Elevated levels of interleukin-9 in the serum of bullous pemphigoid: possible association with the pathogenicity of bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease (sAIBD). In addition to disease causing autoantibodies, several leukocyte subsets, including mast cells and eosinophils, play key roles in mediating skin inflammation. Detailed immunophenotyping and, more recently, the therapeutic effects of interleukin-4 (IL-4) receptor alpha inhibition in BP pointed to a prominent role of T helper 2 (Th2) cells. Among other cell types, IL-9 is expressed by Th2 and mast cells and potentially drives allergic, Th2-dominated inflammation. Although cytokines in BP have been relatively well investigated, the role of IL-9 has remained enigmatic. This study aimed to evaluate the effect of IL-9 in BP. Serum IL-9 levels were significantly elevated in patients with BP and decreased upon induction of remission. Serum IL-9 levels were not elevated in epidermolysis bullosa acquisita, another sAIBD. The time-course analysis using serum sets from four patients with BP revealed that serum IL-9 was a sensitive biomarker of BP. IL-9-positive cells infiltrated dominantly in BP lesions, especially in the blister fluid, and Th9 cells were abundant. Therefore, IL-9 was elevated in the serum and lesions of BP, which could be a biomarker of BP.

Lichen planus-like lesion preceding bullous pemphigoid development after programmed cell death protein-1 inhibitor treatment.

Immune checkpoint inhibitors including programmed cell death protein 1 (PD-1) antibody are used in major breakthrough therapies in cancer, however they cause unique adverse events, termed immune-related adverse events (irAEs). Among the various dermatological irAEs, an autoimmune bullous disease, bullous pemphigoid (BP), the hallmarks of which are circulating autoantibodies to epidermal basement membrane zone (BMZ) including BP180, have been noted. However, the mechanism and timing of autoantibody production in PD-1 inhibition remains unclear. Herein we report the case of a lichen planus (LP)-like lesion in presence of anti-BMZ antibodies, preceding BP in a patient treated with pembrolizumab, a PD-1 antibody. A 72-year-old Japanese woman with a 3-month history (6 cycles) of pembrolizumab was referred to our department for pruritic purple-red papules or plaques. Histological finding revealed LP-like dermatitis. Although pembrolizumab was stopped because of disease progression, she developed edematous erythematous lesions and tense blisters seven weeks later. Based on histopathological findings, direct immunofluorescence (DIF) assay and positive findings on chemiluminescent enzyme immunoassay (CLEIA) for BP180, she was diagnosed with BP and administered oral prednisolone. The blisters and erythemas improved, whereas her respiratory condition worsened and she died 29 days after the development of BP. We performed DIF of formalin-fixed, paraffin-embedded specimens biopsied from the LP-like lesion and revealed IgG deposition at the epidermal BMZ. This finding showed anti-BMZ antibodies had already existed at LP-like lesion preceding development of BP; this suggests that the preceding LP-like lesion induced anti-BMZ antibody production, resulting in the development of BP.