Impact of body mass index on the severity of bexarotene-associated hypertriglyceridemia: A post hoc analysis of an open-labeled clinical study of combined bexarotene and phototherapy in Japanese patients with cutaneous T-cell lymphoma.

Bexarotene is an effective oral drug for the treatment of cutaneous T-cell lymphoma, but careful management is required due to its various side effects. In particular, hypertriglyceridemia often requires a reduction or even suspension of bexarotene therapy. The risk factors of bexarotene-associated severe hypertriglyceridemia are not clear. Here, we conducted a post hoc analysis of the data from our previous clinical trial, which confirmed the efficacy and safety of combined bexarotene and phototherapy, to evaluate the effect of body mass index on bexarotene-associated hypertriglyceridemia. Twenty-five subjects were divided into two subgroups: normal and underweight (body mass index [BMI] <25 kg/m2 group) and overweight and obese (BMI ≥25 kg/m2 group) patients. The overall incidence of hypertriglyceridemia was 81.3% (13/16) in the BMI <25 kg/m2 group and 88.9% (8/9) in the BMI ≥25 kg/m2 group. The incidence of grade ≥3 hypertriglyceridemia (≥500 mg/dL) was 7.7% (1/13) in the BMI <25 kg/m2 group and 7/8 (87.5%) in the BMI ≥25 kg/m2 group (P < 0.001). Consequently, dose reduction in the BMI ≥25 kg/m2 group was larger than that in the BMI <25 kg/m2 group. The bexarotene-induced change in the serum triglyceride concentration was significantly increased in cutaneous T-cell lymphoma patients with a higher body mass index (ρ = 0.508, P = 0.009). The area under the curve was 0.886 (95% confidence interval 0.748-1.000, P = 0.002). With a body mass index cut-off of 24.85 kg/m2 , the sensitivity and specificity for identifying grade ≥3 hypertriglyceridemia were 0.875 and 0.882, respectively. The present findings suggest that BMI ≥25 kg/m2 is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.

Efficacy and safety of apremilast and phototherapy versus phototherapy only in psoriasis vulgaris.

Phototherapy and apremilast (oral phosphodiesterase-4 inhibitor) are well-known in the treatment of moderate to severe psoriasis vulgaris. However, current evidence on the efficacy and safety of their combination is not sufficient. This multicenter, randomized controlled study compared the efficacy and safety between phototherapy as monotherapy and phototherapy and apremilast as combination therapy in patients with psoriasis vulgaris. Patients with moderate to severe psoriasis vulgaris were assigned to combination (n = 29) and monotherapy (n = 13) groups. All patients underwent an 8-week phototherapy regimen comprising irradiation with narrowband UV-B. The patients in the combination group were also administered 10 mg to 60 mg of oral apremilast. We evaluated the improvement percentage based on the Psoriasis Area and Severity Index (PASI) score from baseline to week 8. Additionally, we evaluated the percentage of patients who achieved ≥75% improvement; changes in body surface area (BSA) and scores of EuroQol 5-dimensions 5-level, Dermatology Life Quality Index, and visual analog scale for pruritis from baseline to 4 and 8 weeks; and adverse events. Compared with the monotherapy group, the combination group had significantly lower PASI scores at 4 and 8 weeks and more patients who achieved a PASI score improvement of ≥75% at 8 weeks. Both groups exhibited a significant decrease in BSA; at 8 weeks, no significant difference was observed between the two groups, although the combination group tended toward a greater reduction in BSA. The intergroup differences in the changes at the three time points were not significant. Adverse events were more frequent in the combination group than in the monotherapy group. Our findings suggest that an 8-week combined apremilast and phototherapy regimen may not be adequate in patients for improvements in their subjective assessment of psoriasis, and longer treatment periods may be necessary.

Comparison of the Efficacy and Safety of Bexarotene and Photo(Chemo)Therapy Combination Therapy and Bexarotene Monotherapy for Cutaneous T-Cell Lymphoma.

INTRODUCTION: Cutaneous T-cell lymphoma (CTCL) is a chronic condition with low malignancy. The combined use of therapeutic agents and photo(chemo)therapy is widely applied for the treatment of CTCL. The efficacy and safety of bexarotene and photo(chemo)therapy combination therapy were previously confirmed in Japanese patients with CTCL. The efficacy and safety of the bexarotene and photo(chemo)therapy combination therapy was compared with bexarotene monotherapy in Japanese patients with CTCL. METHODS: This was a randomized, open-label, two-parallel-group, active-control specified clinical study in Japanese patients diagnosed with CTCL carried out over 8 weeks with a study extension conducted at two institutions. This study was registered in Japan Registry of Clinical Trials (jRCTs041180094). RESULTS: In the combination therapy group, 22 subjects received oral bexarotene (300 mg/m2 body surface area) once daily, followed by bath-psoralen and ultraviolet (UV) A or narrowband UVB. In the monotherapy group, 24 subjects received oral bexarotene (300 mg/m2) once daily. The efficacy analysis using the modified Severity-Weighted Assessment Tool, which included 39 patients, showed a response rate of 81.0% (17/21) in the combination therapy group and 83.3% (15/18) in the monotherapy group. No statistically significant difference was detected between groups. In the combination therapy group, four subjects showed a complete clinical response or complete response, and subjects with a partial response exhibited a high rate of skin lesion resolution, significantly better than in the monotherapy group. In the safety analysis, which included 46 treated subjects (22 in the combination therapy group and 24 in the monotherapy group), no adverse events or adverse drug reactions were reported in either group. CONCLUSION: Both bexarotene and photo(chemo)therapy combination therapy and bexarotene monotherapy were therapeutically effective in Japanese patients with CTCL and well tolerated. Combination therapy led to a higher skin lesion resolution rate and greater therapeutic effects compared with monotherapy. TRIAL REGISTRATION: jRCTs041180094.

This study evaluated the efficacy and safety of bexarotene monotherapy compared with bexarotene and photo(chemo)therapy combination therapy in Japanese patients with cutaneous T-cell lymphoma (CTCL). The study was a randomized, open-label, two-parallel-group, active-control specified clinical study in patients diagnosed with CTCL performed over an 8-week period with a study extension conducted in two institutions. In the combination therapy group, bexarotene (300 mg/m² body surface area) was administered orally once daily to 22 subjects, followed by treatment with bath-psoralen and ultraviolet A (bath-PUVA) or narrowband UVB. In the bexarotene monotherapy group, bexarotene (300 mg/m²) was administered orally once daily to 24 subjects. Efficacy was assessed using the modified Severity-Weighted Assessment Tool. Among the 39 subjects analyzed for treatment efficacy, the response rate of the combination therapy group was 81.0% (17/21) and that of the monotherapy group was 83.3% (15/18). Differences between the two treatment groups were not statistically significant. Of the 21 subjects in the combination therapy group, 4 had a complete clinical response or complete response, and those with a partial response showed a higher skin lesion resolution rate than in the monotherapy group. The safety analysis revealed no reports of adverse events or adverse drug reactions among the 46 treated subjects (combination therapy group = 22; monotherapy group = 24). Thus, both bexarotene and photo(chemo)therapy combination therapy and bexarotene monotherapy were therapeutically effective and well tolerated in Japanese patients with CTCL. Patients receiving the combined therapy, however, showed a higher rate of skin lesion resolution.

Efficacy of bath-psoralen and ultraviolet A therapy for mycosis fungoides - retrospective analysis of 62 cases.

Photochemotherapy with psoralen and ultraviolet A (PUVA) is widely used for refractory skin diseases. Bathwater delivery of 8-methoxypsoralen (8-MOPS) with subsequent UVA irradiation (bath-PUVA) or oral administration of 8-MOPS with UVA is used to treat mycosis fungoides. We retrospectively analyzed 62 patients with mycosis fungoides (8 stage IA, 30 stage IB, 5 stage IIB, 18 stage IIIA, and 1 stage IVA2) treated with bath-PUVA at the Dermatology Clinic of Nagoya City University Hospital from November 2004 to December 2013. A complete response was achieved in 37 (59.7%) patients, a partial response was achieved in 16 (25.8%), and stable disease was achieved in 6 (9.7%). Progressive disease was observed in 3 (4.8%) patients. Almost all patients in stage IA/IB achieved a complete response. Of the 5 stage IIB patients, 2 achieved a partial response, 1 achieved stable disease, and 2 had progressive disease. The serum concentrations of soluble interleukin-2 receptor and lactate dehydrogenase decreased significantly following treatment with bath-PUVA (p < 0.001). We examined the risk factors of patients whose stage progressed despite PUVA treatment. A multivariate Cox regression analysis of risk factors associated with stage progression yielded a hazard ratio of 28.5 for stage IIb. Treatment with bath-PUVA is highly effective in the early stages of mycosis fungoides, and partially effective in advanced stages.

Bath Psoralen Plus UVA Therapy Suppresses Keratinocyte-Derived Chemokines in Pathogenetically Relevant Cells.

Psoriasis is a chronic inflammatory proliferative skin disease involving various types of chemokines regulating immune cell migration, localization, and activation. Bath psoralen plus UVA (PUVA) treatment is an established phototherapy for psoriasis, but its effects on chemokine levels remain unknown. We investigated the levels of 22 serum chemokines in 20 patients with psoriasis first treated with bath PUVA therapy between 2007 and 2011 in a single center and analyzed the associations between the chemokines and disease severity (PASI) before and after therapy to investigate the mechanisms of action of bath PUVA therapy. Before bath PUVA therapy, the PASI scores correlated with the serum levels of CCL17 (r = 0.581), CCL18 (r = 0.462), CCL19 (r = 0.477), and CXCL16 (r = 0.524). After bath PUVA, the serum levels of CCL17, CCL22, CXCL1, and CXCL9 were significantly decreased. Heatmap clustering and network analysis based on statistically significant Spearman correlations among the chemokines showed distinctive changes in the chemokine signature. Our findings revealed that the levels of several chemokines correlated with the disease state of psoriasis. Furthermore, bath PUVA therapy reduced the secretion of keratinocyte-derived chemokines that induce the migration of immune cells important for psoriasis pathogenesis, partly revealing the mechanism of the therapeutic activity.

Ultraviolet A1 phototherapy for the treatment of localized scleroderma.

Ultraviolet (UV)A1 phototherapy is effective for T-cell-mediated skin diseases such as atopic dermatitis and mast cell-mediated skin diseases such as mastocytoma. UVA1 phototherapy is also effective against the sclerotic lesions of systemic sclerosis and morphea. Currently, in Japan, access to UVA1 phototherapy is limited because the UVA1 phototherapy device has not yet been approved. On the basis of our experience, we report three patients with localized scleroderma who responded successfully to UVA1 phototherapy. Efficacy was assessed by histological analysis and elastography. UVA1 successfully ameliorated sclerotic lesions, including morphea, linear scleroderma and morphea lesions in a patient with limited cutaneous systemic sclerosis. No side-effects were observed during UVA1 phototherapy.

Hyperglycemia Is Associated with Psoriatic Inflammation in Both Humans and Mice.

Chronic low-grade inflammation can cause several metabolic syndromes. Patients with psoriasis, a chronic immunological skin inflammation, often develop diabetes. However, it is not clear to date how psoriasis leads to, or is correlated with, glucose intolerance. Here, we investigate whether psoriasis itself is correlated with hyperglycemia in humans and mice. In patients, the severity of psoriasis was correlated with high blood glucose levels, and treatment of psoriasis by phototherapy improved insulin secretion. Imiquimod-induced systemic and cutaneous inflammation in mice, with features of human psoriasis, also resulted in hyperglycemia. Although it should be determined if psoriasis-like cutaneous inflammation alone can induce hyperglycemia, imiquimod-treated mice showed impairment of insulin secretion without significant islet inflammation. Administration of anti-IL-17A monoclonal antibody improved hyperglycemia in patients with psoriasis and imiquimod-treated mice with psoriasiform features. These results suggest that hyperglycemia is highly associated with psoriasis, mainly through IL-17.