BACKGROUND: Azathioprine, off-label used long time ago to treat multiple sclerosis (MS) patients, has recently received approval from the Spanish Medicine Agency (Agencia Española del Medicamento) in relapsing-remitting (RR) forms of this condition. Clinical efficacy of azathioprine is due to the enzymatic conversion to 6-thioguanine (the active metabolite). The key enzyme in this process is thio purine methyl transferase (TPMT), converting 6-MP to 6-methylMP. A specific genetic polymorphism has been described affecting this enzyme. With the aim of optimizing purine therapy in a variety of autoimmune diseases, monitoring of TPMT phenotype has been performed in a vast number of patients. The TPMT activity frequency distribution histogram from a Spanish population sample has been compared with the corresponding ones to Crohn's disease, ulcerative colitis and MS patients. METHODS AND RESULTS: TPMT activity has been studied in red blood cells obtained from 3,640 clinical laboratory samples in Spain of which 1,249 corresponded to patients affected by Crohn's disease, 589 to ulcerative colitis, 348 to MS, 487 to several autoimmune diseases apart from the previously mentioned and 967 to a group of blood donors. The mean TPMT activity in the MS group (17.1 6.1 U/ml) was significantly lower (p < 0.001) than in Crohn's disease (20.0 5.8 U/ml), ulcerative colitis (19.7 6.1 U/ml) and donors group (19.9 6.3 U/ml). CONCLUSION: Defective methylation profile and subsequent hyperhomocysteinemia leading to a widespread impairment of the methyl-transferase activity (in this case affecting MBP methylation) is a vicious circle we propose as a MS susceptibility factor.
BACKGROUND:Azathioprine, off-label used long time ago to treat multiple sclerosis (MS) patients, has recently received approval from the Spanish Medicine Agency (Agencia Española del Medicamento) in relapsing-remitting (RR) forms of this condition. Clinical efficacy of azathioprine is due to the enzymatic conversion to 6-thioguanine (the active metabolite). The key enzyme in this process is thio purine methyl transferase (TPMT), converting 6-MP to 6-methylMP. A specific genetic polymorphism has been described affecting this enzyme. With the aim of optimizing purine therapy in a variety of autoimmune diseases, monitoring of TPMT phenotype has been performed in a vast number of patients. The TPMT activity frequency distribution histogram from a Spanish population sample has been compared with the corresponding ones to Crohn's disease, ulcerative colitis and MS patients. METHODS AND RESULTS: TPMT activity has been studied in red blood cells obtained from 3,640 clinical laboratory samples in Spain of which 1,249 corresponded to patients affected by Crohn's disease, 589 to ulcerative colitis, 348 to MS, 487 to several autoimmune diseases apart from the previously mentioned and 967 to a group of blood donors. The mean TPMT activity in the MS group (17.1 6.1 U/ml) was significantly lower (p < 0.001) than in Crohn's disease (20.0 5.8 U/ml), ulcerative colitis (19.7 6.1 U/ml) and donors group (19.9 6.3 U/ml). CONCLUSION: Defective methylation profile and subsequent hyperhomocysteinemia leading to a widespread impairment of the methyl-transferase activity (in this case affecting MBP methylation) is a vicious circle we propose as a MS susceptibility factor.