Leflunomide blocked de novo pyrimidine synthesis and RANKL-induced calcium signaling in osteoclast precursor cells in vitro; hence, the induction of nuclear factor of activated T cells c1 (NF-ATc1) was strongly inhibited. The inhibition of this pathway is central to the action of leflunomide, since the inhibition was overcome by ectopic expression of NF-ATc1 in the precursor cells. Leflunomide suppressed endotoxin-induced inflammatory bone destruction even in rag-2(-/-) mice.
All patients with RA at seven centres in southern Sweden, for whom at least two disease modifying antirheumatic drugs, including methotrexate, had failed or not been tolerated, who started treatment with either infliximab, etanercept, or leflunomide were included. They were evaluated at predefined times using a standardised protocol including items required for evaluating response to the American College of Rheumatology (ACR) or EULAR criteria. All adverse events were recorded using World Health Organisation terminology. Concomitant treatment and survival while receiving a drug were recorded.
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The current study aimed to determine whether long-term oral treatment with leflunomide prevents allergic sensitization permanently.
Uveitis, or intraocular inflammation, remains an ongoing challenge to ophthalmologists and patients alike. In most patients, uveitis is limited to the anterior ocular structures and is readily managed with topical steroids. The inflammatory process can extend behind the lens to involve the pars plana, the vitreous cavity, the choroid and the retina. These intermediate and posterior uveitides are relatively rare but contribute disproportionately to visual morbidity and present serious diagnostic and therapeutic difficulties. Systemic steroids constitute the first line of treatment for most sight-threatening uveitides. Their long term use is limited by universal and debilitating adverse effects. Second-line, steroid-sparing agents allow a reduction in steroid dosage. Cyclosporin and azathioprine are the main steroid-sparing agents currently in use. However, these compounds are limited by a narrow therapeutic window and significant adverse effects. This paper offers a brief discussion of some of the immune mechanisms involved in the pathogenesis of uveitis and reviews categories of investigational compounds. Inhibitors of T cell function: tacrolimus (previously FK506), licensed for use in liver transplantation, and sirolimus (rapamycin) are macrolide antibiotics. Sirolimus is a functional cytokine antagonist and in vitro studies suggest it could be up to 100 times more potent than cyclosporin. Drug synergy between sirolimus and cyclosporin has been demonstrated, resulting in immunosuppression at lower drug doses and with fewer adverse effects. Nucleotide synthesis inhibitors: mycophenolate mofetil (MMF) and leflunomide. Human lymphocytes are only able to synthesise nucleic acids de novo. Having no alternative or 'salvage' pathway, they are exquisitely sensitive to interference with the de novo nucleotide synthesis enzymatic pathway. MMF is a purine synthesis inhibitor. Compared to other purine inhibitors, early data suggest that MMF is more efficacious and less toxic than azathioprine. Leflunomide is an inhibitor of pyrimidine synthesis. Monoclonal surface receptor antibodies and immunoadhesins: the IL-2 receptor is essential for clonal expansion of activated T cells; this has led to the development of anti-IL-2 receptor antibodies. Daclizumab is a genetically engineered humanised IgG1 monoclonal antibody. In conjunction with cyclosporin, it significantly reduces renal allograft rejection rates and is also showing promise in the treatment of T cell mediated autoimmune disorders. The mechanism of action of monoclonal antibodies to other pro-inflammatory cytokines such as TNFalpha and IL-12 and data from animal and human uveitis trials are also discussed. Finally, new avenues of research in immunopharmaco-modulation are mentioned.
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This paper aims to investigate the prevalence of anxiety, depression and suicidal ideation in patients with rheumatoid arthritis taking different drugs to control the disease.
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We describe a 54-year-old woman with rheumatoid arthritis (RA), who developed acute respiratory failure 2 weeks after cessation of 6-week treatment with leflunomide. We diagnosed interstitial pneumonia, probably induced by leflunomide because acute respiratory failure was preceded by elevated serum liver enzyme concentration and hypertension. She showed dramatic improvement with prednisolone and cholestyramine. Prompt treatment may improve the prognosis. In Japan, leflunomide has been implicated as a possible cause to initiate or exacerbate interstitial pneumonia in patients with RA according to postmarketing surveillance. Clinicians should exclude pulmonary disease prior to initiating leflunomide treatment in patients with RA on the basis of a thorough history and physical examination, and chest radiograph.
Using the ACR20 criteria, the NNT with leflunomide and methotrexate are 4 (95% CI, 2.56-7.71) and 5 (95% CI, 3.03-14.3) respectively. Using the ACR50 criteria, NNT are 4 (95% CI, 2.72-6.54) and 7 (95% CI, 4.03-19.3). In the case of leflunomide, annual treatment costs per patient-year equals 1,793.30€; in the case of methotrexate total treatment costs amounts to 2,149.20€.
Wistar rats were used for aorta denudations. The rats remained untreated or received either FK778 or imatinib (STI571) at decreasing oral doses from 10 mg/kg per day. Half of the animals in both treatment groups also received uridine to reverse DHODH activity. Morphometric analysis was done after 14 day follow-up. In the untreated group, moderate neointima formation was detected. FK778 almost completely inhibited intimal formation, with or without uridine addition (P<0.05). Imatinib also inhibited neointima formation (P<0.05), whereas exogenous uridine reversed its effect.
Leflunomide was found to be metabolized predominantly to A77-1726 and two novel hydroxylated metabolites, M1 and M2, in microsomes while A77-1726 was only biotransformed to M1. M1 and M2 were proposed to be the hydroxylated alpha-cyanoenol form of A77-1726 and the hydroxylated 5 methyl-isoxazole form of leflunomide, respectively.
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358 patients were randomly assigned leflunomide (100 mg daily on days 1-3, then 20 mg daily), placebo, or sulphasalazine (0.5 g daily, titrated progressively to 2.0 g daily at week 4). The primary endpoints were tender and swollen joint counts and investigator's and patient's overall assessments. Analyses were by intention to treat.
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Malononitrilamide 715 (FK778) is a new class of immunosuppressant, derived from the active metabolite of leflunomide A77 1726. We investigated the efficacy of two different immunosuppressive induction protocols with tacrolimus plus FK778 followed by FK778 monotherapy. In a swine model of small bowel transplantation, we observed three groups, divided by different therapy regimens: group 1 (n = 5): no immunosuppressant (control group); group 2 (n = 10): oral tacrolimus (from postoperative day [POD] 0 to 30) and FK778 (from POD 0 to 60); group 3 (n = 8): oral tacrolimus, as group 2, and FK778 (from POD 7 to POD 60). Median survival was 11, 60, and 21 days in groups 1, 2, and 3, respectively. In group 1 all animals died of acute rejection; in group 2 the causes of death were technical complication (n = 1) and sepsis (n = 1); in group 3, one animal died from obstruction, two from pneumonia, one from peritonitis, one from sepsis. Group 2 accounted for 0.5 infection episode/animal versus 0.62 in group 3 (P < .05). Acute rejection was absent or mild in 66% and 75% of group 3 and 2 biopsies, respectively (P < .05). The D-xylose absorption curves from groups 2 and 3 were similar to those of the nontransplanted healthy animals. In conclusion, FK778 monotherapy after a consistent induction period with tacrolimus combined immunosuppression is able to extend survival and preserve optimal absorptive capacity of the small bowel allograft in our pig model. The association of tacrolimus and FK778 from day 1, compared to the delayed administration of FK778 from day 7, results in a significant reduction of infections and postoperative complications.
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To explore the onset and molecular mechanism of resistance to the antimalarial disease-modifying antirheumatic drug (DMARD) chloroquine (CQ) in human CEM T cells.