Comparative study of cutaneous adverse reactions induced by a proteasome inhibitor with skin eruptions in Nakajo-Nishimura syndrome

Nakajo-Nishimura syndrome (NNS) is an autosomal recessively-inherited autoinflammatory disorder that onsets in infancy with pernio-like rashes, nodular skin eruptions, myositis and remittent fever, and gradually develops into partial lipodystrophy and contracture of the joints. This disease is caused by a unique mutation of the PSMB8 gene, which not only impairs chymotrypsin-like activity of the encoding beta5i subunit, but also causes severe defects in overall proteasome activities due to disturbing formation of the immunoproteasome complex. Bortezomib, a molecular target drug to inhibit proteasome complex, has been applied to the treatment of multiple myeloma by its antitumor effect. Whereas, a number of cases with cutaneous adverse events have been reported. The most common clinical appearance of these cutaneous lesions is erythematous nodules or papules, which histopathologically shows perivascular dermatitis infiltrated with lymphocytes and some neutrophils. However, more extensive lesions with interface, perivascular, periadnexal, or interstitial dermatitis accompanied with infiltration of neutrophils like Sweet's syndrome or pyoderma gangrenosum have been observed in some cases. These reactions are known to be a biomarker for antitumor efficacy of bortezomib. To comparatively study the genetically-defined and drug-induced proteasome disabilities, we collected skin biopsy specimens of Japanese cases with bortezomib-induced cutaneous adverse reactions, and their immunohistochemical features on accumulation of ubiquitin and infiltrating cells were compared with those of the cutaneous eruptions in NNS. Furthermore, we searched for a PSMB8 mutation in the cases with bortezomib-induced cutaneous adverse reactions, using genomic DNA extracted from the skin specimens.