Rheumatoid Arthritis: Jakez-Ocampo J

Richaud-Patin Y, Soto-Vega E, Jakez-Ocampo J, Llorente L. · Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga #15, Tlalpan, 14000 Mexico City, Mexico. · Autoimmun Rev. · Pubmed #15110230 No free full text.

Abstract: Multidrug resistance-1 (MDR-1) is characterized by overfunction of P-glycoprotein (P-gp), a pump molecule that decreases intracellular drug concentration by effluxing them from the intracellular space. Broad ranges of structurally unrelated compounds are transported by P-gp, including antineoplastic agents, HIV protease inhibitors, prednisone, gold salts, methotrexate, colchicine as well as several antibiotics. In contrast, many other compounds such as calcium channel blockers (verapamil) and immunosupressors (cyclosporine-A) are able to inhibit P-gp function. The P-gp role in therapeutic failures has been extensively studied in cancer; however, there is little information regarding MDR-1 phenotype in autoimmune disorders. It has been reported that an increased number of lymphocytes are able to extrude P-gp substrates in rheumatoid arthritis, immune thrombocytopenic purpura and systemic lupus erythematosus, the patients with poor response to treatment being the ones that exhibit the highest values. This may be due, at least in part, to a simultaneous long-term usage of several drugs that induce P-gp function. Since abnormally activated cell compartments characterize autoimmune diseases, it is possible that those cells are the ones that exhibit drug resistance. The study of drug resistance mechanisms in autoimmunity may be helpful for the optimization of the current therapeutic schemes through their combination with low doses of P-gp inhibitors.

Jakez-Ocampo J, Richaud-Patin Y, Simón JA, Llorente L. · Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. · Joint Bone Spine. · Pubmed #12102278 No free full text.

Abstract: AIMS: To assess the therapeutic effect of leflunomide in weekly dose of 100 mg in patients with refractory rheumatoid arthritis. MATERIAL AND METHODS: Sixteen patients were included (18-72 years, disease duration 2-32 years). Eight patients received a weekly dose of 100 mg of leflunomide and 8 the conventional dose. Current treatment was not modified. All patients underwent a monthly evaluation for one year, applying the 1995 ACR preliminary definition of improvement in rheumatoid arthritis. RESULTS: After 2 months, the group treated with the conventional leflunomide dose evidenced a remarkable improvement (7/8 patients achieving ACR 20), while the group receiving the weekly dose, the improvement was not as clearly evident (3/8 patients achieving ACR 20). By the fourth to sixth month, the response was comparable on both groups (6/6 and 6/8 patients achieving ACR 50 in the daily and weekly dose, respectively) and prevailed through the end of the study. There were no statistical differences between groups at any evaluation. Side effects made itself clear in 6 patients in the daily leflunomide group, and 2 patients withdrawn leflunomide because severe gastrointestinal symptoms and hepatotoxicity, respectively. In the group of weekly leflunomide 2 patients presented side effects which disappeared spontaneously. CONCLUSION: The use of leflunomide in a weekly dose of 100 mg proved to have similar therapeutic benefit as that of the conventional scheme and might represent a new option for the treatment of refractory rheumatoid arthritis patients.

Llorente L, Richaud-Patin Y, Díaz-Borjón A, Alvarado de la Barrera C, Jakez-Ocampo J, de la Fuente H, Gonzalez-Amaro R, Diaz-Jouanen E. · Department of Immunology and Rheumathology, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City, Mexico. · Joint Bone Spine. · Pubmed #10773966 No free full text.

Abstract: BACKGROUND: Multidrug resistance (MDR) is characterized by overexpression of P-glycoprotein, a pump molecule that decreases intracellular drug concentrations by increasing drug efflux from cells. OBJECTIVE: To look for correlations between clinical status and P-glycoprotein activity and/or TNF-alpha mRNA levels in patients with rheumatoid arthritis. METHODS: Sixteen patients were studied. Based on response to therapy, eight were refractory and eight nonrefractory to treatment. Findings were compared to those in 24 healthy controls. Flow cytometry was used to evaluate P-glycoprotein activity in peripheral blood mononuclear cells isolated by gradient centrifugation and incubated with the P-glycoprotein substrate daunorubicin. TNF-alpha mRNA levels were determined using quantitative PCR. RESULTS: Patients with rheumatoid arthritis showed an increased number of lymphocytes with high P-glycoprotein activity (p = 0.0001) as compared to the normal controls. P-glycoprotein activity was higher in the refractory than in the non-refractory patient subgroup (p = 0.006). Also, TNF-alpha mRNA levels were markedly higher in the refractory subgroup than in the nonrefractory subgroup, and were undetectable in the normal controls. CONCLUSIONS: Enhanced P-glycoprotein activity may be closely related to an unfavorable clinical course and a poor response to treatment. Increased TNF-alpha expression and chronic exposure to various drugs, including glucocorticoids, may contribute to increase P-glycoprotein activity. Both high P-glycoprotein activity and excessive amounts of TNF-alpha seem associated with poor outcome in rheumatoid arthritis.

Jakez-Ocampo J, Richaud-Patin Y, Granados J, Sánchez-Guerrero J, Llorente L. · No affiliation provided · Arthritis Rheum. · Pubmed #14872469 links to  free full text

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