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Distinct Metabolite Profile in Pemphigus Vulgaris

      Because of their high prevalence, (co)morbidity, still unsatisfactory treatment options, and imposed economic impact, chronic inflammatory skin diseases pose a major medical burden (
      • Lamberts A.
      • Yale M.
      • Grando S.A.
      • Horváth B.
      • Zillikens D.
      • Jonkman M.F.
      Unmet needs in pemphigoid diseases: an international survey amongst patients, clinicians and researchers.
      ). In the past, multidimensional datasets unraveled novel pathways of disease pathogenesis and have led to the discovery of innovative therapeutic targets, exemplified by the discovery of Jak/nonreceptor tyrosine protein kinase 2 inhibitors for the treatment of psoriasis and alopecia areata (
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • Knight J.
      • Weale M.E.
      • et al.
      Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • Cerise J.E.
      • Higgins C.A.
      • Gong W.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      ). In addition to genetics and transcriptomics, analysis of metabolites revealed the differences between patients with chronic inflammatory diseases and healthy controls, which may translate into therapeutic consequences (
      • Saibeni S.
      • Cattaneo M.
      • Vecchi M.
      • Zighetti M.L.
      • Lecchi A.
      • Lombardi R.
      • et al.
      Low vitamin B(6) plasma levels, a risk factor for thrombosis, in inflammatory bowel disease: role of inflammation and correlation with acute phase reactants.
      ;
      • Selhub J.
      • Byun A.
      • Liu Z.
      • Mason J.B.
      • Bronson R.T.
      • Crott J.W.
      Dietary vitamin B6 intake modulates colonic inflammation in the IL10-/- model of inflammatory bowel disease.
      ). Pemphigus vulgaris (PV) is an orphan but severe autoimmune skin blistering disease that is clinically characterized by mucocutaneous blistering and erosions. The standard of care is immunosuppression; however, approximately 20% of patients do not achieve remission despite vigorous immunosuppression, and relapses are frequent (
      • Schmidt E.
      • Kasperkiewicz M.
      • Joly P.
      ). In contrast to common chronic inflammatory skin diseases, a limited number of multidimensional data are available for PV. Previous studies showed associations with the HLA locus as well as a few associated genes outside the HLA (
      • Olbrich M.
      • Künstner A.
      • Witte M.
      • Busch H.
      • Fähnrich A.
      Genetics and omics analysis of autoimmune skin blistering diseases.
      ). Transcriptomics showed unique profiles of autoreactive B cells contrasted to those of nonautoreactive B cells (
      • Hébert V.
      • Petit M.
      • Maho-Vaillant M.
      • Golinski M.L.
      • Riou G.
      • Derambure C.
      • et al.
      Modifications of the transcriptomic profile of autoreactive B cells from pemphigus patients after treatment with rituximab or a standard corticosteroid regimen.
      ). Global peripheral blood gene expression showed unique signatures in patients with pemphigus than in healthy controls (
      • Dey-Rao R.
      • Seiffert-Sinha K.
      • Sinha A.A.
      Genome-wide expression analysis suggests unique disease-promoting and disease-preventing signatures in pemphigus vulgaris.
      ). However, these insights have not been translated into diagnostic or therapeutic use. To contribute to the molecular understanding of pemphigus, we performed a longitudinal analysis of the metabolome and lipidome of patients with pemphigus and controls because these techniques allow us to capture the metabolites from the persons’ own metabolism and from the environment, such as diet and microbiota, which have a significant impact on the pathogenesis of chronic inflammatory diseases (
      • Vorobyev A.
      • Gupta Y.
      • Sezin T.
      • Koga H.
      • Bartsch Y.C.
      • Belheouane M.
      • et al.
      Gene-diet interactions associated with complex trait variation in an advanced intercross outbred mouse line.
      ).

      Abbreviation:

      PV (pemphigus vulgaris)
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