Lupus Eritematoso Sistémico

Epidemiología y Etiología

Epidemiología

• Prevalencia en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum Estados Unidos:
  • Total: 20–150 por 100 000
  • Mujeres: 100–400 por 100 000
  • Lupus eritematoso sistémico (LES) pediátrico: aproximadamente 2,5 por 100 000
• Más prevalente en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum personas de ascendencia afroamericana o asiática
• Más común en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum áreas urbanas
• 10 veces más común en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum mujeres que en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum hombres (sin preferencia de género en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el lupus inducido por medicamentos)
• Edad pico de inicio:
  • Adultos: 18–55 años
  • Niños: 9–15 años

Etiología

• Se desconoce la etiología exacta.
• Factores predisponentes:
  • Genéticos:
    • HLA-DR2
    • HLA-DR3
    • Deficiencias congénitas de los LOS Neisseria factores del complemento C1q, C2 y C4
  • Hormonales:
    • Aumento de estrógeno (e.g., anticonceptivos orales, reemplazo hormonal)
    • Testosterona disminuida
    • Hiperprolactinemia
    • Anomalías de la tiroides
  • Ambientales:
    • Tabaquismo
    • Exposición al AL Amyloidosis virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology de Epstein-Barr ( EBV EBV Epstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus, por sus siglas en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum inglés)
    • Exposición a la luz ultravioleta
    • Exposición a la sílice
  • Inducido por medicamentos

Fisiopatología

Se desconoce el mecanismo exacto. Es probable que los LOS Neisseria pacientes tengan una predisposición genética a las células inmunitarias autorreactivas (linfocitos B y T).

• Daño celular debido a un desencadenante ambiental → defectos en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum la apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage y la eliminación de desechos celulares → ↑ exposición a antígenos nucleares (ADN y ARN de células dañadas)
• Las linfocitos T y B autorreactivas se activan → producción de autoanticuerpos:
  • ANA
  • Anticuerpos anti-ADN de doble cadena
  • Anticuerpos anti-Smith
  • Anticuerpos anti-histona
  • Anticuerpos anti-Ro y anti-La
  • Anticuerpos anti-ribonucleoproteína
  • Anticuerpos antifosfolípidos
• Se forman inmunocomplejos anticuerpo-antígeno → endocitosis por linfocitos B y células dendríticas
  • Linfocitos B: activación de los LOS Neisseria receptores tipo Toll en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum los LOS Neisseria endosomas → los LOS Neisseria inmunocomplejos se degradan mediante proteasas → los LOS Neisseria péptidos resultantes se presentan a los LOS Neisseria linfocitos T → activación de los LOS Neisseria linfocitos T → activación adicional de los LOS Neisseria linfocitos B
  • Células dendríticas: liberación de interferón → mayor activación de linfocitos B
• La activación perpetua de las linfocitos T y B da como resultado un ↑ persistente en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum los LOS Neisseria niveles de anticuerpos
• Los LOS Neisseria anticuerpos causan daño a los LOS Neisseria órganos a través de:
  • Depósito de inmunocomplejos (antígeno-anticuerpo) en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum la microvasculatura → activación excesiva del complemento → inflamación
  • Depósito de inmunocomplejos en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum la membrana basal de órganos (e.g., piel, riñones)
  • Interacción directa con antígenos nucleares en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum las superficies celulares → activación del complemento → lesión celular y apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage

Presentación Clínica

La presentación clínica del LES es muy variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables y puede incluir varios sistemas.

General

• Fatiga (síntoma más común)
• Fiebre
• Debilidad
• Pérdida de peso
• Linfadenopatía

Musculoesquelético

• 80%‒90% de los LOS Neisseria casos
• Artritis:
  • Migratoria
  • Simétrica
  • Poliarticular
  • No destructiva
  • Localizaciones comunes:
    • Rodillas
    • Manos
    • Dedos
• Deformidades articulares (raras):
  • Deformidad en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum cuello de cisne:
    • Hiperextensión de la articulación interfalángica proximal
    • Flexión interfalángica distal
  • Desviación cubital
  • Debido a laxitud articular
• Artralgia
• Mialgia

Mucocutáneo

• > 50% de los LOS Neisseria casos
• Fotosensibilidad
• Lupus eritematoso cutáneo agudo:
  • Una erupción puede preceder por meses o años a los LOS Neisseria síntomas sistémicos.
  • Localizado:
    • Erupción malar (“erupción en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum mariposa”)
    • Eritema rojo o morado en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum las mejillas y el puente nasal
    • No afecta los LOS Neisseria pliegues nasolabiales
    • Aparece después de la exposición al AL Amyloidosis sol
  • Generalizado:
    • Lesiones maculopapulares eritematosas
    • Visto en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum la piel expuesta al AL Amyloidosis sol
    • Sitios comunes: superficies extensoras de brazos, manos
    • Puede no afectar los LOS Neisseria nudillos.
• Erupción discoide:
  • Pápulas brillantes y descamativas
  • Tiende a dejar cicatrices
• Alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia no cicatricial
• Úlceras orales o nasales indoloras

Manifestaciones sistémicas

• Renales (> 50% de los LOS Neisseria casos):
  • Nefritis lúpica (de gravedad variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables):
    • Proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children o hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma asintomática
    • Síndrome nefrótico
    • Glomerulonefritis rápidamente progresiva
  • Hipertensión
• Cardíacas:
  • Derrame pericárdico
  • Pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis
  • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis de Libman-Sacks
  • Miocarditis severa
  • Enfermedad de las arterias coronarias
• Vasculares:
  • Fenómeno de Raynaud
  • Tromboembolismo
  • Vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus
• Neuropsiquiátricas:
  • Cefaleas
  • Convulsiones
  • Neuropatías:
    • Neuropatía periférica
    • Neuropatía craneal
    • Neuropatía autonómica
    • Mononeuritis múltiple
  • Accidente cerebrovascular isquémico
  • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis aséptica
  • Síndromes desmielinizantes:
    • Neuritis óptica
    • Mielitis
  • Psicosis
  • Ansiedad
  • Depresión
  • Disfunción cognitiva
• Pulmonares:
  • Pleuritis Pleuritis Pleuritis, also known as pleurisy, is an inflammation of the visceral and parietal layers of the pleural membranes of the lungs. The condition can be primary or secondary and results in sudden, sharp, and intense chest pain on inhalation and exhalation. Pleuritis
  • Derrame pleural
  • Dolor Dolor Inflammation torácico
  • Hipertensión pulmonar
  • Enfermedad pulmonar intersticial:
    • Neumonía intersticial inespecífica
    • Neumonía intersticial típica
  • Hemorragia alveolar difusa
  • Síndrome del pulmón encogido (raro):
    • Disnea progresiva
    • Elevación del diafragma
    • Volúmenes pulmonares disminuidos
    • Patrón restrictivo en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum la prueba de función pulmonar
• Gastrointestinales (40% de los LOS Neisseria casos):
  • Esofagitis
  • Enteropatía perdedora de proteínas
  • Hepatitis
  • Esplenomegalia
  • Pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis aguda
  • Vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus mesentérica
• Hematológicas:
  • Leucopenia (> 50% de los LOS Neisseria casos)
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types:
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types ferropénica
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types hemolítica autoinmune
  • Trombocitopenia

Subtipos

Lupus inducido por medicamentos

• Etiología:
  • Procainamida
  • Hidralazina
  • Isoniazida
  • Quinidina
  • Metildopa
  • Diltiazem Diltiazem A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of calcium ion on membrane functions. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)
  • Sulfasalazina
  • Inhibidores del factor de necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage tumoral ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF), por sus siglas en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum inglés) (e.g., etanercept Etanercept A recombinant version of soluble human tnf receptor fused to an IgG Fc fragment that binds specifically to tumor necrosis factor and inhibits its binding with endogenous tnf receptors. It prevents the inflammatory effect of tnf and is used to treat rheumatoid arthritis; psoriatic arthritis and ankylosing spondylitis. Immunosuppressants, infliximab Infliximab A chimeric monoclonal antibody to tnf-alpha that is used in the treatment of rheumatoid arthritis; ankylosing spondylitis; psoriatic arthritis and Crohn’s disease. Disease-Modifying Antirheumatic Drugs (DMARDs))
• Teorías de la patogénesis:
  • Metabolismo alterado de medicamentos
  • Respuesta alterada a los LOS Neisseria metabolitos de las medicamentos
  • Activación anormal de linfocitos
• Presentación clínica
  • Similar al AL Amyloidosis LES idiopático
  • Generalmente, las manifestaciones cutáneas son menos comunes.
  • Las manifestaciones sistémicas graves son menos frecuentes, pero pueden variar según el medicamento causante.
  • La duración de la exposición al AL Amyloidosis medicamento antes de la aparición puede variar.
• Diagnóstico: asociado a anticuerpos antihistona positivos
• Tratamiento: mejora con la eliminación del medicamento causante

Lupus eritematoso discoide

• Subconjunto del lupus cutáneo crónico
• Presentación clínica:
  • Lesiones cutáneas fotodistribuidas
  • Puede ser localizado o difuso
  • Características:
    • Placas escamosas, eritematosas, violáceas
    • Taponamiento folicular
  • Resulta en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum cicatrización y atrofia
  • La enfermedad sistémica generalmente no está presente.

Lupus neonatal

• Etiología:
  • Transferencia pasiva de autoanticuerpos de la madre al AL Amyloidosis feto
  • Particularmente involucra anticuerpos anti-Ro y anti-La
• Presentación clínica:
  • Cutánea:
    • A menudo se evidencia en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el momento del parto, pero es posible que no se observe hasta haya exposición a la luz ultravioleta
    • Reversible
    • Lesiones anulares eritematosas
    • Ligera atrofia central
    • Márgenes elevados
    • Escamosas
    • Ubicaciones: periorbital Periorbital Orbital and Preseptal Cellulitis, cuero cabelludo, palmas, plantas, región del pañal
  • Cardíaca:
    • Ocurre entre las 18 y 25 semanas de gestación
    • Niveles variables de bloqueo cardíaco auriculoventricular y bradicardia fetal
    • Insuficiencia cardíaca congestiva
    • Miocarditis
    • Dilatación aórtica
  • Otros:
    • Transaminitis Transaminitis Tick-borne Encephalitis Virus
    • Hepatomegalia o hepatitis
    • Citopenias
    • Hidropesía fetal
• Diagnóstico:
  • Anticuerpos anti-Ro y anti-La en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum la madre o el niño
  • Manifestaciones clínicas (mencionadas anteriormente)
• Tratamiento:
  • Prenatal:
    • Controversial
    • Esteroides fluorados: dexametasona, betametasona
    • Beta-agonistas para la frecuencia cardiaca < 50/minuto
    • Parto temprano si la condición general es mala
  • Postnatal:
    • Depende de la gravedad de la afectación cardíaca
    • Observación
    • Marcapasos cardíaco para casos con bloqueo cardíaco completo
    • La erupción generalmente se resolverá sin dejar cicatrices.

Diagnóstico

Prueba de anticuerpos

Ante la sospecha inicial de LES: ANA

• Inespecíficos, pero son la prueba de tamizaje más sensible
• Vistos en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum > 95% de los LOS Neisseria casos
• El patrón de inmunofluorescencia puede ser difuso o moteado.

Si los LOS Neisseria ANA son positivos, se debe evaluar lo siguiente:

• Anticuerpos anti-ADN de doble cadena:
  • Específicos para LES
  • Vistos en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el 70% de los LOS Neisseria casos
  • Se correlacionan con la actividad de la enfermedad
• Anticuerpos anti-Smith:
  • Altamente específicos, pero menos sensibles que los LOS Neisseria anti-ADN de doble cadena
  • Solo vistos en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el 30% de los LOS Neisseria casos
  • No presentes en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el lupus inducido por medicamentos
• Anticuerpos antihistona: positivos en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum lupus inducido por medicamentos
• Anticuerpos antifosfolípidos:
  • Anticoagulante lúpico, anticuerpo anticardiolipina y anticuerpo anti-beta 2-glucoproteína
  • Asociados con eventos trombóticos y aborto espontáneo
• Anti-Ro o anti-La:
  • Vistos en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum 20%‒30% de los LOS Neisseria casos
  • Frecuentemente presentes en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum aquellos con síndrome de Sjögren
  • El anti-Ro está asociado con el lupus neonatal.
• Anticuerpos anti-ribonucleoproteína:
  • Vistos en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el 25% de los LOS Neisseria casos
  • Asociados con enfermedad mixta del tejido conectivo

Estudios de apoyo

• Hemograma:
  • Trombocitopenia
  • Leucopenia
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types → debe evaluarse en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum busca de hemólisis autoinmune:
    • ↑ Lactato deshidrogenasa
    • ↑ Bilirrubina indirecta
    • ↓ Haptoglobina
    • Prueba de Coombs directa positiva
• ↑ Velocidad de eritrosedimentación (VES) y PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR)
• ↓ Niveles de componentes del complemento (C3 y C4):
  • Serán normales en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el lupus inducido por medicamentos
  • Se correlacionan con la actividad de la enfermedad
• Descartar lo siguiente:
  • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus y C
  • Serología de Borrelia Borrelia Borrelia are gram-negative microaerophilic spirochetes. Owing to their small size, they are not easily seen on Gram stain but can be visualized using dark-field microscopy, Giemsa, or Wright stain. Spirochetes are motile and move in a characteristic spinning fashion due to axial filaments in the periplasmic space. Borrelia ( en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum áreas endémicas)
  • EBV EBV Epstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus
• Evaluación de compromiso renal:
  • ↑ Nitrógeno ureico en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum sangre (BUN, por sus siglas en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum inglés) y creatinina
  • Análisis de orina:
    • Proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
    • Hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma
    • Cilindros de eritrocitos
  • ↑ Relación urinaria de proteína:creatinina
  • Se puede considerar la biopsia renal para clasificar la enfermedad y guiar el tratamiento:
    • Clase I: nefritis lúpica mesangial mínima
    • Clase II: nefritis lúpica mesangial proliferativa
    • Clase III: nefritis lúpica focal proliferativa
    • Clase IV: nefritis lúpica difusa segmentaria o difusa global
    • Clase V: nefritis lúpica membranosa
    • Clase VI: nefritis lúpica esclerosante avanzada

Criterios diagnósticos

• Basados en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum los LOS Neisseria criterios de clasificación del European League Against Rheumatisms/American College of Rheumatology (EULAR/ACR) del 2019
• Todos los LOS Neisseria pacientes deben tener un título de ANA > 1:80.
• Una puntuación de ≥ 10 con ≥ 1 hallazgo clínico confirma un diagnóstico de LES.
• Los LOS Neisseria criterios anteriores de ACR (de 1997) requerían 4 de 11 hallazgos.

Mnemotecnia

Para ayudar a recordar algunos criterios, recuerde “SOAP BRAIN MD” ( en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum inglés):

• S – Serositis Serositis Inflammation of a serous membrane. Systemic Lupus Erythematosus (e.g., pleuritis Pleuritis Pleuritis, also known as pleurisy, is an inflammation of the visceral and parietal layers of the pleural membranes of the lungs. The condition can be primary or secondary and results in sudden, sharp, and intense chest pain on inhalation and exhalation. Pleuritis, pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis)
• O – Oral or nasopharyngeal ulcers (úlceras orales o nasofaríngeas; indoloras)
• A – Arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis (artritis)
• P – Photosensitivity Photosensitivity Tetracyclines (fotosensibilidad)
• B – Blood disorders (trastornos de la sangre; e.g., citopenias)
• R – Renal disease (enfermedad renal)
• A – ANA
• I – Immunological disorders (trastornos inmunológicos; e.g., anti-ADN de doble cadena, anti-Smith, antifosfolípido)
• N – Neurological disorders (trastornos neurológicos; e.g., convulsiones, psicosis)
• M – Malar rash Malar Rash Systemic Lupus Erythematosus (erupción malar)
• D – Discoid rash Discoid Rash Systemic Lupus Erythematosus (erupción discoide)

Tratamiento

Como no existe un tratamiento definitivo disponible, el tratamiento está dirigido a controlar los LOS Neisseria brotes agudos, suprimir los LOS Neisseria síntomas y prevenir el daño a los LOS Neisseria órganos.

General

• Educar al AL Amyloidosis paciente sobre la enfermedad.
• Cesar el tabaquismo
• Protección a la luz ultravioleta:
  • Protector solar
  • Evitar los LOS Neisseria medicamentos que causan fotosensibilidad.
  • Evitar broncearse.
• Ejercicio isométrico
• Técnicas de relajación para disminuir el estrés
• Acetaminofén y AINE para controlar el dolor Dolor Inflammation

Tratamiento cutáneo

• Corticosteroides tópicos
• Inhibidores tópicos de la calcineurina
• Hidroxicloroquina

Tratamiento sistémico

• Todos los LOS Neisseria pacientes deben utilizar hidroxicloroquina.
• Síntomas leves a moderados:
  • Dosis bajas de glucocorticoides
  • Se pueden agregar inmunosupresores ahorradores de esteroides:
    • Metotrexato
    • Azatioprina
• Síntomas severos con daño a órganos:
  • Alta dosis de glucocorticoides
  • Agentes inmunosupresores o biológicos:
    • Ciclofosfamida
    • Micofenolato
    • Rituximab Rituximab A murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis. Immunosuppressants
    • Belimumab Belimumab Immunosuppressants (empleado si la enfermedad es resistente a las terapias anteriores)
    • Inhibidores de la ECA o ARA II para la enfermedad renal proteinúrica, a menos que estén contraindicados
    • Manejar las infecciones urinarias recurrentes cuando estén presentes

Prevención de complicaciones

• Profilaxis para la osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
• Vacunas contra la influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza, el virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology del papiloma humano y el neumococo
• Supresión de infecciones recurrentes del tracto urinario
• Debe tratarse la presión arterial para prevenir el daño renal.

Complicaciones y Pronóstico

Nefritis lúpica

• Visto en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el 30%-50% de los LOS Neisseria pacientes con LES
• Debido al AL Amyloidosis depósito subendotelial de inmunocomplejos
• Los LOS Neisseria pacientes generalmente presentan síndromes nefríticos o nefróticos.
• El tratamiento depende de la gravedad de la enfermedad y puede incluir:
  • Tratamiento antihipertensivo/antiproteinúrico:
    • Inhibidores de la enzima convertidora de la angiotensina
    • Antagonistas de los LOS Neisseria receptores de la angiotensina (ARA) II
  • Alta dosis de corticosteroides
  • Inmunosupresores:
    • Azatioprina
    • Micofenolato
    • Tacrolimus Tacrolimus A macrolide isolated from the culture broth of a strain of streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. Immunosuppressants
    • Ciclofosfamida
  • Diálisis

Síndrome antifosfolípido

• El 40% de los LOS Neisseria pacientes con LES son positivos para anticuerpos antifosfolípidos.
• Solo el 20% de los LOS Neisseria pacientes presentan síntomas (trombosis).
• Tratamiento:
  • Anticoagulantes
  • Hidroxicloroquina

Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis de Libman-Sacks

• Una de las presentaciones cardíacas más comunes del LES
• Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis no bacteriana:
  • Deposición de trombos plaquetarios estériles en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum las válvulas cardíacas
  • Afecta comúnmente a las válvulas mitral y aórtica
• Los LOS Neisseria pacientes generalmente presentan:
  • Insuficiencia valvular
  • Insuficiencia cardíaca
  • Embolia
  • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis infecciosa secundaria
• Tratamiento:
  • Tratamiento del LES
  • Anticoagulantes sistémicos
  • Cirugía en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum caso de enfermedad grave

Pronóstico

• La tasa de supervivencia es muy buena con una terapia óptima.
• Supervivencia a los LOS Neisseria 5 años: > 90%
• Causas de muerte más comunes:
  • Enfermedad cardiovascular
  • Infecciones
  • Enfermedad renal terminal
• El mal pronóstico se ha HA Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia asociado con:
  • ↑ Niveles de creatinina sérica y síndrome nefrótico
  • Hipertensión
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, hipoalbuminemia o hipocomplementemia
  • Anticuerpos antifosfolípidos
  • Género masculino
  • Etnia afroamericana
  • Nivel socioeconómico bajo

Mnemotecnia

Para recordar las 3 causas más comunes de muerte en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum LES, recuerde: “ Los LOS Neisseria pacientes con lupus mueren con enrojecimiento en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum las mejillas (Redness In their Cheeks)”.

• R – Renal disease (enfermedad renal)
• I – Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (infecciones)
• C – Cardiovascular disease (enfermedad cardiovascular)

Diagnóstico Diferencial

• Artritis reumatoide: una enfermedad autoinmune que produce inflamación y destrucción de las articulaciones. La artritis reumatoide es típicamente simétrica con sensibilidad e inflamación de las articulaciones de las manos y los LOS Neisseria pies. Las manifestaciones sistémicas pueden incluir síndrome de Sjögren, enfermedad pulmonar intersticial, derrame pleural, pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis, vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus y anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types. Pueden observarse factor reumatoide y anticuerpos antipéptido citrulinado cíclico positivos. El tratamiento es con AINE, medicamentos antirreumáticos modificadores de la enfermedad, esteroides y medicamentos inmunosupresores.
• Enfermedad de Still del adulto: una rara enfermedad inflamatoria sistémica caracterizada por fiebres diarias, artritis y una erupción evanescente de color salmón en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el tronco y las extremidades. La evaluación de laboratorio mostrará leucocitosis, transaminitis Transaminitis Tick-borne Encephalitis Virus, ANA negativos y marcadores inflamatorios elevados. En EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum general, el diagnóstico de la enfermedad de Still del adulto se basa en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum la exclusión. El tratamiento depende de la gravedad de la afección. El tratamiento es con AINE, glucocorticoides, medicamentos antirreumáticos modificadores de la enfermedad y agentes biológicos.
• Enfermedad de Behcet: vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus inflamatoria de pequeños y grandes vasos. Los LOS Neisseria síntomas pueden incluir artritis y úlceras orales y genitales dolorosas. También se observan manifestaciones oculares, neurológicas, gastrointestinales y vasculares. El diagnóstico se basa en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum criterios clínicos y las pruebas características de anticuerpos del LES serán negativa. El tratamiento depende de las manifestaciones clínicas. El tratamiento es con corticoides, medicamentos antirreumáticos modificadores de la enfermedad e inhibidores del TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF).
• Fibromialgia: un trastorno no articular de etiología desconocida que causa dolor Dolor Inflammation generalizado en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum los LOS Neisseria músculos, puntos de inserción de los LOS Neisseria tendones y tejidos blandos. Los LOS Neisseria síntomas asociados incluyen fatiga, rigidez muscular, trastornos cognitivos, depresión y ansiedad. El diagnóstico se basa en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum criterios clínicos. La imagenología y las pruebas de laboratorio serán normales. El tratamiento incluye ejercicio y analgésicos no opioides, y tiene como objetivo mejorar el sueño y reducir el estrés.
• Síndrome de Sjogren: una afección autoinmune e inflamatoria de los LOS Neisseria tejidos glandulares que provoca una disminución de la producción de lágrimas y saliva Saliva The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptyalin. Salivary Glands: Anatomy. Los LOS Neisseria síntomas incluyen ojos y boca secos. Las manifestaciones sistémicas incluyen el fenómeno de Raynaud, neuropatía y vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus cutánea. El diagnóstico se basa en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum los LOS Neisseria síntomas, los LOS Neisseria hallazgos clínicos, la determinación de anticuerpos anti-Ro y anti-La y la biopsia de las glándulas salivales. El tratamiento está dirigido a lograr el alivio sintomático y la terapia inmunosupresora se reserva para los LOS Neisseria síntomas graves.
• Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis: trastorno inflamatorio que causa granulomas Granulomas A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. Sarcoidosis no caseificantes en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum órganos y tejidos. La etiología no está clara y los LOS Neisseria síntomas pueden variar ampliamente. Los LOS Neisseria pacientes pueden desarrollar tos TOS Thoracic outlet syndrome (TOS) is a broad term used for a spectrum of syndromes related to the general region of the thoracic outlet, which involves the compression or irritation of elements of the brachial plexus, subclavian artery, or subclavian vein. Thoracic Outlet Syndrome, disnea, fatiga, fiebre, artritis, eritema nodoso, uveítis, bloqueo cardíaco y manifestaciones neuropsiquiátricas. El diagnóstico se basa en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum los LOS Neisseria hallazgos de la biopsia, ya que la prueba de anticuerpos tiende a ser negativa. El tratamiento es con corticoides.
• Linfoma no Hodgkin: un grupo diverso de neoplasias malignas originadas de linfocitos B, linfocitos T y linfocitos NK. La mayoría de los LOS Neisseria casos involucran los LOS Neisseria ganglios linfáticos. El linfoma no Hodgkin a menudo se presenta con fatiga, fiebre, sudores nocturnos, pérdida de peso, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types y linfadenopatía. Pueden ocurrir otros síntomas en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum pacientes con afectación extraganglionar (e.g., gastrointestinal, SNC). La biopsia de ganglio linfático o de médula ósea es útil en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum el diagnóstico. El tratamiento es principalmente con quimioterapia, inmunoterapia y terapia dirigida.