sirolimus and Pemphigus

Topics: Administration, Topical; Adult; Female; Humans; Immunosuppressive Agents; Middle Aged; Mouth Diseases; Mouth Mucosa; Mouthwashes; Pemphigus; Sirolimus; Treatment Failure

Topics: Acute Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Keratinocytes; Male; Middle Aged; Pemphigus; Sirolimus

Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by the presence of IgG autoantibodies against Dsg3. Our aim was to investigate the molecular events implicated in the development and localization of apoptosis and acantholysis in PV. We used a passive transfer mouse model together with immunohistochemical (IHC) techniques and the TUNEL assay, with quantification analysis in the basal layer of the epidermis. The activated signalling molecules analysed and apoptotic cells detected showed an identical localization. Herein, we found for the first time in vivo an increased expression of activated HER receptor isoforms in the basal layer in PV lesions. Besides, we observed the almost total lack of activated Akt compared with a higher level of activated mTOR within the basal cells of the epidermis. Our observations strongly support that the restriction of acantholysis to the basal layer may be due, at least in part, to the selective and increased presence of activated HER receptor isoforms in these cells. After phosphorylation of HER receptor isoforms, intracellular signalling pathways are activated in the basal layer. In addition, the imbalance in Akt/mTOR that takes place in the basal cells may provide intracellular signals necessary for the development of apoptosis and acantholysis.

Topics: Acantholysis; Animals; Apoptosis; Betacellulin; Carrier Proteins; Disease Models, Animal; Enzyme Activation; Epidermal Growth Factor; Epidermis; ErbB Receptors; Erlotinib Hydrochloride; Humans; Immunoglobulin G; Intercellular Signaling Peptides and Proteins; Intradermal Tests; Isoenzymes; Mice; Mice, Inbred C57BL; Pemphigus; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Quinazolines; Sirolimus; src-Family Kinases; TOR Serine-Threonine Kinases; Transforming Growth Factor alpha

Iatrogenic Kaposi's sarcoma (KS) has been reported in patients who use immunosuppressive regimens for the treatment of autoimmune disorders, malignant neoplasms, and organ transplant rejection. However, iatrogenic KS in the setting of pemphigus vulgaris (PV) has been infrequently observed. The conventional treatment strategy for iatrogenic KS has focused on reducing immunosuppression, which carries a poor prognosis owing to a substantial risk for exacerbation of the primary disease.. A 49-year-old man developed KS on his wrist after 2 years of long-term immunosuppressive therapy with prednisone, methotrexate, and dapsone for well-controlled PV. Three months after the substitution of methotrexate with sirolimus, the KS gradually resolved. With the patient on a maintenance regimen of sirolimus, in conjunction with low-dose prednisone and dapsone therapy, KS and PV have remained in remission, without further recurrence, during a 24-month follow-up period.. The present case introduces a novel therapy for this patient population, highlighting the efficacy of sirolimus in treating iatrogenic KS without sacrificing the immunosuppression necessary to maintain control of PV.

Topics: Humans; Iatrogenic Disease; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Pemphigus; Retreatment; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms