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      Attenuation of inflammatory polyarthritis in TNF transgenic mice by diacerein: comparative analysis with dexamethasone, methotrexate and anti-TNF protocols

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          Abstract

          The impact of diacerein, an effective cartilage targeted therapy that is used in patients with osteoarthritis, on the development and progression of chronic inflammatory arthritis was evaluated in a tumor necrosis factor (TNF) transgenic mouse model (Tg197). The response to diacerein at 2, 20, or 60 mg/kg daily, as well as the comparative effects of other antiarthritis drugs including dexamethasone (0.5 mg/kg daily), methotrexate (1 mg/kg three times weekly) and an anti-TNF agent (5 mg/kg weekly), were assessed in the Tg197 mice. Treatment was initiated before the onset of arthritis and was continued for 5 weeks. A significant improvement in clinical symptoms was found in all three diacerein treated groups in comparison with untreated groups. Confirming these data, semiquantitative histopathologic analysis of the hind paws revealed a significant reduction not only in cartilage destruction but also in the extent of synovitis and bone erosion in diacerein treated groups in comparison with untreated groups. At the most effective dose tested (2 mg/kg daily), diacerein inhibited the onset of arthritis in 28% and attenuated the progression of arthritis in 35% of the Tg197 mice. Comparative analyses showed diacerein to be more potent than methotrexate but not as effective as dexamethasone or anti-TNF agents in suppressing the progression of the TNF mediated arthritis in this model. These results indicate that diacerein has a disease modifying effect on the onset and progression of TNF driven chronic inflammatory arthritis, suggesting that the prophylactic or therapeutic potential of diacerein in patients with RA should be further examined.

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          Most cited references 43

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          Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.

          Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis. We analyzed all reports of tuberculosis after infliximab therapy that had been received as of May 29, 2001, through the MedWatch spontaneous reporting system of the Food and Drug Administration. There were 70 reported cases of tuberculosis after treatment with infliximab, for a median of 12 weeks. In 48 patients, tuberculosis developed after three or fewer infusions. Forty of the patients had extrapulmonary disease (17 had disseminated disease, 11 lymph node disease, 4 peritoneal disease, 2 pleural disease, and 1 each meningeal, enteric, paravertebral, bone, genital, and bladder disease). The diagnosis was confirmed by a biopsy in 33 patients. Of the 70 reports, 64 were from countries with a low incidence of tuberculosis. The reported frequency of tuberculosis in association with infliximab therapy was much higher than the reported frequency of other opportunistic infections associated with this drug. In addition, the rate of reported cases of tuberculosis among patients treated with infliximab was higher than the available background rates. Active tuberculosis may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent tuberculosis infection or disease.
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            Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group.

            Neutralization of tumor necrosis factor a (TNF-alpha) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known. We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-alpha, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically. The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P<0.001). The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone. Radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6, P<0.001). Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response. In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.
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              Role of cytokines in rheumatoid arthritis.

              Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.
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                Author and article information

                Journal
                Arthritis Res Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                2004
                7 November 2003
                : 6
                : 1
                : R65-R72
                Affiliations
                [1 ]Institute of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', Athens, Greece
                [2 ]First Department of Propedeutic and Internal Medicine, Laikon Hospital, Athens University Medical School, Athens, Greece
                [3 ]Hellenic Pasteur Institute, Athens, Greece
                [4 ]Trans Bussan Chemedica International, Geneva, Switzerland
                Article
                ar1028
                10.1186/ar1028
                400419
                14979939
                Copyright © 2004 Douni et al., licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
                Categories
                Research Article

                Orthopedics

                diacerein, inflammation, arthritis, transgenic, tumor necrosis factor

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