Necrobiotic xanthogranuloma developing in a patient with diffuse normolipemic plane xanthoma: association of two monoclonal gammopathy‐related disorders

Lopez‐Trujillo, Emilio; Pedro, Carme; March-Rodríguez, Álvaro; Pujol, Ramón M.

doi:10.1111/ajd.13198

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“…There have been conjectures, including the presence of qualitatively different lipoproteins at normal plasma lipid concentrations; increased extravasation of lipids (increased vascular permeability, increased local circulation, chronic inflammation); lipid synthesis in situ and their deposition; and dysfunction of the reverse cholesterol transport ( 6 ). In addition, as xanthoma is accompanied by monoclonal gammopathy in some patients, there is a view that IgG antibodies may participate in the formation of xanthoma by promoting the phagocytosis of LDL by macrophages, which can also explain why some xanthoma patients have normal blood lipid levels ( 3 , 30 , 31 ). Smith described a case of DNPX associated with multiple myeloma, where glucocorticoid therapy relieved IgG proteinemia and the whole-body skin lesions significantly improved ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Topical Simvastatin Improves Lesions of Diffuse Normolipemic Plane Xanthoma by Inhibiting Foam Cell Pyroptosis

et al. 2022

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Xanthoma pathogenesis is speculated to be associated with oxidized low-density lipoprotein (ox-LDL) deposition, although this remains unclear. Most patients with diffuse plane xanthomas present elevated blood lipid levels, and they benefit from treatment with oral lipid-lowering agents. However, there is no available treatment for diffuse normolipemic plane xanthoma (DNPX). In this study, for the first time, we used a topical simvastatin ointment to treat DNPX in three pediatric patients and observed favorable results. Immunofluorescence staining showed that the pyroptotic pathway was significantly attenuated after topical simvastatin application on the skin lesions of the patients. As ox-LDL deposition was observed in the lesions, we used ox-LDL to build a foam cell model in vitro. In the ox-LDL-induced foam cell formation, simvastatin consistently inhibited pyroptotic activation and inflammation in the macrophages. Additionally, the overexpression of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) or 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), the known target of statins, reversed the effects of simvastatin. Moreover, gasdermin D (GSDMD) or HMGCR knockdown inhibited ox-LDL-induced pyroptosis. Furthermore, the immunoprecipitation results confirmed the interaction between NLRP3 and HMGCR, and this interaction was inhibited by simvastatin. In conclusion, we demonstrated that topical application of simvastatin ointment might be a promising treatment for DNPX skin lesions and that this therapeutic effect may be related to pyroptosis inhibition via HMGCR inhibition in foam cells. Moreover, xanthoma pathogenesis might be associated with ox-LDL deposition and inflammation.

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