Contributions
Abstract: P552
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by demyelination and neurodegeneration. A number of proinflammatory molecules released by activated T and B lymphocytes and local immune cells negatively influence MS disease course. Lymphocytes are very sensitive to impaired nucleotide metabolism. The activity of the enzyme adenosine deaminase (ADA) is critically involved in the regulation of the immune response homeostasis, as shown in ADA genetically deficient patients and in response to cladribine treatment.
Objective: To explore in a large cohort of MS patients the association between single nucleotide polymorphisms (SNP) of ADA gene, and both CSF inflammation and disease characteristics.
Methods: A number of ADA SNPs (rs244072, rs452159, rs181828191, rs73598374, rs244076, rs1799880) were determined in a group of 590 MS patients. CSF proinflammatory and anti-inflammatory molecules were measured at the time of diagnosis in a subgroup of 234 MS patients. Clinical and radiological disease characteristics were assessed at baseline, and during median follow-up period of 44 months.
Results: A significant association emerged between ADA rs244072 SNP and the levels of central inflammation. In particular, in patients presenting the C allele, significantly higher CSF levels of TNFα (TT patients median =0.68, IQR = 0 - 1.15; CT/CC median = 1.42, IQR = 0.31 - 3.45; p = 0.023), IL-5 (TT patients median = 0, IQR = 0 - 0.63; CT/CC median = 0.39, IQR = 0 - 17.8; p = 0.0274) and RANTES (TT patients median = 4.49, IQR = 0 - 99.9; CT/CC median = 157.3, IQR = 0.99 - 1129.5; p = 0.0403) have been observed. In addition, patients with the C allele showed lower CSF levels of IL-10 (TT patients median = 2.64, IQR = 1.14-4.07; CT/CC median = 1.91, IQR = 0 - 2.94; p = 0.044). Finally, a significant association emerged between the presence of the C allele and higher expanded disability status score (EDSS) at the time of diagnosis (TT patients median = 2, IQR = 1 - 3; CT/CC median = 2.5, IQR = 2 - 3.5; p = 0.0158).
Discussion: ADA SNP rs244072 influences central inflammation and disease characteristics in MS patients. These results suggest that pharmacological modulation of ADA pathway with cladribine could be effective in MS by targeting a pathogenetically relevant biological mechanism.
Disclosure: Dr. Buttari acted as Advisory Board member of Teva.
Dr. Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi- Genzyme e Teva.
Dr. Furlan has nothing to declare.
Dr. Marfia is an Advisory Board member of Biogen Idec, Genzyme, Merck-Serono, Novartis, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Teva. She is the principal investigator in clinical trials for Actelion, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva.
Dr. Matarese has nothing to declare.
Dr. Salvetti is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi- Genzyme e Teva.
Dr. Sica has nothing to declare.
Dr. Simonelli has nothing to declare.
Dr. Stampanoni Bassi has nothing to declare.
Dr. Uccelli is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi- Genzyme e Teva.
Dr. Visconti has nothing to declare.
Abstract: P552
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by demyelination and neurodegeneration. A number of proinflammatory molecules released by activated T and B lymphocytes and local immune cells negatively influence MS disease course. Lymphocytes are very sensitive to impaired nucleotide metabolism. The activity of the enzyme adenosine deaminase (ADA) is critically involved in the regulation of the immune response homeostasis, as shown in ADA genetically deficient patients and in response to cladribine treatment.
Objective: To explore in a large cohort of MS patients the association between single nucleotide polymorphisms (SNP) of ADA gene, and both CSF inflammation and disease characteristics.
Methods: A number of ADA SNPs (rs244072, rs452159, rs181828191, rs73598374, rs244076, rs1799880) were determined in a group of 590 MS patients. CSF proinflammatory and anti-inflammatory molecules were measured at the time of diagnosis in a subgroup of 234 MS patients. Clinical and radiological disease characteristics were assessed at baseline, and during median follow-up period of 44 months.
Results: A significant association emerged between ADA rs244072 SNP and the levels of central inflammation. In particular, in patients presenting the C allele, significantly higher CSF levels of TNFα (TT patients median =0.68, IQR = 0 - 1.15; CT/CC median = 1.42, IQR = 0.31 - 3.45; p = 0.023), IL-5 (TT patients median = 0, IQR = 0 - 0.63; CT/CC median = 0.39, IQR = 0 - 17.8; p = 0.0274) and RANTES (TT patients median = 4.49, IQR = 0 - 99.9; CT/CC median = 157.3, IQR = 0.99 - 1129.5; p = 0.0403) have been observed. In addition, patients with the C allele showed lower CSF levels of IL-10 (TT patients median = 2.64, IQR = 1.14-4.07; CT/CC median = 1.91, IQR = 0 - 2.94; p = 0.044). Finally, a significant association emerged between the presence of the C allele and higher expanded disability status score (EDSS) at the time of diagnosis (TT patients median = 2, IQR = 1 - 3; CT/CC median = 2.5, IQR = 2 - 3.5; p = 0.0158).
Discussion: ADA SNP rs244072 influences central inflammation and disease characteristics in MS patients. These results suggest that pharmacological modulation of ADA pathway with cladribine could be effective in MS by targeting a pathogenetically relevant biological mechanism.
Disclosure: Dr. Buttari acted as Advisory Board member of Teva.
Dr. Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi- Genzyme e Teva.
Dr. Furlan has nothing to declare.
Dr. Marfia is an Advisory Board member of Biogen Idec, Genzyme, Merck-Serono, Novartis, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Teva. She is the principal investigator in clinical trials for Actelion, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva.
Dr. Matarese has nothing to declare.
Dr. Salvetti is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi- Genzyme e Teva.
Dr. Sica has nothing to declare.
Dr. Simonelli has nothing to declare.
Dr. Stampanoni Bassi has nothing to declare.
Dr. Uccelli is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi- Genzyme e Teva.
Dr. Visconti has nothing to declare.