Erupción, linfadenopatía y nefritis¿siempre es lupus?

Indicaciones terapéuticas

RINVOQ está indicado para el tratamiento de la artritis reumatoide activa de moderada a grave en pacientes adultos con respuesta inadecuada o intolerancia a uno o más fármacos antirreumáticos modificadores de la enfermedad (FAMEs). RINVOQ se puede utilizar en monoterapia o en combinación con metotrexato.

Posología y forma de administración

El tratamiento con upadacitinib debe ser iniciado y supervisado por médicos con experiencia en el diagnóstico y el tratamiento de la artritis reumatoide. Posología La dosis recomendada de upadacitinib es de 15 mg una vez al día. El tratamiento no se debe iniciar en pacientes con un recuento absoluto de linfocitos (RAL) que sea < 500 células/mm3 , un recuento absoluto de neutrófilos (RAN) que sea < 1.000 células/mm3 o con niveles de hemoglobina (Hb) que sean < 8 g/dl (ver secciones 4.4 y 4.8). Interrupción de la dosis Si el paciente presenta una infección grave, se debe interrumpir el tratamiento hasta que la infección esté controlada. La interrupción de la administración puede ser necesaria para el control de anomalías analíticas.

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FICHA TÉCNICA

RINVOQ

Abstract

Background

Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.

Methods

We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9–edited zebrafish were used as an in vivo model to assess gene function.

Results

We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet’s syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.

Conclusions

Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.)