Punto de encuento Foto cedida por Montserrat Villanueva Del Moral https://www.flickr.com/photos/mon06/

Fiebre Mediterránea Familiar

¿En qué consiste la enfermedad?

Es una enfermedad genética, rara (afecta a menos de 5/10000 habitantes en Europa) y constituye el síndrome febril periódico más frecuente entre los síndromes autoinflamatorios. Es una enfermedad crónica en la que tenemos alterado el mecanismo que la regula la inflamación. Es como si nuestros órganos pensaran que están siendo agredidos y se produce una inflamación sin haber infección ni agresión por virus, bacterias, etc… Esta inflamación provoca los síntomas típicos incluyendo elevación de las “proteínas” de la inflamación en la sangre. Esto ocurre cíclicamente y la inflamación es de mayor o menor intensidad. Tanto es así que muchas veces pasa inadvertida y otras veces los dolores son tan intensos que a muchos les han operado de apendicitis o de vesícula por los dolores abdominales tan fuertes que han tenido.

Además existen tres tipos de FMF:

  1. FMF tipo I: Es la enfermedad típica que cursa con síntomas: Cortos episodios recurrentes de inflamación y serositis, incluyendo fiebre, peritonitis, sinovitis, pleuritis y, en menor proporción, episodios de pericarditis, orquitis o meningitis.
  2. FMF tipo II: Asíntomática. Sólo se descubre mediante un estudio genético positivo o cuando el enfermo ha desarrollado amiloidosis, la complicación más grave de la FMF, como primera manifestación clínica de la enfermedad en un individuo que no refiere otros síntomas.
  3. FMF tipo III: Se refiere al estado de las personas heterocigotos “silenciosos” u homocigotos compuestos, en el que dos mutaciones MEFV se detectan sin signos o síntomas de la FMF ni de amiloidosis AA.

En los últimos años se ha observado que también los portadores de mutaciones heterocigotas pueden sufrir de una forma leve o incompleta de FMF, llamada “enfermedad similar a FMF”. La influencia de otros modificadores de genes y / o factores ambientales pueden contribuir a la penetrancia variable y a la variabilidad fenotípica de la FMF.

Esta enfermedad es, también, conocida como: Enfermedad Periódica, Peritonitis Paroxística benigna, Poliserositis Paroxística Benigna, Síndrome Armenio, Poliserositis Paroxística Familiar, FMF, MEF, Síndrome Periódico Amiloide, Síndrome de Peritonitis Periódica, Poliserositis Recurrente, Enfermedad Periódica de Reimann, Síndrome de Reimann, Síndrome de Siegel-Cattan-Mamou, Trastorno Periódico, etc…

Los diversos nombres que se le han dado a la enfermedad han generado confusión respecto a su cuadro clínico. Ninguno, incluido el de Fiebre Mediterránea Familiar es totalmente satisfactorio. Sin embargo, éste último es el que habitualmente se utiliza con mayor frecuencia.

Resulta indispensable diferenciar los cuadros clínicos de éstos enfermos de cuadros abdominales infecciosos, como apendicitis, pancreatitis u otros para no someterlos a tratamientos quirúrgicos inútiles.

Es interesante decir que los enfermos no tienen por qué experimentar todos los síntomas y varían mucho de uno a otro. Además pueden experimentar tipos diferentes de crisis durante toda su vida.

La edad de aparición de los síntomas es, en un 90 % de los casos, alrededor de los 20 años pero se han descrito casos en la lactancia y la niñez.

La consanguinidad en las familias de los afectados es un factor a tener en cuenta. Sin embargo, a veces, no se conoce con exactitud porque muchos enfermos provienen de grupos étnicos con gr1375917_470271519757864_493124858_nan endogamia. Afecta predominantemente a individuos con antepasados provenientes de los países de la cuenca mediterránea (España, Italia, Francia, etc…) de ahí su nombre. Hablamos de judíos, armenios, árabes, etc… pero puede afectar a todo tipo de personas de todos los países debido a las migraciones producidas a lo largo de la historia.

 

¿Cuál es la causa?

La causa es una de las diferentes mutaciones genéticas del brazo corto del cromosoma 16. La más habitual es el gen M694V MEFV en 16p13.3. Este gen alterado (MEFV) produce, en un individuo sano, una proteína que regula la inflamación en los tejidos llamada Pirina o Marenostrina. En nosotros no se fabrica esa proteína correctamente y por ello sufrimos episodios repetitivos de inflamación en los que pueden participar todos los órganos del cuerpo y producir todos los síntomas posibles con relación a la inflamación de ese órgano (artritis en las articulaciones, sarpullido en la piel, dolor abdominal sobre todo localizado en la parte baja derecha y en el lado de hepático, dolor costal, dolores en las plantas de los pies). Los brotes se autolimitan y pueden ir o no acompañados de fiebre. Lo característico de la enfermedad es que es cíclica. Se repite cada cierto número de días invariable si no hay tratamiento y en cada enfermo de forma característica. Aunque las manifestaciones de la enfermedad, son distintas en cada enfermo y también varían a lo largo de su vida (de niño puede tener más dolores abdominales, luego puede pasar periodos de remisión, luego dolores articulares, depresiones,….etc.), todo esto cuando no se trata.

Al ser genética es hereditaria. Por eso es muy importante hacer un estudio familiar de padres y hermanos principalmente, para saber quien es enfermo y quien es portador y actuar en consecuencia. Los patrones de herencia son variables. Antes se creía que era autosómica recesiva (tenían que estar alterados los dos genes) pero también se han descubierto casos en los que con un único gen mutado desarrollan la enfermedad.

Como los síntomas son muy variados, muchos niños antes del diagnóstico son etiquetados de “enfermos psicosomáticos” y tienen que pasar por muchas consultas antes de ser diagnosticados. Es muy importante que el pediatra detecte a tiempo y sospeche esta enfermedad cuanto antes. Es difícil cuando no hay antecedentes familiares o por la rareza de la enfermedad el médico no tiene experiencia y no se puede diagnosticar lo que no se conocfig1e.

¿Qué síntomas provoca?

 

Existen, básicamente, 5 tipos diferentes de crisis:

  1. Crisis febriles aisladas de corta duración (entre 12 y 48 horas). Sin dolor.
  2. Crisis peritoneales (95% de los pacientes) expresadas por: fiebre, dolor abdominal, estreñimiento o diarrea y náuseas.
  3. Artritis – inflamación de las articulaciones (75% de los pacientes) caracterizada por: fiebre, hinchazón de las articulaciones y restricción de su función.
  4. Crisis pleurales manifestadas como dolores en un lado del pecho, (pueden extenderse al otro lado), intensificados con la inspiración (inhalación), respiraciones breves y fiebre (30% de los pacientes).
  5. Otros tipos de crisis, como urticaria, erisipelas y mialgia son mucho menos comunes.
Tabla de síntomas (basada en un artículo del Dr. Daniel Kastner)
Tabla de síntomas (basada en un artículo del Dr. Daniel Kastner)

 

¿Cómo se puede detectar?

__tn_colchique_1Se detecta clínicamente (síntomas y signos), por la respuesta positiva a la colchicina (remite la enfermedad con el tratamiento correcto) y los antecedentes familiares porque, aunque hay una prueba genética, esta puede dar negativa al haber muchas variaciones genéticas aún no estudiadas.

Sin embargo es recomendable una prueba genética para saber si la mutación que se posee es conocida y actuar en función de ello (la enfermedad evoluciona de forma diferente dependiendo de la mutación).

En 1997, el gen causante de la FMF fue identificado y se desarrolló un test sanguíneo para el análisis de las mutaciones. En este test sanguíneo, las mutaciones del gen FMF pueden buscarse, pero debido a dificultades técnicas y a razones genéticas, sólo es posible identificar dos mutaciones en sólo un 60% de los pacientes con FMF. Sin embargo, es necesario luchar por esta prueba, porque dependiendo de la mutación que presente el paciente su enfermedad puede desarrollarse de una forma diferente. Es necesario que cada paciente y cada médico conozca la/s mutación/es que presenta el paciente para poder ser tratado de manera correcta y preventiva. La elaboración de un diagnóstico genético es un tema principal para la investigación.

notaclinica1_tabla1

En el laboratorio de Inmunología del Hospital Clínico de Barcelona se inició una Unidad de diagnostico de Síndromes febriles como la FMF en el año 1998 y desde entonces han realizado el estudio a 375 familias distintas con uno o más miembros afectos de fiebre periódica. En el transcurso de estos últimos años se han ido identificando nuevas enfermedades que presentan una clínica similar a la FMF pero que se producen por la alteración de genes distintos al de la FMF. En éste laboratorio se realiza el estudio de las mutaciones asociadas a los diferentes síndromes hereditarios de fiebre periódica (HPFS) que incluyen FMF, TRAPS, HIDS, Musckle-Wells, PFAPA, Urticaria Familiar Fría, (FCU) y CINCA. En la actualidad, existen distintos tratamientos que son efectivos en algunas de estas enfermedades mientras que en otras no tienen ningún efecto. Por este motivo, es muy importante llegar a un diagnostico lo mas acertado posible para poder iniciar la terapia que mejor combata los síntomas de cada paciente. Para ello, el estudio genético puede ayudar a precisar el diagnostico en caso de sospecha clínica y confirmar el tipo de síndrome que padece. Es cierto que en algunos casos no es posible llegar a un diagnostico genético de la enfermedad exacta. Actualmente es posible diagnosticar genéticamente el 55% de los pacientes con síndromes de fiebre periódica que llegan para estudio. A este grupo de pacientes con un diagnostico genético claro se les puede iniciar el tratamiento mas adecuado para solucionar sus síntomas teniendo en cuenta la alteración responsable de su clínica. En el resto de pacientes en los que actualmente, no se puede detectar la base genética de su enfermedad se puede iniciar un proceso de tratamiento con los diversos fármacos que disponemos actualmente para tratar los síndromes de fiebre periódica y que van desde la Colchicina hasta las nuevas terapias biológicas de ultima generación.En estos casos se debe ajustar el tratamiento según la respuesta de cada paciente.

A continuación adjuntamos los detalles de dicha unidad de diagnóstico y los médicos responsables con los que pueden ponerse en contacto:

CENTRO DE REFERENCIA PARA EL ESTUDIO DE FMF EN ESPAÑA

Unidad de Diagnostico de Enfermedades Autoinflamatorias y Síndromes Hereditarios de Fiebre Periódica.

Dr. Juan Ignacio Arostegui Dr. Jordi Yagüe

Telf del Laboratorio de Inmunogenética 93 2275400 - ext 2195 o 2155

Telf del Servicio de Inmunología 93 2275490

e-mail: jyague@clinic.ub.es

¿Existe un tratamiento efectivo?

El tratamiento más habitual es la colchicina que previene las crisis y la aparición de amiloidosis. El pronóstico con este medicamento es bueno. Este tratamiento es el único que previene la amiloidosis (complicación grave de la enfermedad) y es muy seguro, con pocos efectos secundarios (diarrea,disminución de los glóbulos rojos, blancos, debilidad muscular, caída del cabello, pérdida de apetito), pero hay gente que no la tolera a la dosis óptima para controlar la enfermedad. Por eso es tan importante, la investigación de nuevos medicamentos para estas enfermedades raras (“medicamentos huérfanos”) y muchas veces a los laboratorios no les interesa investigar en ellas, porque no salen beneficiados económicamente. Por eso se necesita el apoyo del gobierno e instituciones. Aún así existen sustitutos para la colchicina (Anakinra, Infliximab, Interferon alfa, etc…) debido a que algunos enfermos desarrollan efectos secundarios, haciendo que la terapia con colchicina sea imposible. Otros no la toman y la amiloidosis, que puede ser mortal, puede desarrollarse. Algunos enfermos experimentan mejoría con inyecciones de un medicamento alternativo que frena las crisis pero no la amiloidosis.

¿Qué consecuencias tiene en la vida del enfermo?

El principal problema es llegar a un diagnóstico porque es una enfermedad difícil de diagnosticar y hasta que se llega a él, el niño/adulto, sufre mucho; de incomprensión, porque esta enfermo y sin el tratamiento, los brotes hacen perder jornadas de clase/trabajo, el paciente ha de sufrir dolores y si no se diagnóstica y trata a tiempo, se desarrolla la temida amiloidosis.

Es importante concienciar al niño una vez diagnosticado, de que tiene una enfermedad para toda la vida. Pero con el tratamiento correcto, que no debe abandonar nunca (la colchicina), con una buena alimentación (rica en frutas y verduras, pobre en grasas) y ejercicio físico adecuado, puede hacer una vida normal, con una supervivencia igual que el resto, puede estudiar, viajar, casarse, etc… No estigmatizar al niño, pero si hacerle comprender la necesidad de llevar un control médico y una medicación de por vida, cuidarse de no realizar sobreesfuerzos físicos y de no exponerse al frío/calor excesivo, o a demasiado estrés emocional. La tranquilidad es muy importante. Puede necesitar ayuda psicológica y apoyo emocional en muchos momentos de su vida para sobrellevar mejor su enfermedad.Respecto al adulto; si quiere tener hijos, puede acudir al consejo genético, para que no lo trasmita a su descendencia.

Respecto a la amiloidosis; Es la complicación más temida en la FMF.En lenguaje coloquial: Amiloidosis es un término aplicado a un grupo de enfermedades metabólicas, en las cuales el amiloide (una glicoproteína fibrosa parecida al almidón) se acumula en los tejidos del organismo. La acumulación excesiva de amiloide en un órgano hace que este órgano afectado funcione incorrectamente. El acúmulo puede ser localizado y generalizado o sistémico. Existen varios sistemas para clasificar las diversas formas de la enfermedad; el más utilizado se basa en las características químicas de las fibrillas (estructuras fibrilares dentro del amiloide): 1.- Amiloidosis primaria: es la forma más común de amiloidosis también llamada, de cadena ligera (en inglés: forma AL). Esta forma clínica puede darse independientemente de cualquier otra enfermedad, o asociada a múltiples tumores, especialmente los mielomas (tumores de la médula ósea). Esta forma de enfermedad afecta generalmente a la lengua, la glándula tiroides, el tracto intestinal, el hígado y el bazo. La afectación cardiaca puede dar lugar a insuficiencia cardiaca congestiva. 2.- Amiloidosis secundaria, amiloidosis asociada (en inglés: forma AA), se descubre por lo general durante el curso de una enfermedad inflamatoria crónica, tal como la artritis reumatoide, de infecciones crónicas o de la fiebre mediterránea familiar. En la amiloidosis secundaria se suele afectar el normal funcionamiento de riñones, hígado y bazo y con menor frecuencia se afectan glándulas suprarrenales, ganglios linfáticos y sistema vascular.

La inflamación de la piel que ocurre tras las inyecciones repetidas para el tratamiento de algunas enfermedades inflamatorias parece inducir una amiloidosis secundaria. El fracaso renal, se manifiesta como un síndrome nefrótico (hinchazón por retención de líquido generalizada, pérdida de proteínas abundante por orina y disminución de las proteínas sanguíneas) y es el responsable de la evolución fatal (evolución hacia la muerte) en este tipo de amiloidosis. Otra forma de amiloidosis que se asocia comúnmente al envejecimiento, afecta por lo general al corazón. Esta forma de amiloidosis también puede afectar al páncreas y al cerebro. La amiloidosis asociada a la hemodiálisis (un procedimiento para eliminar las impurezas o residuos de la sangre cuando los riñones no funcionan correctamente y no pueden filtrar las mismas), se presenta en los pacientes que han sido tratados durante mucho tiempo con hemodiálisis. La amiloidosis familiar se presenta asociada a una serie de enfermedades transmitidas genéticamente que afectan típicamente al riñón, al corazón, a la piel y a otras áreas del organismo. Con cada crisis hay más probabilidades de que esto ocurra. Sin el tratamiento y la dosis correcta de colchicina la mayor parte de los enfermos acaban desarrollando fallo renal antes de los 40 años, además de otras complicaciones. Por eso la información al paciente sobre su enfermedad y cómo le salva la vida el tratamiento adecuado resulta tan importante desde la primera crisis.

(Basado en un texto de los Drs. M. Izquierdo, A. Avellaneda)

 ¿Hay asociaciones de apoyo a los pacientes?

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La había pero tuvimos que disolvernos al no haber suficientes personas en la Junta Directiva. Sin embargo nos hemos constituído como foro de enfermos en internet y constituimos una comunidad en diferentes redes sociales. Nuestros objetivos como foro son, practicamente los mismos, que teníamos en nuestra asociación:

  1. Dar a conocer la enfermedad
  2. Acoger, informar y orientar a los enfermos y personal sanitario que nos lo solicita.
  3. Procurar ser un grupo de apoyo, tanto para los familiares, como para los enfermos.

Estamos en permanente contacto con la Unidad de Diagnostico de Enfermedades Autoinflamatorias y Síndromes Hereditarios de Fiebre Periódica del Hospital Clínico de Barcelona. Dicha unidad se encuentra a su vez en permanente contacto con las dos vías de investigación internacionales sobre las Enfermedades Autoinflamatorias y Síndromes Hereditarios de Fiebre Periódica.

Consideramos que la investigación que se hace de esta enfermedad es, claramente insuficiente, debido a motivos económicos. Para investigar es necesario el dinero y muchas veces no se invierte lo suficiente en las enfermedades poco frecuentes como la Fiebre Mediterránea Familiar ya que, muy a menudo, a los laboratorios, en general, no les interesa investigar en ellas, porque no salen beneficiados económicamente. Por eso se necesita el apoyo del gobierno e instituciones.

Respecto a la comunicación de la Fiebre Mediterránea Familiar es también insuficiente. Esto es debido a que, al ser una enfermedad rara, es poco conocida y es fácil pensar erróneamente que el público al que se dirige la información de la enfermedad es minoritario también. Nada más lejos de la realidad. Lo cierto es que la información se puede dirigir al personal sanitario, al público en general (no hay que olvidar que muchos enfermos están mal diagnosticados), a los laboratorios farmacéuticos, políticos… En fin, el campo es infinitamente grande. Lo importante es que se conozca para que la gente se implique.

¿Qué cambios reclaman a las autoridades sanitarias?

  1. Nos gustaría que se invirtiese más en investigación de este tipo de enfermedades. En concreto sobre la Fiebre Mediterránea Familiar pero también sobre el resto de Enfermedades Autoinflamatorias y Síndromes Hereditarios de Fiebre Periódica.
  1. Reclamamos más formación del personal sanitario sobre Enfermedades Autoinflamatorias y Síndromes Hereditarios de Fiebre Periódica.
  1. Muchos de los enfermos de Enfermedades Autoinflamatorias y Síndromes Hereditarios de Fiebre Periódica entre los que se encuentra la FMF se encuentran en situación crítica ya que no responden al tratamiento y su calidad de vida es pésima, pero no pueden pedir minusvalías por este tipo de enfermedades porque no se contemplan. Esto es algo que debe cambiar con urgencia para mejorar la calidad de vida de estos enfermos.

¿Qué carencias que existen en el sistema nacional de salud que hayáis detectado?

Hay enfermos que, cuando acuden al médico de familia o al especialista, éste no sabe lo que es la Fiebre Mediterránea Familiar. Por esto creemos que sería deseable una mayor formación de estos profesionales acerca de las Enfermedades Autoinflamatorias y Síndromes Hereditarios de Fiebre Periódica. Pensamos que esto contribuirá a diagnosticar a los enfermos y darles tratamiento mucho antes. Lo cual a prevenir las complicaciones de la enfermedad.

colchicine

En estos momentos tenemos el problema del desabastecimiento, en las farmacias, de COLCHIMAX. En España la colchicina es comercializada por un sólo laboratorio en dos presentaciones: COLCHICINA SEID y COLCHIMAX. Las principales diferencias entre ambas presentaciones es que COLCHICINA SEID contiene lactosa como excipiente y COLCHIMAX no tiene lactosa y está compuesto por la colchicina y un anticolinérgico: Dicicloverina. Muchos enfermos de Fiebre Mediterránea Familiar son intolerantes a la lactosa por lo que no pueden tomar COLCHICINA SEID. Sólo pueden tomar COLCHIMAX. En principio y según la Agencia Española del Medicamento, el fin del desabastecimiento de COLCHIMAX, está previsto para el 16 de mayo de 2014 pero si no se soluciona para esa fecha y tarda en solucionarse, muchos de los enfermos estarán en serias dificultades.

 

Este artículo ha sido escrito por Monica Tortosa (Ex Secretaría de la antigua asociación de enfermos de Fiebre Mediterránea Familiar de España. Hoy Foro/Comunidad on line de enfermos de Fiebre Mediterránea Familiar en Español) como colaboración con Raras pero no invisibles. Podéis seguirlos en http://fmf.portalsolidario.net

fiebre_mediterranea_familiar@yahoo.es

También disponen de los teléfonos de contacto:

96 325 31 16 /  645 378 068 / 658 078 630 / 692 872 820 / 618 126 822

Disponen también de un grupo de Yahoo que constituye nuestro primer punto de encuentro en la red para intercambiar información, mensajes, opiniones, noticias, etc. La dirección es: http://es.groups.yahoo.com/group/fiebre_mediterranea_familiar

Foto de portada: Montserrat Villanueva Del Moral “Punto de Encuentro” cedida para este artículo como colaboración con Raras pero no invisibles.  http://www.flickr.com/photos/mon06/

 

 

 

Enlaces de interés

1)       Página de la comunidad de enfermos de FMF: http://fmf.portalsolidario.net/

2)       Foro / Grupo español de enfermos de FMF en Yahoo: https://es.groups.yahoo.com/neo/groups/fiebre_mediterranea_familiar/

3)       Foro / Grupo argentino de enfermos de FMF en Yahoo: https://ar.groups.yahoo.com/neo/groups/fmfargentina/

4)       Foro / Grupo en inglés de enfermos de FMF en Yahoo: https://groups.yahoo.com/neo/groups/fmf_support/

5)       Foro / Grupo en italiano de enfermos de FMF en Yahoo: https://it.groups.yahoo.com/neo/groups/gruppo_italiano_fmf/

6)       Foro / Grupo en francés de enfermos de FMF en Yahoo: https://fr.groups.yahoo.com/neo/groups/mpfmf/

7)       Fundación sobre Enfermedades Raras en Latinoamérica: http://www.fundaciongeiser.org/

8)       Información sobre FMF a nivel pediátrico: http://www.printo.it/pediatric-rheumatology/information/Spagna/14.htm

9)       Comunidad internacional de enfermos de FMF: https://www.rareconnect.org/es/community/fiebre-mediterranea-familiar

10)   Página de la Asociación francesa de FMF: http://www.affmf.org/

11)   Página de la Asociación italiana de FMF: http://www.febbriperiodiche.it/

12)   Página de la Asociación canadiense de FMF: http://www.fmfmontreal.org/

13)   Página de la Asociación turca de FMF: http://aileviakdenizatesi.com/

14)   FEDER: Federación de Asociaciones de Enfermedades Raras: http://www.enfermedades-raras.org/

15)   Investigación genética de enfermedades autoinflamatorias. Equipo europeo: http://www.igh.cnrs.fr/equip/dupont-touitou/

16)   Grupo en español en Facebook sobre FMF: https://www.facebook.com/groups/1381388728755706/

17)   Página en español en Facebook sobre FMF: https://www.facebook.com/fmfspain

18)   Web secundaria de la antigua asociación española FMF (El correo ya no sirve): http://fmf.org.es/

19)   Información sobre Síndromes autoinflamatorios del Hospital Clínico de Barcelona: http://www.autoinflamatorias.com/

 

 

2.755 pensamientos sobre “Fiebre Mediterránea Familiar”

  1. Gracias por la información, yo estoy en el grupo de FMF, gracias al cual y fundamentalmente a Mónica, he recibido esta información.
    Me gustaría que se insista en la necesidad de incluirse en el registro de enfermedades raras, para que realmente se conozca el volumen de gente que la padecemos y conseguir más investigación sobre la enfermedad.
    Gracias.,

    1. Soy Laura y padezco de FMF desde hace aproximadamente 4 años, el sentimiento de incomprensión es muy grande. Lucho por tener calidad de vida pero no es fácil porque el sistema parece que no acepta ni reconoce ésta enfermedad discapacitante y que me limita en mi vida diaria. Ahora estoy en un punto que ando perdida, desesperada por no saber que más puedo hacer… pero mi lucha continúa.

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