Amenamevir, a Helicase-Primase Inhibitor, for the Optimal Treatment of Herpes Zoster.

Acyclovir, valacyclovir, and famciclovir are used for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Helicase-primase inhibitors (HPIs) inhibit replication fork progression that separates double DNA strands into two single strands during DNA synthesis. The HPIs amenamevir and pritelivir have novel mechanisms of anti-herpetic action, and their once-daily administration has clinical efficacy for genital herpes. Among HPIs, amenamevir has anti-VZV activity. The concentrations of HSV-1 and VZV required for the 50% plaque reduction of amenamevir were 0.036 and 0.047 µM, respectively. We characterized the features of amenamevir regarding its mechanism, resistance, and synergism with acyclovir. Its antiviral activity was not influenced by the viral replication cycle, in contrast to acyclovir. A clinical trial of amenamevir for herpes zoster demonstrated its non-inferiority to valacyclovir. To date, amenamevir has been successfully used in over 1,240,000 patients with herpes zoster in Japan. Post-marketing surveillance of amenamevir in Japan reported side effects with significant potential risk identified by the Japanese Risk Management Plan, including thrombocytopenia, gingival bleeding, and palpitations, although none of these were serious. The clinical efficacy and safety profiles of amenamevir were established in patients with herpes zoster. Therefore, amenamevir as an HPI opens a new era of anti-herpes therapy.

Efficacy and Safety of the Traditional Japanese Medicine Keigairengyoto in the Treatment of Acne Vulgaris.

Several traditional Japanese medicines including Keigairengyoto (KRT) are used to treat acne vulgaris, but there is no robust evidence of their effectiveness. In this study, we examined the effectiveness and safety of KRT in treating acne vulgaris. An open-label, randomized, parallel control group comparison was conducted with a conventional treatment group (adapalene and topical antibiotics; control group) and a KRT group (control treatment plus KRT). The test drugs were administered for 12 weeks to patients (15 to 64 years, outpatient) with inflammatory acne on their face, and the amount of acne at 2, 4, 8, and 12 weeks was measured. Sixty-four patients were enrolled; 29 patients in each group were included in the analysis. Twenty-eight patients in the control group and 24 patients in the KRT group were included in the efficacy analysis. The number of inflammatory skin rashes at 4 and 8 weeks in the KRT group was significantly decreased compared with the control group. There was no significant difference between the two groups in noninflammatory eruptions and general rashes. There were no serious adverse events in both groups. KRT may be a useful agent in patients with inflammatory acne in combination with conventional treatments. This trial is registered with UMIN 000014831.

Microarray analysis of gene expression by microdissected epidermis and dermis in mycosis fungoides and adult T-cell leukemia/lymphoma.

The characteristic histopathological feature of mycosis fungoides (MF) and adult T-cell leukemia/lymphoma (ATLL) is epidermotropism. To identify the mechanism for epidermotropism of lymphoma cells, total RNAs were obtained from skin biopsies of epidermis and dermis of MF and ATLL patients by means of laser capture microdissection, and used for subsequent complementary DNA (cDNA) microarray experiments. This procedure has made it possible for us to observe and evaluate the regional environment of MF and ATLL. Hierarchical cluster analysis revealed that the cDNAs could be clearly differentiated into MF and ATLL. CCL27 was expressed in the dermis generated from keratinocytes, CCR4/CCR6/CCR7/CCR10/cutaneous lymphocyte-associated antigen (CLA) lymphoma cells in the dermis, and CCL21 in the extracellular matrix (stroma). Lymphotoxin (LT) ß and CCL21 expression was significantly higher and that of CCR10 relatively for MF, while CCR4 and CLA expression was relatively higher for ATLL. In the epithelium, keratinocytes expressed CCL20/CCL27, and lymphoma cells CCR4/CCR6/CCR10, while CCR4, CCR6, CCL20 and CCL27 expression was relatively higher for ATLL than MF. The dermis of MF, but not that of ATLL, showed correlation between CCR7 and CCL21. These findings support the suggestion that chemokines and chemokine receptors are involved in the pathogenesis of MF and ATLL, indicate that cutaneous homing seems to be different for MF and ATLL, and point to the possibility that cutaneous T-cell lymphomas originate in regulatory T cells, especially in the case of ATLL.

Comparative study for the effect of photodynamic therapy, imiquimod immunotherapy and combination of both therapies on 40 lesions of actinic keratosis in Japanese patients.

We treated 12, 15 and 13 Japanese actinic keratosis (AK) lesions with 5-aminolevulinic acid photodynamic therapy (PDT), 5% imiquimod cream and combination of both therapies, respectively, and compared the effects. Patients underwent the second course, when AK lesions remained after the first course. Efficacy was evaluated 1 month after each treatment. Combination therapy cleared all AK lesions only after the first course, while PDT and imiquimod therapy cleared 41.7% and 66.7% of AK lesions after the first course, respectively. All residual AK lesions after the first course were cleared by the second courses of PDT or imiquimod therapy. During the course, erosion and crust developed significantly more frequently in combination therapy (P < 0.001). Most Japanese AK lesions can be satisfactorily treated with either PDT or imiquimod monotherapy. However, only severe cases may better be treated with combination therapy, which show higher efficacy even though adverse events occur frequently.

Therapeutic effect of mizoribine on pemphigus vulgaris and pemphigus foliaceus.

We evaluated the effectiveness of mizoribine, a newly developed immunosuppressive agent, as an adjuvant therapy in the treatment of both pemphigus vulgaris and pemphigus foliaceus. Eleven pemphigus patients (eight pemphigus vulgaris and three pemphigus foliaceus) received the combination therapy of prednisolone and mizoribine. Complete remission was observed in three of the eight patients with pemphigus vulgaris and in one of the three patients with pemphigus foliaceus. The four patients with complete remission had a rapid clinical response and achieved remission at a median of 11.8 months. Partial remission was achieved in two of the three patients with pemphigus foliaceus. The median time to achieve partial remission was 16.0 months. Six (55.6%) of the 11 patients with pemphigus had complete or partial remission and were able to taper their prednisolone. The cumulative probability of having a complete remission was 64.3% at 19 months of follow-up using Kaplan-Meier analysis. The effectiveness of the additional mizoribine therapy could be attributed to its corticosteroid-sparing properties as well as its immunosuppressive effects. The serum concentration titer of mizoribine was around 1.0 µg/mL 2 hours after administration. Patients who were not improved by the additional mizoribine might require a continuously higher dose of mizoribine to achieve effective therapy.

Low-dose cyclosporin improves the health-related quality of life in Japanese psoriasis patients dissatisfied with topical corticosteroid monotherapy.

Psoriasis greatly impacts the health-related quality of life of patients, including any dermatological conditions that are listed in the dermatology life quality index (DLQI). We investigated the relationships between DLQI and the degree of patient satisfaction using questionnaires among psoriasis patients treated only with topical corticosteroids. Patients who were dissatisfied with topical corticosteroids alone and agreed to receive cyclosporin were given low-dose oral cyclosporin. We assessed changes of the DLQI and the psoriasis area and severity index (PASI) scores in patients dissatisfied with treatment during the period of cyclosporin addition. Of 32 enrolled patients, 17 reported dissatisfaction with the current treatment of topical corticosteroids alone. There was a significantly positive correlation between the degree of patient satisfaction questionnaires and the DLQI of these 32 patients. Among the 17 dissatisfied patients, 12 patients agreed to receive additional cyclosporin therapy and five did not. The 12 patients who started on cyclosporin had a significantly lower PASI after 12 weeks than they did at baseline. The DLQI improved significantly after 12 weeks in the cyclosporin-treated patients. The 12 patients who agreed to receive cyclosporin showed a significantly lower DLQI at 12 weeks compared to the five patients who declined the addition of cyclosporin to their treatment. Assessing the degree of patient satisfaction with therapy using a questionnaire could be useful for improving clinical interventions in psoriasis patients. Low-dose oral cyclosporin could be effective in patients who are dissatisfied with topical corticosteroid treatment alone.

Comparison between famciclovir and valacyclovir for acute pain in adult Japanese immunocompetent patients with herpes zoster.

Famciclovir is a guanine analog antiviral drug used commonly for herpes zoster. Efficacy of famciclovir treatment has been reported to be comparable to valacyclovir treatment. Both of these medications reduce the time to complete cessation of zoster-associated pain including post-herpetic neuralgia, as compared to acyclovir. We conducted a multicenter, randomized, open clinical trial in order to evaluate the extent of pain relief afforded by these two antiviral drugs during the acute disease phase of herpes zoster. The study group comprised 86 immunocompetent adult patients suffering from herpes zoster, who were treated with either famciclovir or valacyclovir for 7 days. Of these, 55 patients enrolled in this study within 72 h of the onset of the rash and 31 patients after 72 h of the onset. There was a significant reduction in acute herpes zoster pain with famciclovir on day 7 and at 2-3 weeks in both of these patient groups, while with valacyclovir, there was not significant reduction in pain on day 7. Of patients aged 50 years or older, there was a significantly earlier reduction in pain with famciclovir than with valacyclovir. In addition, a significant reduction in the number of patients with pain was observed as early as days 3-4 with famciclovir treatment as compared with valacyclovir treatment. We conclude that famciclovir was superior to valacyclovir in the relief of acute pain of herpes zoster. Accordingly, famciclovir is recommended for herpes zoster patients with moderate symptoms and a visual analog scale score of under 50 mm.

Clinicopathological features and prognostic significance of CXCL12 in blastic plasmacytoid dendritic cell neoplasm.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDC) is a rare hematologic neoplasm, which almost always involves the skin and shows poor prognosis. OBJECTIVE: The aim of our study was to enhance BPDC diagnosis and indications for prognosis. METHODS: This study involved 26 patients with BPDC. To investigate the histogenesis of BPDC, we reviewed the clinical features and stained markers of various hematopoietic lineages, chemokines, and their receptors. RESULTS: Bone-marrow infiltration was detected in 13 of the 19 cases examined and leukemic changes in 18. Complete remission was achieved in 14 cases, but more than half of the patients showed recurrence within a short time, and 14 patients died of the disease after 1 to 25 months (mean 8.5 months). Positivity for CD123 was detected in 18 of 24 cases and for T-cell leukemia 1 in 18 of 22 cases. Of the chemokines and their receptors, 8 of 15 skin biopsy specimens proved to be positive for CXCL12. Leukemic change subsequent to skin lesions occurred in 7 of 8 CXCL12-positive cases (87.5%) and in 3 of 6 CXCL12-negative cases (50%). Seven of the 8 CXCL12-positive patients (87.5%) and two of the 6 CXCL12-negative patients (33.3%) have died, whereas one of 8 CXCL12-positive patients (12.5%) and 4 of 6 CXCL12-negative patients (66.7%) remain alive. LIMITATIONS: The number of patients was limited. CONCLUSIONS: We speculate that the presence of CXCL12-positive cells in the skin may be associated with leukemic change and a poor prognosis.

Lesional Th17 cells and regulatory T cells in bullous pemphigoid.

Th17 cells play crucial roles in the pathogenesis of autoimmune diseases. We previously reported that Th17 cells are recruited to the lesional skin in pemphigus vulgaris (PV) and pemphigus foliaceus (PF). The aim of this study was to evaluate lesional Th17 cells and Treg cells in bullous pemphigoid (BP). Correlations between these cells and disease severity of BP were also evaluated. Immunohistochemical studies showed that both IL-17+ and Foxp3+ cells were present in higher numbers in BP lesions, compared with control skin. IL-17/CD4 ratio in BP was significantly higher than that in PF. Foxp3/CD4 ratio in BP was significantly less than that in either PV or PF. There were no obvious correlations between these cells and disease severity of BP. This study suggests that, compared with pemphigus, BP shows more Th17 cell-related inflammation and less Treg-related regulation.

A novel splicing variant of CADM2 as a protective transcript of psoriasis.

CADM2, a candidate gene for psoriasis, was identified by a genome-wide association study using microsatellites in the Japanese population (561 cases and 561 controls). Moreover, haplotype analysis included an additional 68 SNPs and indicated that a 110-kb haplotype block was detected for the protective risk haplotype of psoriasis. We also identified an initial exon of novel splicing variants in this haplotype block. A functional analysis by qRT-PCR using RNAs from the blood of 56 cases and 64 controls significantly demonstrated an inverse correlation between expression frequencies in a novel splicing variant and the number of alleles associated with psoriasis. To confirm these results, we must perform replication studies using other ethnic groups and more functional analysis particularly for skin tissues.

Effects of olopatadine hydrochloride, a histamine h(1) receptor antagonist, on histamine-induced skin responses.

Effects of olopatadine hydrochloride, a histamine H(1) receptor antagonist, on histamine-induced skin responses were evaluated in 10 healthy subjects in comparison with placebo, fexofenadine hydrochloride, and bepotastine besilate. Olopatadine significantly suppressed histamine-induced wheal, flare, and itch, starting 30 minutes after oral administration. Olopatadine was more effective than fexofenadine and bepotastine. None of the drugs studied impaired performance of word processing tasks. These results suggest that olopatadine can suppress skin symptoms caused by histamine soon after administration.

Epidermolysis bullosa acquisita: what's new?

Type VII collagen is an adhesion molecule of the extracellular matrix in epithelial basement membranes, and the main constituent of anchoring fibrils at the dermal-epidermal junction (DEJ). Autoimmunity against this protein is causing the rare organ-specific epidermolysis bullosa acquisita (EBA). EBA is a rare acquired, heterogeneous, chronic blistering disease of skin disease of skin and mucous membranes characterized by subepidermal blisters and tissue-bound as well as circulating autoantibodies to the DEJ. EBA has several distinct clinical presentations with other subepidermal bullous diseases, such as mainly dystrophic epidermolysis bullosa or bullous pemphigoid. The circulating immunoglobulin G autoantibodies for EBA react with a 290-kDa dermal protein, type VII collagen, as detected by immunoblot analysis using dermal extracts. The pathogenicity of these autoantibodies has been demonstrated by experimental animal models, in which anti-type VII collagen antibodies injected into a mouse produced an EBA-like blistering disease in the animal. EBA cases often require high doses of systemic corticosteroids and a variety of immunosuppressants. Although treatment for EBA is frequently difficult and unsatisfactory, some therapeutic success has been reported with colchicine, dapsone, infliximab and i.v. immunoglobulin. In this review, we will focus on recent progress in our understanding of the clinical manifestations, the etiopathogenesis as well as the management of EBA.

From anti-p200 pemphigoid to anti-laminin gamma1 pemphigoid.

Anti-laminin gamma1 pemphigoid is an autoimmune subepidermal bullous disease first described in 1996, and has been distinct from previously known subepidermal blistering diseases, such as bullous pemphigoid and epidermolysis bullosa acquisita. Circulating autoantibodies of the patients do not react to any known autoantigen of the skin, but react to a 200-kDa molecule (p200) from dermal extracts. The identity of p200 was unmasked as laminin gamma1, an extracellular matrix glycoprotein composing several forms of laminin heterotrimers. We renamed this disease from the previously used anti-p200 pemphigoid to anti-laminin gamma1 pemphigoid, a new entity of an autoimmune bullous disease. In this decade, we have experienced over 70 cases of this disease. Although the number of the cases of anti-laminin gamma1 pemphigoid is half as many as the number of definitely diagnosed cases of epidermolysis bullosa acquisita in the same duration, a considerable number of the cases could be clinically misdiagnosed as epidermolysis bullosa acquisita. Unveiling the pathogenicity and development of a useful diagnostic method is necessary for appropriate management of this new disease.

Successful treatment with mycophenolate mofetil of four Japanese patients with pemphigus vulgaris.

Mycophenolate mofetil has been used as an immunosuppressive agent to prevent acute rejection in kidney transplantation since the early 1990s. There are several reports that mycophenolate mofetil is effective in autoimmune bullous diseases including pemphigus vulgaris in combination with high doses of systemic corticosteroids or as a monotherapy. In Japan, however, there are few reports of pemphigus vulgaris treated with mycophenolate mofetil. The present study showed that mycophenolate mofetil treatment combined with systemic corticosteroid was successful in four Japanese patients with pemphigus vulgaris who were refractory to therapies including systemic corticosteroids, plasmapheresis, and oral immunosuppressives. For Japanese and European patients, mycophenolate mofetil may be an excellent therapy in a combination with systemic corticosteroid for refractory patients with pemphigus vulgaris.