Distribución geográfica de la mortalidad por esclerosis múltiple en adultos Colombia (2010-2015) / Geographic distribution of mortality due to multiple sclerosis in Colombia, 2010-2015

RESUMEN Objetivo Caracterizar la distribución geográfica de la mortalidad por esclerosis múltiple en Colombia entre 2010 y 2015. Métodos Estudio descriptivo. Análisis de la mortalidad a partir de certificados de defunción entre 2010 y 2015. Cálculo de tasas de mortalidad departamentales y municipales ajustadas por sexo y edad. Resultados El 56,8% de las defunciones ocurrieron en mujeres y 28,7% en personas de 50 a 59 años. En 2010 la tasa de mortalidad nacional fue de 0,28 por cada 100 000 personas, y Casanare registró la más alta (0,59 por cada 100 000 personas). En 2011, la tasa fue de 0,24, y Buenaventura registró la más alta (0,51). En 2012, la tasa fue de 0,27, y Guajira registró la más alta (0,34). En 2013, la tasa fue de 0,27, y la más alta se presentó en Arauca (0,83). En 2014, la tasa fue de 0,32, y la más alta ocurrió en Putumayo (1,14). En 2015 la tasa fue de 0,23 y Santa Marta registró la más alta (0,58). Por municipios, Sativanorte, Arcabuco (Boyacá), San Miguel, la Paz (Santander) y la Merced (Caldas) registraron las mayores tasas. Conclusiones El comportamiento de la mortalidad por esclerosis múltiple es similar en el periodo de estudio. La mayor carga de mortalidad se registró en mujeres y en los municipios de Santander y Boyacá.(AU)

ABSTRACT Objective To characterize the geographical distribution of extended mortality due to multiple sclerosis in Colombia between 2010 and 2015. Materials and Methods Descriptive study to analyze the geographical distribution of mortality rates from the death certificates between 2010 and 2015. State and municipal mortality rates were calculated and adjusted by age and sex. Results 56.8% of deaths occurred in women and 28.7% in people aged 50 to 59 years. In 2010, the national mortality rate was 0.28 per 100,000 people, and the highest was recorded in Casanare (0.59 per 100,000). In 2011, the rate was 0.24, and Buenaventura recorded the highest (0.51). In 2012, the rate was 0.27, and la Guajira recorded the highest (0.34). In 2013, the rate was 0.27, and the highest was in Arauca (0.83). In 2014, the rate was 0.32, and the highest was occurred in Putumayo (1.14). In 2015 the rate was 0.23 and Santa Marta recorded the highest (0.58). By municipalities, Sativanorte, Arcabuco (Boyacá), San Miguel, la Paz (Santander) and la Merced (Caldas) recorded the highest rates. Conclusion The pattern of mortality due to multiple sclerosis is similar in the study period. The highest burden of mortality was recorded in women and in municipalities of Santander and Boyacá.(AU)

Polymorphisms in the CIITA -168A/G (rs3087456) and CIITA +1614G/C (rs4774) may influence severity in multiple sclerosis patients.

It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS). OBJECTIVE: We examined the impact of CIITA polymorphisms -168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. METHODS: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). RESULTS: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA -168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA -168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA -168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. CONCLUSION: These data suggest that CIITA -168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management.

Polymorphisms in the CIITA -168A/G (rs3087456) and CIITA +1614G/C (rs4774) may influence severity in multiple sclerosis patients / Os polimorfismos no gene CIITA - 168A/G (rs3087456) e CIITA +1614G/C (rs4774) podem influenciar a gravidade em pacientes com esclerose múltipla

ABSTRACT It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS). Objective: We examined the impact of CIITA polymorphisms −168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. Methods: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). Results: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA −168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA −168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA −168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. Conclusion: These data suggest that CIITA −168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management.

RESUMO Atualmente não se sabe como os fatores genéticos podem influenciar o curso clínico da esclerose múltipla (EM). Objetivo: Examinamos o impacto dos polimorfismos CIITA −168A/G (rs3087456) e CIITA +1614G/C (rs4774) no risco de progressão da incapacidade, gravidade e resposta aos tratamentos imunomoduladores de primeira linha. Métodos: O DNA genômico foi extraído de amostras de sangue. Utilizamos o software ABI3730xl e GeneMapper v.4.0 (Applied Biosystems) para identificar variações genotípicas. Todos os pacientes foram acompanhados e reavaliados clinicamente em intervalos de três meses. A progressão da incapacidade foi medida pela EDSS e a gravidade da doença pelo MSSS. Resultados: Incluímos 37 homens e 80 mulheres. Não encontramos evidências sobre a influência dos SNPs estudados no EDSS e na resposta terapêutica aos fármacos avaliados. Realizamos uma análise de regressão logística com o MSSS e observamos uma evolução menos grave da EM associada aos tipos selvagens CIITA −168AA e CIITA +1614GG, pois a chance do paciente atingir MSSS2 e MSSS3 diminuiu em 61%/75%, e 66/75% respectivamente (p < 0,0001). Embora menos significativo, o CIITA +1614GC também foi relacionado com evolução menos grave da EM e a chance do paciente atingir o MSSS3 diminuiu 79% (p = 0,015). Nós também observamos que o genótipo CIITA −168GG foi mais frequente no MSSS2 e MSSS3 e teve uma razão de chance 40% menor para atingir forma mais grave da EM. Conclusão: Estes dados sugerem que os polimorfismos CIITA −168AA, CIITA +1614GG e CIITA +1614GC podem estar associados a um melhor curso clínico da EM. Este conhecimento pode ser útil para uma melhor compreensão da EM e o seu manejo terapêutico.

Multiple sclerosis outcomes after cancer immunotherapy.

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes. METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution. RESULTS: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors. CONCLUSIONS: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.

Central Nervous System Idiopathic Inflammatory Demyelinating Disorders in South Americans: A Descriptive, Multicenter, Cross-Sectional Study.

The idiopathic inflammatory demyelinating disease (IIDD) spectrum has been investigated among different populations, and the results have indicated a low relative frequency of neuromyelitis optica (NMO) among multiple sclerosis (MS) cases in whites (1.2%-1.5%), increasing in Mestizos (8%) and Africans (15.4%-27.5%) living in areas of low MS prevalence. South America (SA) was colonized by Europeans from the Iberian Peninsula, and their miscegenation with natives and Africans slaves resulted in significant racial mixing. The current study analyzed the IIDD spectrum in SA after accounting for the ethnic heterogeneity of its population. A cross-sectional multicenter study was performed. Only individuals followed in 2011 with a confirmed diagnosis of IIDD using new diagnostic criteria were considered eligible. Patients' demographic, clinical and laboratory data were collected. In all, 1,917 individuals from 22 MS centers were included (73.7% female, 63.0% white, 28.0% African, 7.0% Mestizo, and 0.2% Asian). The main disease categories and their associated frequencies were MS (76.9%), NMO (11.8%), other NMO syndromes (6.5%), CIS (3.5%), ADEM (1.0%), and acute encephalopathy (0.4%). Females predominated in all main categories. The white ethnicity also predominated, except in NMO. Except in ADEM, the disease onset occurred between 20 and 39 years old, early onset in 8.2% of all cases, and late onset occurred in 8.9%. The long-term morbidity after a mean disease time of 9.28±7.7 years was characterized by mild disability in all categories except in NMO, which was scored as moderate. Disease time among those with MS was positively correlated with the expanded disability status scale (EDSS) score (r=0.374; p=<0.001). This correlation was not observed in people with NMO or those with other NMO spectrum disorders (NMOSDs). Among patients with NMO, 83.2% showed a relapsing-remitting course, and 16.8% showed a monophasic course. The NMO-IgG antibody tested using indirect immunofluorescence (IIF) with a composite substrate of mouse tissues in 200 NMOSD cases was positive in people with NMO (95/162; 58.6%), longitudinally extensive transverse myelitis (10/30; 33.3%) and bilateral or recurrent optic neuritis (8/8; 100%). No association of NMO-IgG antibody positivity was found with gender, age at onset, ethnicity, early or late onset forms, disease course, or long-term severe disability. The relative frequency of NMO among relapsing-remitting MS (RRMS) + NMO cases in SA was 14.0%. Despite the high degree of miscegenation found in SA, MS affects three quarters of all patients with IIDD, mainly white young women who share similar clinical characteristics to those in Western populations in the northern hemisphere, with the exception of ethnicity; approximately one-third of all cases occur among non-white individuals. At the last assessment, the majority of RRMS patients showed mild disability, and the risk for secondary progression was significantly superior among those of African ethnicity. NMO comprises 11.8% of all IIDD cases in SA, affecting mostly young African-Brazilian women, evolving with a recurrent course and causing moderate or severe disability in both ethnic groups. The South-North gradient with increasing NMO and non-white individuals from Argentina, Paraguay, Brazil and Venezuela confirmed previous studies showing a higher frequency of NMO among non-white populations.

Esclerosis múltiple en pacientes pediátricos: fisiopatología, diagnóstico y manejo / Pediatric multiple sclerosis: pathophysiology, diagnosis, and management

Objetivo: Realizar una revisión acerca de la esclerosis múltiple en pacientes pediátricos, haciendo énfasis en los factores fisiopatológicos, los métodos diagnósticos, los principales diagnósticos diferenciales, el tratamiento y el pronóstico, para, de esta forma, lograr suministrar conocimientos claves y actualizados sobre esta patología. Métodos: La búsqueda de artículos se realizó en las bases de datos PubMed y Scopus, introduciendo las palabras clave “multiple sclerosis”, “children”, “pediatric multiple sclerosis”, “pathophysiology”, “diagnosis”, “diagnostic criteria” y “treatment”. Los artículos seleccionados debían tener fecha de publicación posterior al año 2000, ser revisiones de tema o ensayos clínicos y estar publicados en los idiomas inglés o español. Resultados y Conclusiones: La esclerosis múltiple es una enfermedad con una tasa de incidencia de 2 a 4 por 100.000 habitantes en Colombia, de la cual la población pediátrica representa entre 2,7 a 5.0% de los casos. Las causas que se han atribuido a la enfermedad son múltiples, incluyendo factores ambientales como infecciones virales o bacterianas, exposición a humo de cigarrillo o deficiencia de vitamina D, entre otras, factores genéticos y factores inmunológicos. Su diagnóstico se basa en los hallazgos clínicos e imagenológicos, previa exclusión de enfermedades más comunes. Su tratamiento se divide en tres ejes: el tratamiento de eventos agudos, el tratamiento modificador de la enfermedad y el tratamiento sintomático. Para el primero los medicamentos de primera elección son los corticoides, para el segundo son los medicamentos inmunomoduladores como acetato de glatiramer, y para el tercero se debe realizar un enfoque multidisciplinario. Su pronóstico a largo plazo es variable y depende en alguna medida de la respuesta al tratamiento.

Objective: Review about Multiple Sclerosis in pediatric patients, emphasizing in pathophysiological factors, di agnos t i c met hods , mai n di f f er ent i al di agnos i s ,t r eat ment , and pr ognosi s, t hus pr ovi di ng cur r entknowledge about this pathology. Methods: Search of articles was made in PubMed and Scopus databases with key words “multiple sclerosis”, “children”, “pediatric mul t i pl e scl er osi s” , “ pat hophysi ol ogy” , “ di agnosi s” ,“diagnostic criteria”, and “treatment”. Selected articles must have a publication date after 2000, reviews or clinical trials, and have been published in English or Spanish languages. Results and Conclusions: Multiple sclerosis is a disease with an incidence of 2 to 4 per 100,000 habitants in Colombia, and pediatric population represents 2.7 to 5% of the cases. Multiple causes had been related to the disease, including environmental factors, such as viral or bacterial infections, tobacco smoke exposure or Vitamin D deficiency, among others; genetic and immunologic causes are exposed too. Diagnosis is based in clinical and imaging features, excluding previously other morecommon diseases. Management is divided in three axes: treatment of acute event, disease-modifying therapies and symptomatic therapy. The treatment of acute events is usually with corticoid therapy, for disease-modifying therapy the first election are immunomodulatory drugs, such as Glatiramer Acetate and for symptomatic therapy is necessary a mul t i di sci pl i nary approach. Long-termprognosis is variable and depends of treatment response. [Farfán JD, Espitia OM. Pediatric multiple sclerosis: pathophysiology, diagnosis, and management. MedUNAB 2011; 14:167-179].

CD24 as a genetic modifier of disease progression in multiple sclerosis in Argentinean patients.

INTRODUCTION: Previous reports have shown that CD24 gene polymorphisms have an important role in the risk of development and progression of multiple sclerosis (MS). OBJECTIVE: To investigate the association between P226 polymorphisms (T/C), P1056 (A/G), P1527 (TG/del) and P1626 (A/G) of the CD24 gene and MS, comparing allele and genotype frequencies of patients versus controls. MATERIALS AND METHODS: We analyzed DNA samples from 102 MS patients and from 205 unrelated healthy individuals. DNA was extracted from peripheral blood and polymorphic regions were amplified by nested PCR. Genotyping was performed by restriction fragments length polymorphisms. Time from disease onset to reach EDSS 6 and time to conversion to secondary progressive phase (SP) were used as variables of survival as well as percentage of patients that reached those endpoints. We used the log Rank test for data comparison (significant p≤0.05). RESULTS: We found no differences between cases and controls in frequency of polymorphisms at the CD24 gene. 44.6% of patients with the AA genotype (P1626) reached an EDSS 6 vs 16% of patients with other genotypes (p<0.001, HR 3.2, 95% CI 1.4 to 7.4). 45.8% of patients with the AA genotype reached SPMS vs 16.7% without this genotype (p<0.001, HR 3.4, 95% CI 1.5 to 7.8). CONCLUSIONS: This study showed a strong association between the presence of AA genotype in the 1626 polymorphism of the CD24 gene and the risk of disease progression in MS patients.

Tasa de mortalidad de la esclerosis múltiple en Venezuela según edad y género / Mortality rate of multiple sclerosis in Venezuela according to age and gender

La esclerosis múltiple o esclerosis en placa, es una enfermedad desmielinizante del sistema nervioso central, de etiología desconocida. Ocurre en aproximadamente 0,1 por ciento de la población de Europa central. Se presenta en adultos jóvenes entre los 20-40 años de edad y es más frecuente en las hembras, con una relación de 2:1. El número de casos es menor en la raza negra y en los grupos asiáticos. En el presente estudio se determinó la tasa de mortalidad de la esclerosis múltiple en Venezuela, según género y edad entre los años 1988 y 1998. La información del número de defunciones se obtuvo de los Anuarios Epidemiológicos del Ministerio de Salud y Desarrollo Social. Nuestros resultados están de acuerdo con lo observado en la población mundial, en lo que respecta a una mayor tasa de mortalidad en las hembras y a inicio entre 11 a 19 años de edad.

Motor neuron disease and multiple sclerosis among immigrants to England from the Indian subcontinent, the Caribbean, and east and west Africa

The mortality from motor neuron disease (MND) and multiple sclerosis (MS) was studied among immigrants to England and Wales from the Indian subcontinent, the Caribbean, and East and West Africa during the 10 years 1979-88. The MND mortality among ethnic Asian males was only half and for females one fifth of that expected at English rates. MND mortality in Caribbean immigrants was somewhat lower than expected. White immigrants from the Indian subcontinent had the expected MND mortality. MS mortality was low among Asian, West Indian, and African immigrants. This study is evidence that MND mortality is not the same in all ethnic groups (AU)

World-wide trends in multiple sclerosis mortality.

Mortality attributed to multiple sclerosis (MS) was analyzed for 35 countries around the world using World Health Organization reports from 1965 to 1984. Trends were plotted for the United States and Canada, for various regions of Europe, Israel, South America, Asia, Australia and some Pacific countries. In general, MS mortality has declined steadily in North America and most of western Europe as well as in countries with a western culture but has remained stable or increased in eastern and northern Europe. Although several Mediterranean countries reported a recent increased frequency of MS, it was not (yet?) evident in mortality data. Intensive prospective surveillance of MS frequency trends in selected regions of the world will determine the validity of the trends based on mortality.

Multiple sclerosis and childhood infections.

Migration from an area where MS is common to an area where it is rare (and vice versa) affects the risk of MS, provided migration occurs in childhood. A childhood infection might explain this effect. Therefore, the age pattern of infectious diseases in different regions was examined. A higher proportion of children showed positive titers to many viral diseases early in life in areas where MS is rare compared with those where MS is common. Also, mortality rates from a variety of infectious diseases correlated negatively with the MS mortality. Thus, infection early in life may "protect" against MS, and conversely, later infection, when the immune system has partially matured, may increase risk. MS may be an age-dependent, host-immune response to childhood infection.

Multiple sclerosis among immigrants in Greater London.

Among immigrants resident in greater London from Europe, Ireland, the USSR, the old Commonwealth countries of Australia, Canada, and New Zealand, North and South America, Egypt, Turkey, and Iran the incidence of admission to hospital for probable multiple sclerosis (MS) between 1960 and 1972 was high or moderately high. The incidence was the same order as that found in those born in the United Kingdom. Immigrants from India, Pakistan, and other Asian countries and from new Commonwealth Africa and America, which includes the West Indies, had a low incidence of hospital admission for MS. Immigrants from countries where the risk of MS is low whose parents were born in Europe had a reduced incidence of admission to hospital but not the very low incidence found in those parents were also born in these countries. Emigrating to England from low risk parts of the world did not seem to increase the risk of developing MS.