Browsing by Author "Alvarez-Lobos, Manuel"

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    Clinical and genetic features of hereditary periodic fever syndromes in Hispanic patients: the Chilean experience
    (2012) Vergara, Cristian; Borzutzky, Arturo; Gutierrez, Miguel A.; Iacobelli, Sergio; Talesnik, Eduardo; Martinez, Maria E.; Stange, Lilith; Basualdo, Javier; Maluje, Viviana; Jimenez, Renato; Wiener, Roberto; Tinoco, Javier; Jarpa, Elena; Arostegui, Juan I.; Yaguee, Jordi; Alvarez-Lobos, Manuel
    Hereditary periodic fever syndromes (HPFS) are rare genetic diseases characterized by recurrent episodes of inflammation. Little information is available concerning HPFS in Latin American Hispanic population. The purpose of this study was to determine the clinical and genetic features of HPFS in Chilean population. A multicenter retrospective study of Hispanic Chilean patients with genetically confirmed HPFS was performed. We included 13 patients, 8 with familial Mediterranean fever (FMF) and 5 with TNF receptor-associated periodic syndrome (TRAPS), evaluated at rheumatology or pediatric rheumatology clinics between January 2007 and December 2010. Median age of symptoms onset was 8 years (range 1-35) and 8 years (range 0.3-21) for FMF and TRAPS, respectively. Median duration of fever was 3 days (range 2.5-15) for FMF and 21 days (range 9.5-30) for TRAPS. Genotyping of the MEFV gene in FMF patients revealed a homozygous M694V missense mutation in one patient, and heterozygous missense mutations in seven patients: M694V (n = 3), E148Q, R717H, A744S, and A511V. Sequencing of the TNFRSF1A gene in TRAPS patients revealed heterozygous missense mutations in four patients: T50M, C30R, R92Q, and IVS3+30:G -> A, and a two-base pair deletion (IVS2-17_18del2bpCT) in one patient. Mutation in MEFV R717H and mutations in TNFRSF1A IVS2-17_18del2bpCT and IVS3+30:G -> A are novel and have not been described previously. This study reports the largest series of genetically confirmed HPFS in Latin America, and adds evidence regarding the clinical and genetic characteristics of patients with FMF and TRAPS in Hispanic population. Mutations identified in MEFV and TNFRSF1A genes include defects reported in other ethnicities and novel mutations.
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    Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis
    (2021) Perez-Jeldres, Tamara; Alvarez-Lobos, Manuel; Rivera-Nieves, Jesus
    Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.