Rheumatoid Arthritis: Furst DE

Furst DE, Halbert RJ, Bingham CO, Fukudome S, Anderson L, Bonafede P, Bray V, Cohen SB, Sherrer YR, St Clair EW, Tesser JR, Weinblatt M, Dubois RW. · Geffen School of Medicine, University of California at Los Angeles, 1000 Veteran Ave Rm 32-59, Los Angeles, CA 90095-1670, USA. · Rheumatology (Oxford). · Pubmed #18178593 No free full text.

Abstract: OBJECTIVES: There is a lack of agreement on assessing disease activity in patients with RA and determining when the RA treatment should be changed or continued. A panel of rheumatologists was convened to develop guidelines to assess adequacy of disease control, focusing on the use of disease-modifying anti-rheumatic drugs. METHODS: The Research and Development/University of California in Los Angeles (RAND/UCLA) Appropriateness Method was used to evaluate disease control adequacy. After a literature review, 108 scenarios were developed to simulate situations most likely to be encountered in clinical practice and rated on a 9-point scale by a 10-member expert panel. RESULTS: Final appropriateness rankings for the scenarios were as follows: 37% 'appropriate', 48% 'inappropriate', and 16% 'neutral'. The panelists felt that patients with disease control in the 'appropriate' range have adequate control with their current therapy, whereas those in the 'inappropriate' range should be considered for a change in therapy. Those in 'neutral' areas should have their therapy reviewed carefully. The panelists recommended that the clinically active joint count should be considered the most important decision factor. In patients with no clinically active joints, regardless of other factors no change in therapy was felt to be warranted. Patients with five or more active joints should be considered inadequately treated, and in patients with one to four active joints other variables must be considered in the decision to change therapy. CONCLUSION: These preliminary guidelines will assist the clinician in determining when a patient's clinical situation warrants therapy escalation and when continuing the current regimen would be appropriate.

Furst DE, Cush J, Kaufmann S, Siegel J, Kurth R. · UCLA Medical School, Los Angeles, USA Presbyterian Hospital, Dallas, USA. · Ann Rheum Dis. · Pubmed #12379625 links to  free full text

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Furst DE. · No affiliation provided · Arthritis Rheum. · Pubmed #15934125 links to  free full text

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Beenhouwer D, Wallis R, Broder M, Furst DE. · No affiliation provided · J Rheumatol. · Pubmed #15487038 links to  free full text

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Furst DE. · No affiliation provided · J Rheumatol. · Pubmed #15338482 links to  free full text

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Furst DE. · No affiliation provided · J Rheumatol. · Pubmed #15290723 links to  free full text

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McSweeney PA, Furst DE, West SG. · No affiliation provided · Arthritis Rheum. · Pubmed #10555019 links to  free full text

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Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Sieper J, Emery P, Keystone EC, Schiff MH, Mease P, van Riel PL, Fleischmann R, Weisman MH, Weinblatt ME. · David Geffen School of Medicine, UCLA - RM 32-59, 1000 Veteran Avenue, Los Angeles, CA 90025, USA. · Ann Rheum Dis. · Pubmed #17934088 No free full text.

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Ranganath VK, Furst DE. · Division of Rheumatology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, 1000 Veteran Avenue, Room 32-59, Los Angeles, CA 90025-1670, USA. · Rheum Dis Clin North Am. · Pubmed #17367700 No free full text.

Abstract: During the 10-year period since the last review was done by Gardner and Furst, studies have furthered the knowledge of the use of disease-modifying antirheumatic drugs (DMARDs) in the elderly rheumatoid arthritis (RA) patient. This article briefly reviews the clinical pharmacology of humans as they age, and details the effects of aging on the specific pharmacokinetics and responses to commonly used DMARDs. There has been some progress in understanding the elderly RA patient; however, data are insufficient to provide much confidence in DMARDs effects in the elderly.

Desai SB, Furst DE. · Department of Rheumatology, University of California, Los Angeles, CA 90095-1670, USA. · Best Pract Res Clin Rheumatol. · Pubmed #16979537 No free full text.

Abstract: Worldwide, over 400,000 patients have been treated with tumour necrosis factor (TNF)-alpha antagonists for indications that include rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis and ankylosing spondylitis. Since their approval, concerns regarding safety have been raised. There is a risk of re-activation of granulomatous diseases, especially tuberculosis, and measures should be taken for detection and treatment of latent tuberculosis infections. Preliminary data suggest that anti-TNF therapy may be safe in chronic hepatitis C. However, TNF-alpha antagonists have resulted in re-activation of chronic hepatitis B if not given concurrently with antiviral therapy. Solid tumours do not appear to be increased with anti-TNF therapy. Variable rates of increased lymphoma risk have been described with anti-TNF therapy compared with the general population, although no increased risk was found compared with a rheumatoid arthritis population. Large phase II and III trials with TNF-alpha antagonists in advanced heart failure have shown trends towards a worse prognosis, and should therefore be avoided in this population. Both etanercept and infliximab are associated with the formation of autoantibodies, and these autoantibodies are rarely associated with any specific clinical syndrome. Rare cases of aplastic anaemia, pancytopenia, vasculitis and demyelination have been described with anti-TNF therapy. This chapter will discuss the safety profile and adverse events of the three commercially available TNF-alpha antagonists: etanercept, infliximab and adalimumab. The data presented in this review have been collected from published data, individual case reports or series, package inserts, the Food and Drug Administration postmarketing adverse events surveillance system, and abstracts from the American College of Rheumatology and European Congress of Rheumatology meetings for 2005.

Furst DE, Wallis R, Broder M, Beenhouwer DO. · Department of Rheumatology, University of California at Los Angeles, Los Angeles, CA, USA. · Semin Arthritis Rheum. · Pubmed #16884970 No free full text.

Abstract: OBJECTIVE: Tumor necrosis factor (TNF) antagonists fall into 2 classes:etanercept (ETA) is a soluble TNF receptor, while infliximab (INF) and adalimumab (ADA) are monoclonal antibodies against TNF. All 3 drugs are effective in treating rheumatoid arthritis. However, these agents have been associated with an increased risk of granulomatous infections, such as tuberculosis and histoplasmosis. Several reports indicate that the incidence of granulomatous infections may potentially be higher in individuals treated with INF than ETA. METHODS: We conducted a comprehensive literature search (1966 to 2004) to review the role of TNF in normal and disease states, and the mechanisms of action of the TNF inhibitors. Specifically, we searched for possible mechanisms for the apparent increase in granulomatous infections associated with TNF inhibitors and for reasons that there may be differences between them. RESULTS: Infection may result from a number of differences between ETA and INF or ADA. First, binding avidities are different, with ETA binding in a 1:1 ratio and INF/ADA binding in 2 to 3:1 ratios. Second, the clearances of ADA, ETA, and INF are different, being about 13 times higher for ETA than INF or ADA, thus resulting in higher steady-state drug levels for ADA and INF. Also, the methods of administration are different, intravenously (for INF) versus subcutaneously (for ETA and ADA), which results in lower peak concentrations for ETA and ADA, potentially explaining some of the differences in effects on granuloma formation. Third, INF and ADA have somewhat different mechanisms of action from ETA: INF and ADA are associated with antibody-mediated cell lysis, while ETA is not; INF may induce apoptosis in some tissues (eg, gastrointestinal [GI] mucosa) while ETA does not--although this is controversial and may not be true at steady state in synovium, where both drugs seem to cause apoptosis; ETA binds lymphotoxin-alpha while INF does not (ETA may thus be more efficient at preventing granuloma formation by this mechanism than INF); finally, ADA and INF seem to inhibit IFN-gamma expression (probably indirectly), while ETA does not. CONCLUSIONS: There are significant differences between the 2 classes of TNF antagonists in terms of both their kinetics and mechanisms of action. These differences may help explain the apparent differences in the incidence of granuloma-dependent infections among them.

Ahmed M, Khanna D, Furst DE. · David Geffen School of Medicine, Los Angeles, CA, USA. · Expert Opin Drug Metab Toxicol. · Pubmed #16863437 No free full text.

Abstract: Rheumatoid arthritis (RA), a chronic inflammatory multisystem disorder marked by joint pain, stiffness, swelling and multiple systemic involvements, requires a multifaceted approach for its management. It includes symptomatic treatment with analgesics as well as disease-modifying medications to alter the course of RA over time. NSAIDS have been widely used for their symptomatic effects, but their use is not free from adverse effects, which may include life-threatening adverse events such as gastrointestinal (GI) bleeding and perforation. Meloxicam, an oxicam derivative that is a member of the enolic acid group of NSAIDs, has recently been approved by the US FDA for use in RA and osteoarthritis. At the FDA-recommended doses meloxicam is COX-2 preferential. By virtue of this COX-2 preferential activity it is expected to have lower GI toxicity as compared with COX-2 nonselective NSAIDs. Clinical trials have shown that meloxicam at 7.5 - 15 mg/day is as effective as diclofenac, piroxicam and naproxen as an anti-inflammatory and analgesic, and was associated with fewer GI adverse effects.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, Dougados M, Emery P, Keystone EC, Klareskog L, Mease PJ. · 1000 Veteran Avenue Rehabilitation Centre, Room 32-59, Los Angeles, CA 90024, USA. · Ann Rheum Dis. · Pubmed #16239380 links to  free full text

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de Buys P, Khanna D, Furst DE. · Division of Immunology, Department of Medicine, University of Cincinnati, Cincinnati, OH, United States. · Autoimmun Rev. · Pubmed #16137610 No free full text.

Abstract: Hematopoietic stem cell transplant (HSCT) for autoimmune diseases has been recognized as a potential treatment for patients who have failed conventional therapy. Autologous (self) donor cells have been preferred over allogeneic (HLA-matched) cells for rescue after high dose immunotherapy, given the previous higher rates of mortality, graft versus host disease (GVHD), and the need for more intense myeloablation associated with the latter. The European Group for bone Marrow Transplantation in Basel Switzerland (EBMT) and various groups within the US funded by the NIH (including the Autologous Blood and Marrow Transplant Registry (ABMTR)) have been pivotal in maintaining registries on patients transplanted as well as promoting homogeneity for future studies including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (SSc). Although, patients transplanted for RA show initial success, relapse of the disease is common. In many, however, a second positive result can be obtained with the addition of DMARD therapy to which they were previously unresponsive, suggesting a "debulking" of disease by HSCT. SLE patients also have a high rate of success after HSCT, although current mortality rates appear high. Transplant in SSc patients has offered durable responses with improving transplant-related mortality related to careful patient selection.

Ranganath VK, Furst DE. · Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90025-1670, USA. · Clin Geriatr Med. · Pubmed #15911212 No free full text.

Abstract: During the 10-year period since the last review was done by Gardner and Furst, studies have furthered our knowledge of use of disease-modifying antirheumatic drugs (DMARDs) in the elderly rheumatoid arthritis (RA) patient. This article will briefly review the clinical pharmacology of human as they age, and detail the effects of aging on the specific pharmacokinetics and responses to commonly used DMARDs. There has been some progress in understanding the elderly RA patient, however, there is insufficient data for much confidence in DMARDs effects in the elderly.

Furst DE. · Rheumatology Division, Geffen School of Medicine, University of California-Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90025-1670, USA. · Clin Ther. · Pubmed #15823761 No free full text.

Abstract: BACKGROUND: Interleukin-1 (IL-1) plays an important role in the pathophysiology and progression of rheumatoid arthritis (RA) by contributing to destruction of cartilage, bone, and periarticular tissues. Inhibiting IL-1 synthesis or activity with the use of recombinant human IL-1 receptor antagonist (anakinra) may prove to be an effective approach to the treatment of RA. OBJECTIVE: The purpose of this article is to review the effects of anakinra in the treatment of RA. METHODS: A MEDLINE search from 1982 to 2003 was used to identify animal studies and randomized clinical trials of anakinra and other therapies that target IL-1. RESULTS: Clinical trials of anakinra have shown that it reduces the signs and symptoms of active disease and slows the rate of radiographic destruction in adults with RA. With anakinra 150 mg/d, 43% of patients achieved an American College of Rheumatology (ACR) 20% response, compared with 27% with placebo (P = 0.014). The ACR20 score indicates at least 20% improvement in the ACR composite score, which includes assessment of tender and swollen joint count, and other clinical end points such as pain and disability assessment. Patients treated with anakinra also experienced a 59% reduction in new bony erosion compared with controls (P < 0.001) and a 65% reduction in joint space narrowing as measured by the modified Sharp score (P = 0.020). Injection-site reactions were the most commonly reported adverse event, occurring in 50%, 73%, and 81% of patients receiving anakinra 30, 75, and 150 mg/d, respectively, compared with 25% of patients receiving placebo. Few serious adverse events were reported, and they typically occurred in patients receiving the highest daily dosage. CONCLUSIONS: IL-1 is an important cytokine in promoting the damage associated with RA. Anakinra is mildly to moderately effective and well tolerated in patients with active RA when used as monotherapy or in combination with methotrexate.

Khanna D, McMahon M, Furst DE. · University of California, Los Angeles 90095, USA. · Arthritis Rheum. · Pubmed #15077286 links to  free full text

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Khanna D, McMahon M, Furst DE. · Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. · Drug Saf. · Pubmed #15061685 No free full text.

Abstract: Tumour necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine that is synthesised by a variety of cell types in response to infectious or inflammatory stimuli. Although TNFalpha plays an adaptive role in immune protection and wound healing at 'physiological' levels, excess TNFalpha production can lead to adverse consequences. TNFalpha is a pivotal cytokine involved in the pathogenesis and progression of rheumatoid arthritis (RA). TNFalpha antagonists have been shown to be effective in the treatment of signs and symptoms of RA and the US FDA has approved three TNFalpha antagonists, etanercept, infliximab, and most recently, adalimumab, for the treatment of RA. However, differences have emerged, with respect to their demonstrated efficacy in other diseases (e.g. Crohn's disease). Worldwide, over half a million patients have been treated with TNFalpha antagonists and concerns regarding their safety have been raised. There is a risk of reactivation of granulomatous diseases, especially tuberculosis, with all three agents and appropriate measures should be taken for detection and treatment of latent infections. An association between non-Hodgkin's lymphoma and treatment with TNFalpha antagonists has been reported, although patients with active, long-standing RA are already known to have an increased incidence of non-Hodgkin's lymphoma. No associations with solid tumours have been found to date. The biological plausibility of lymphomas associated with immunomodulatory agents raises concern and vigilance is appropriate until the relationship is fully characterised. Large phase II and III trials have shown a detrimental effect of TNFalpha antagonists in advanced heart failure and these agents should be avoided in this population. Rare case reports of drug-induced lupus, seizure disorder, pancytopenia and demyelinating diseases have been noted after TNFalpha antagonists and continued vigilance is warranted in patients on TNFalpha antagonists for the development of these diseases. At present there is no evidence implicating TNFalpha antagonists with embryotoxicity, teratogenicity or increased pregnancy loss.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Dougados M, Emery P, Gibofsky A, Kavanaugh AF, Keystone EC, Klareskog L, Russell AS, van de Putte LB, Weisman MH, Kavenaugh AF. · University of California, UCLA, Rheumatology, Division Los Angeles, USA. · Ann Rheum Dis. · Pubmed #14532138 links to  free full text

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Braun-Moscovici Y, Furst DE. · UCLA Medical School, Rheumatology Division, Los Angeles, California 98101, USA. · Curr Opin Rheumatol. · Pubmed #12707576 No free full text.

Abstract: There is no simple answer to the question: intravenous immunoglobulin-take it or leave it? A thorough review of the current data on mechanisms of action, efficacy, and safety of intravenous immunoglobulins in rheumatic diseases demonstrates that the answer depends on the disease and the patients involved.

Braun-Moscovici Y, Furst DE. · UCLA Medical School, Rheumatology Division, Los Angeles, California 98101, USA. · Curr Opin Rheumatol. · Pubmed #12707571 No free full text.

Abstract: As is often the case, one cannot give a simple answer to the question: plasmapheresis-take it or leave it? A thorough review of the current data on the possible mechanisms of action, the efficacy, and the safety of plasmapheresis in rheumatic diseases demonstrates that the answer depends on the disease and the patients involved.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Antoni CE, Bijlsma JW, Burmester GR, Cronstein B, Keystone EC, Kavanaugh A, Klareskog L. · University of California, Los Angeles, CA, USA. · Ann Rheum Dis. · Pubmed #12379612 links to  free full text

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Furst DE. · UCLA Medical School, Rheumatology Division, Los Angeles, California 98101, USA. · Curr Opin Rheumatol. · Pubmed #11981316 No free full text.

Abstract: The current status of stem cell transplantation in rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus, and systemic sclerosis are reviewed. From a large European bone marrow transplant registry, a birds' eye view of stem cell transplantation for autoimmune disease can be obtained. Among 43 rheumatoid arthritis patients, 35 juvenile chronic arthritis patients, 34 systemic lupus erythematosus patients, and 58 systemic sclerosis patients who underwent stem cell transplantation, initial responses in most patients were good to excellent. Although initial transplant related mortality was low for rheumatoid arthritis, somewhat higher rates for juvenile chronic arthritis, systemic lupus erythematosus, and systemic sclerosis may be falling with modifications in the stem cell transplantation regimens. In rheumatoid arthritis and systemic lupus erythematosus treatment, the criteria for patient selection are still not clear and the therapeutic regimens for stem cell transplantation (and whether follow-up treatment is necessary) are not fully defined. In juvenile chronic arthritis, responses are encouraging although little fully published data beyond that from the European Bone Marrow Transplant Registry exist. In systemic sclerosis, criteria for patient selection and a limited number of stem cell transplantation regimens have been agreed on and controlled trials are underway.

Furst DE, Keystone EC, Breedveld FC, Kalden JR, Smolen JS, Antoni CE, Burmester GR, Crofford LJ, Kavanaugh A. · Arthritis Clinical Research Unit, Virginia Mason Research Centre, Seattle, WA 98101, USA. · Ann Rheum Dis. · Pubmed #11890647 links to  free full text

Abstract: TNF blocking agents have proved to be effective DMARDs and they have been a major advance in the treatment of RA. Their use is expanding to other rheumatic diseases. However, rare to uncommon and unexpected toxicities have been found and others may yet be found during their use. Studies in selected areas of efficacy, toxicity, and general use of TNF blocking agents are needed to help further define the most appropriate use of these agents. Use of these drugs will require doctors experienced in the diagnosis, treatment, and assessment of RA and other rheumatic diseases. These doctors will need to make long term observations of efficacy and toxicity. Further considerations which must be made when using TNF blocking agents in this disease include the cost and a recognition that data in subgroups are still being acquired. It is hoped that this statement, which is based upon the best evidence available at the time of its creation, and modified by expert opinion, will facilitate the optimal use of these agents for our patients with RA and other rheumatic diseases.

Abramson SB, Furst DE, Hochberg MC, Patrono C. · Department of Rheumatology/Medicine, Hospital for Joint Surgery/NYU School of Medicine, New York, NY, USA. · Clin Exp Rheumatol. · Pubmed #11695257 No free full text.

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