Treatment of bullous pemphigoid with dupilumab: Dupilumab exerts its effect by primarily suppressing T-helper 2 cytokines.

We report a patient with bullous pemphigoid (BP) who was successfully treated with dupilumab monotherapy. To clarify the underlying mechanism of this effective treatment, we investigated the dynamics of a variety of cytokine-producing T cells before and after treatment in the circulation and in blister fluid using flow cytometry. The patient was a 72-year-old woman who had a pruritic eruption consisting of erythema and tense blisters on the whole body. The skin biopsy and direct immunofluorescence of the skin were typical for BP. The serum level of anti-BP180NC16a antibodies was 111 U/ml. Flow cytometric analyses revealed that the proportions of circulating interleukin (IL)-4-, IL-13-, and IL-31-producing CD4+ and CD8+ T cells were substantially higher in our BP patient than in healthy subjects. Moreover, IL-4- and IL-13-producing CD4+ and CD8+ T cells were much higher in the blister fluids than in the circulation, whereas IL-31-producing CD4+ and CD8+ T cells were only slightly higher in the blister fluids. The proportions of circulating interferon (IFN)-γ-producing CD4+ and CD8+ T cells in the circulation were slightly lower in the patient than in healthy subjects. There was no significant difference in the circulating IL-17-producing CD4+ and CD8+ T cells between the patient and healthy subjects, although IL-17-producing CD4+ and CD8+ T cells were slightly higher in the blister fluids. Treatment with dupilumab promptly improved the pruritus and skin lesions, and anti-BP180 antibodies became negative. After treatment with dupilumab, the proportions of circulating IL-4- and IL-13-producing CD4+ T cells mainly decreased and IL-17- and IL-31-producing CD4+ T cells slightly decreased. There were no significant differences in the proportions of circulating IFN-γ-producing CD4+ and CD8+ T cells between before and after treatment. These results suggest that T-helper (Th)2 cells are involved in the pathogenesis of BP, and dupilumab exerts its effect mainly by suppressing Th2 cytokines.

Interleukin (IL)-13/IL-22/IL-31 skewing within the skin-homing T-cell population in papuloerythroderma.

Papuloerythroderma (PEO) is a representative form of senile erythroderma with an unclear pathogenesis. This study aimed to characterize the T-cell phenotypes responsible for the pathogenesis of PEO. Cytokine profiles and cutaneous lymphocyte antigen (CLA) expression on circulating T lymphocytes in patients with PEO were simultaneously analyzed using flow cytometry. The patients with PEO showed significantly higher circulating interleukin (IL)-4-, IL-13-, IL-22-, and IL-31-producing CD4+ and CD8+ T-cell levels than healthy subjects. However, their levels significantly decreased after remission of PEO. No difference was observed in the proportions of circulating interferon (IFN)-γ- and IL-17-producing CD4+ and CD8+ T cells between the patients with PEO and healthy subjects. In particular, the proportion of circulating IL-4-, IL-13-, IL-22-, and IL-31-producing CD4+ and CD8+ T cells was much higher in the CLA+ subset than in the CLA- subset. There was a positive correlation between IL-13-, IL-22-, and IL-31-producing CD4+ T cells and the disease severity score of PEO. Moreover, a positive correlation was also observed between the proportion of IL-22- or IL-31-producing cells and circulating IL-13-producing cells in both CD4+ and CD8+ T cells, and approximately 50% of both IL-22- and IL-31-producing CD4+ and CD8+ T cells coproduced IL-13. IL-13/IL-22/IL-31 skewing within the skin-homing T-cell population may be involved in the pathogenesis of PEO.

Combination therapy of apremilast and biologics in patients with psoriasis showing biologic fatigue.

Biologics have been shown to constitute a highly effective treatment for patients with psoriasis. However, a significant number of patients treated with biologics will discontinue them due to loss of efficacy over time, a phenomenon known as biologic fatigue or secondary failure. Combination therapy of biologics with other agents can be considered as a treatment option in such cases. Information regarding the efficacy and safety of adding apremilast to biologic therapy in patients with psoriasis is limited. In the present study, we retrospectively evaluated the efficacy and safety of apremilast combined with biologics in 14 patients with psoriasis showing biologic fatigue at a single hospital. Before the addition of apremilast, the mean Psoriasis Area and Severity Index (PASI) score was 3.2 ± 0.4. At week 24 following the addition of apremilast, the mean PASI score decreased to 1.6 ± 0.3, and four (29%) and seven (50%) patients had achieved 75% and 50% reduction in PASI score, respectively. During the 24 weeks of treatment, diarrhea was observed in four patients, and diarrhea and nausea were observed in one patient. Weight loss of more than 5% bodyweight was observed in two patients. None of the patients discontinued therapy because of these side-effects. These results suggest that the combination therapy of apremilast and biologics could be a safe, effective option for the management of patients with psoriasis showing biologic fatigue.

Effects of tumor necrosis factor-α, interleukin-23 and interleukin-17A inhibitors on bodyweight and body mass index in patients with psoriasis.

Treatment with tumor necrosis factor-α inhibitors has been reported to cause weight gain in patients with psoriasis; however, limited information is available in terms of the effects of interleukin (IL)-23 and IL-17A inhibitors on bodyweight (BW) in patients with psoriasis. This study aimed to investigate the effects of infliximab, ustekinumab and secukinumab on BW and body mass index (BMI) in patients with psoriasis. We retrospectively examined changes in BW and BMI among patients treated with these biologics at our hospital. At baseline, no significant differences in BW and BMI were observed among the patients treated with infliximab (n = 18), ustekinumab (n = 30) or secukinumab (n = 20). After 7 months of the therapy, significant increases in mean BW (from 71.4 to 74.3 kg) and mean BMI (from 24.7 to 25.7) were observed in the patients treated with infliximab, whereas no significant changes were observed in those treated with ustekinumab (BW, from 70.3 to 70.1 kg; BMI, from 25.4 to 25.3) or secukinumab (BW, from 69.0 to 68.9 kg; BMI, from 25.2 to 25.2). There were no differences in the proportion of the patients who showed 75% or more improvement in the Psoriasis Area and Severity Index among the three groups. These results suggest that infliximab increases BW in the patients with psoriasis, whereas ustekinumab and secukinumab do not affect the BW in these patients.

Immunoglobulin G4-related disease presenting with prurigo: Circulating T-helper 2 cells may be involved in the pathogenesis.

We report a case of immunoglobulin G4-related disease (IgG4-RD) which presented with prurigo on the trunk and extremities. A 66-year-old man had a 2-month history of itchy erythematous papules on his trunk and extremities. Bilateral eyelid swelling and enlargement of the submandibular and parotid glands were also observed. Computed tomography revealed pleural thickening and diffuse pancreatic enlargement. Serum levels of IgG4 were markedly increased. A biopsy specimen obtained from an erythematous papule showed a perivascular inflammatory infiltrate of lymphocytes with eosinophils in the dermis, whereas a parotid gland biopsy revealed an infiltrate of abundant IgG4-positive plasma cells. Treatment with prednisolone resulted in improvement of the skin and other lesions along with a decrease in IgG4 serum levels. A flow cytometric assay revealed that percentages of interleukin (IL)-4- and IL-13-producing CD4(+) T cells were markedly higher in the circulation of the IgG4-RD patient than in that of healthy subjects. Moreover, those populations dramatically decreased after treatment. Thus, prurigo may be a skin manifestation of IgG4-RD and T-helper 2 cells may contribute to the pathogenesis.

Eosinophilic pustular folliculitis associated with hematological disorders: A report of two cases and review of Japanese literature.

Eosinophilic pustular folliculitis (EPF) occurs in patients with hematological disorders. However, clinical information about hematological disorder-associated EPF is scarce. We report two cases of EPF associated with mantle cell lymphoma and reviewed the available published work on Japanese cases. We identified a total of 23 Japanese cases, including the two cases reported here, who had hematological disorder-associated EPF. Fourteen cases were associated with treatment for hematological malignancies (transplantation-related EPF) and nine cases were associated with hematological malignancies themselves (hematological malignancy-related EPF). Although the skin eruption was clinically indistinguishable between the two subtypes, transplantation-related EPF occurred on the face and trunk of young and middle-aged men and women, whereas hematological malignancy-related EPF occurred mostly on the face of older men. Peripheral blood eosinophilia was more frequently observed in transplantation-related EPF. These observations suggest variations among patients with EPF associated with hematological disorders.

Case of clear cell sarcoma in the left buttock in which serum neuron-specific enolase was a useful marker for monitoring disease progression.

We report a case of clear cell sarcoma (CCS) in the left buttock in which serum neuron-specific enolase (NSE) was useful as a biomarker of CCS progression. A 40-year-old man had a subcutaneous tumor, 1.7 cm in diameter, in the left buttock. Histopathology revealed that the tumor consisted of nests of polygonal or spindle-shaped cells with abundant clear cytoplasm delineated by fibrous septa in the subcutaneous tissue. There was cellular atypia but no melanin deposits. Immunohistochemically, the tumor cells were positive for HMB-45, Melan-A, S-100 protein and NSE. Reverse transcription polymerase chain reaction demonstrated Ewing's sarcoma oncogene-activating transcription factor 1 fusion transcripts in the tumor cells. CCS was diagnosed. There was no metastasis to the lymph nodes and viscera, and the patient was treated by surgical wide resection. The serum NSE levels increased before detection of distant metastasis and further increased in parallel with the expansion of metastasis. The present case suggests that serum NSE could be used as a biochemical marker in the clinical follow up of patients with CCS.

Cutaneous leishmaniasis in a Japanese returnee from West Africa successfully treated with liposomal amphotericin B.

Leishmaniasis has been occasionally reported in returnees from endemic areas. Here, we report a case of cutaneous leishmaniasis in a 33-year-old Japanese man who presented with a skin nodule after returning from an 8-year stay in West Africa including Burkina Faso. He was successfully treated with liposomal amphotericin B with no significant adverse effects. This is the first Japanese case of cutaneous leishmaniasis treated successfully with liposomal amphotericin B.