. · Pubmed #16724374 No free full text.

Abstract: The International COX-2 Study Group, a panel of independent physicians and scientists, convened January 28-30, 2005, in Washington, DC, to discuss the issues concerning the cardiovascular (CV) profile of coxibs. The purpose of the meeting was to review potential mechanisms by which inhibition of COX-2 by selective and nonselective NSAID could increase risk of CV events, to evaluate the similarities and differences between drugs based on mechanism and pharmacology, and to propose potential trial methodology to more definitively answer questions regarding cardiovascular risk.

Wells GA, Boers M, Shea B, Brooks PM, Simon LS, Strand CV, Aletaha D, Anderson JJ, Bombardier C, Dougados M, Emery P, Felson DT, Fransen J, Furst DE, Hazes JM, Johnson KR, Kirwan JR, Landewé RB, Lassere MN, Michaud K, Suarez-Almazor M, Silman AJ, Smolen JS, Van der Heijde DM, van Riel PL, Wolfe F, Tugwell PS. · Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada. · J Rheumatol. · Pubmed #16206362 No free full text.

Abstract: Agreement on response criteria in rheumatoid arthritis (RA) has allowed better standardization and interpretation of clinical trial reports. With recent advances in therapy, the proportion of patients achieving a satisfactory state of minimal disease activity (MDA) is becoming a more important measure with which to compare different treatment strategies. The threshold for MDA is between high disease activity and remission and, by definition, anyone in remission will also be in MDA. True remission is still rare in RA; in addition, the American College of Rheumatology definition is difficult to apply in the context of trials. Participants at OMERACT 6 in 2002 agreed on a conceptual definition of minimal disease activity (MDA): "that state of disease activity deemed a useful target of treatment by both the patient and the physician, given current treatment possibilities and limitations." To prepare for a preliminary operational definition of MDA for use in clinical trials, we asked rheumatologists to assess 60 patient profiles describing real RA patients seen in routine clinical practice. Based on their responses, several candidate definitions for MDA were designed and discussed at the OMERACT 7 in 2004. Feedback from participants and additional on-site analyses in a cross-sectional database allowed the formulation of 2 preliminary, equivalent definitions of MDA: one based on the Disease Activity Score 28 (DAS28) index, and one based on meeting cutpoints in 5 out the 7 WHO/ILAR core set measures. Researchers applying these definitions first need to choose whether to use the DAS28 or the core set definition, because although each selects a similar proportion in a population, these are not always the same patients. In both MDA definitions, an initial decision node places all patients in MDA who have a tender joint count of 0 and a swollen joint count of 0, and an erythrocyte sedimentation rate (ESR) no greater than 10 mm. If this condition is not met: * The DAS28 definition places patients in MDA when DAS28 < or = 2.85; * The core set definition places patients in MDA when they meet 5 of 7 criteria: (1) Pain (0-10) < or = 2; (2) Swollen joint count (0-28) < or = 1; (3) Tender joint count (0-28) < or = 1; (4) Health Assessment Questionnaire (HAQ, 0-3) < or = 0.5; (5) Physician global assessment of disease activity (0-10) < or = 1.5; (6) Patient global assessment of disease activity (0-10) < or = 2; (7) ESR < or = 20. This set of 2 definitions gained approval of 73% of the attendees. These (and other) definitions will now be subject to further validation in other databases.

Russak SM, Croft JD, Furst DE, Hohlbauch A, Liang MH, Moreland L, Ofman JJ, Paulus H, Simon LS, Weisman M, Tugwell P, Anonymous00333. · Zynx Health Incorporated, Beverly Hills, California, USA. · Arthritis Rheum. · Pubmed #12910566 links to  free full text

Abstract: OBJECTIVE: The utilization of health-related quality of life (HRQOL) patient questionnaires by clinical rheumatologists is limited. Yet, considerable literature exists defining the value of such data. In an effort to understand this apparent paradox, we performed a literature review and conducted a survey to describe what has been learned over the past 2 decades concerning the use of these measures in clinical care and explore the reasons for their underutilization. METHODS: A panel of rheumatologists with extensive clinical experience was convened to review the relevant literature pertaining to the use of HRQOL patient instruments in clinical practice. Additionally, a survey of all American College of Rheumatology practicing clinicians was conducted to assess the use of and beliefs about these measures. RESULTS: The literature provided evidence to support the use of HRQOL patient measures in clinical practice. Forty-seven percent of the responding rheumatologists stated that none of their patients complete HRQOL patient questionnaires. The majority of respondents (63%) reported that such information is "somewhat valuable." The most frequently reported reason for the underutilization was that such instruments "require too much staff time." CONCLUSIONS: The literature supports the potential value of HRQOL patient questionnaires in clinical practice. Few rheumatologists routinely gather such information as part of patient care. Reasons for this discrepancy between utility and use are given along with recommendations intended to help increase their utilization in clinical care.

Simon LS. · Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis St Suite 4B, Boston, MA 02215, USA. · Best Pract Res Clin Rheumatol. · Pubmed #15301984 No free full text.

Abstract: The treatment of rheumatoid arthritis has changed dramatically in the last 10 years and in parallel the definition and expectations of patients and clinicians of the effects of disease-modifying anti-rheumatic agents has changed as well. Current expectations of efficacy now include improvement of signs and symptoms of disease activity as well as slowing, if not complete inhibition, of disease progression as measured by X-ray progression along with significant improvement in patient physical function. In addition, clinicians assess the safety profile of these agents more critically in an attempt to improve the risk:benefit profile. Drugs, such as methotrexate, sulfasalazine and leflunomide have provided patients with substantial relief of symptoms and improvement in terms of X-ray progression, but they have been hampered by the occurrence of significant adverse events along with the inability to maintain benefit for prolonged periods of time. With the increased understanding of the basic biological mechanisms of the disease process, there has been the introduction of four biological disease modifying therapies and other drugs into clinical practice, which have altered aspects of the risk:benefit ratio for patients with various rheumatic diseases.