Consistent Efficacy of Apremilast in Patients with Psoriasis Regardless of Baseline Disease Severity or Special Area Involvement: Subgroup Analysis from PROMINENT.

INTRODUCTION: Psoriasis involvement in special areas (e.g., scalp or nails) is associated with a great disease burden yet it is often inadequately treated with topical treatments. The efficacy and tolerability of apremilast plus existing topical therapy in Japanese patients with mild to moderate plaque psoriasis were demonstrated in PROMINENT, a phase 3b, multicenter, open-label, single-arm study. We evaluated the efficacy of apremilast across disease severities and special areas involved in these patients. METHODS: In PROMINENT, patients received apremilast 30 mg twice daily for 16 weeks in addition to their existing topical therapy, with the option of topical therapy reduction at the discretion of their physician while continuing apremilast treatment from Weeks 16 to 32. We performed a post hoc analysis, assessing apremilast efficacy and safety in Japanese patients stratified by baseline static Physician Global Assessment (sPGA) score (2 [mild] or 3 [moderate]) and special area involvement. RESULTS: Of patients with baseline sPGA = 2 and sPGA = 3, 62.7% and 30.7%, respectively, achieved sPGA score 0 or 1 at Week 32. At Week 32, improvements in skin, nail, scalp, and quality of life assessments were observed regardless of baseline sPGA score. Improvements in these endpoints at Week 32 were also observed in patients with special area (scalp or nail) involvement (n = 134). Incidence of adverse events was similar between patients with baseline sPGA = 2 and sPGA = 3. CONCLUSIONS: Apremilast in combination with topical therapy may be a beneficial treatment for Japanese patients, who have limited systemic treatment options for mild to moderate psoriasis or psoriasis in special areas. TRIAL REGISTRATION: NCT03930186.

Efficacy and Safety of Apremilast in the Treatment of Patients with Mild-to-Moderate Psoriasis in Japan: Results from PROMINENT, A Phase 3b, Open-Label, Single-Arm Study.

INTRODUCTION: Patients with mild-to-moderate plaque psoriasis often experience reduced quality of life and increased disease burden due to itch or involvement of psoriasis in special areas such as the scalp and nails. Systemic therapy may be used concurrently with topical therapy in patients with active disease not controlled by topical therapy alone. The objective of PROMINENT was to evaluate the efficacy and safety of apremilast in combination with topical therapy in patients with mild-to-moderate psoriasis in Japan. METHODS: PROMINENT, a phase 3b, open-label, single-arm study in Japan, enrolled adults ≥ 20 years of age with plaque psoriasis [static Physician Global Assessment (sPGA) 2 (mild) or 3 (moderate)] not adequately controlled by topical therapy. Patients received apremilast 30 mg twice daily for 16 weeks in addition to their existing topical therapy, with the option of topical therapy reduction at the discretion of their physician while continuing apremilast treatment from weeks 16 to 32. RESULTS: Of the 152 patients enrolled in the study, 136 completed week 32. The primary endpoint of sPGA response [score 0 (clear) or 1 (almost clear)] was achieved by 43.7% of patients at week 16, and 40.8% maintained response at week 32. Clinically meaningful improvements in skin, scalp, and nails were observed in > 40% of patients at weeks 16 and 32. Similarly, improvements in pruritus, quality of life, and treatment satisfaction were observed at week 16 and maintained at week 32. Common treatment-emergent adverse events through week 32 included gastrointestinal events, nasopharyngitis, and headache. CONCLUSIONS: Apremilast in combination with topical therapy resulted in clinically meaningful and sustained efficacy in physician- and patient-reported outcomes at weeks 16 and 32 in Japanese patients with mild-to-moderate psoriasis. Tolerability was consistent with available prior safety data for apremilast. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03930186.

Mycobacterium tuberculosis infection in psoriatic patients treated with biologics: Real-world data from 18 Japanese facilities.

Although rare, tuberculosis has been reported with biologic treatment against psoriasis in Japan, a tuberculosis medium-burden country. Mycobacterial infection often develops after a long incubation period and might not have been adequately identified in clinical trials or post-marketing surveillance. To determine the real-world incidence of tuberculosis in psoriatic patients treated with biologics, we conducted a retrospective, multicenter, observational study in 18 facilities in Western Japan. Psoriatic patients who visited a participating facility between 2010 and March 2017 and received biologic reagents were enrolled. Information on sex, age at first biologic treatment, results of interferon-γ release assay (IGRA) for Mycobacterium tuberculosis, treatment history with isoniazid, and onset of active and/or latent tuberculosis was collected. A total of 1117 patients (830 men and 287 women) were enrolled. The mean duration of biologic treatment was 3.54 years. Sixty-five patients (5.8%) showed positive IGRA results at screening. Active tuberculosis developed in two patients after the administration of tumor necrosis factor inhibitors (both involved miliary tuberculosis). Latent tuberculosis was observed in two patients treated with anti-interleukin-12/23p40 antibody. The incidence rate of tuberculosis, including latent tuberculosis, in this survey was 0.36%. Although the incidence rate of tuberculosis was low considering the observation period of biologic treatment, active tuberculosis was found in both the screening-negative group and a screening-positive subject after isoniazid prophylaxis (both miliary tuberculosis), concluding that negative screening or isoniazid treatment does not always assure that an individual has no tuberculosis. Hence, dermatologists still need to pay careful attention to tuberculosis at every patient visit.

Cross-sectional multicenter observational study of psoriatic arthritis in Japanese patients: Relationship between skin and joint symptoms and results of treatment with tumor necrosis factor-α inhibitors.

Psoriatic arthritis (PsA) is an inflammatory arthritis with as yet unclear pathophysiology. This retrospective, multicenter, cross-sectional study was conducted in 19 facilities in western Japan and aimed to identify patients' characteristics and factors that affect the results of treatment with biologic agents. Of 2116 patients with psoriasis, 285 (13.5%) had PsA. Skin manifestations preceded joint manifestations in 69.8%, the onset was simultaneous in 17.2%, whereas PsA preceded skin manifestations in 2.5%. Peripheral arthritis was most common, occurring in 73.7%, compared with axial disease in 21.8%, enthesitis in 23.5% and dactylitis in 35.4%. Patients with severe skin manifestations were significantly younger at onset (P = 0.02) and more frequently had axial disease (P < 0.01). Biologic agents were used in 206 patients (72.3%), anti-tumor necrosis factor (TNF)-α antibodies being prescribed first to 157 of them. Anti-TNF-α antibodies were continued by 105 participants and discontinued by 47, the remaining five patients being lost to follow up. Patients who discontinued anti-TNF-α antibodies were significantly older than those who continued (55 vs 51 years, P = 0.04) and significantly older at onset of joint manifestations (50 vs 44 years, P = 0.01). Multivariate analysis revealed that patients over 50 years significantly more frequently terminated anti-TNF-α antibodies (P < 0.01). In conclusion, patients with PsA and severe skin manifestations have earlier onset and axial disease, which seriously impacts on quality of life. Anti-TNF-α antibodies were generally effective enough to continue but less so in patients aged over 50 years. Further detailed research is needed.

Prognostic index for chronic- and smoldering-type adult T-cell leukemia-lymphoma.

Adult T-cell leukemia-lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering ATL. We conducted a nationwide retrospective survey on ATL patients, and 248 fully eligible individuals were used in this analysis. In the univariate analysis, sex, performance status, log10 (soluble interleukin-2 receptor [sIL-2R]), neutrophils count, and lymphadenopathy showed values of P < .05 in training samples. A multivariate analysis was performed on these factors, and only log10 (sIL-2R) was identified as an independent prognostic factor in training samples. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: indolent ATL-PI (iATL-PI) = 1.51 × log10 (sIL-2R [U/mL]). The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6 years, 5.5 years, and not reached for patients in the high-, intermediate-, and low-risk groups, respectively (P < .0001). To make the scoring system clinically practicable, we simplified iATL-PI according to trichotomizing sIL-2R at 1000 and 6000 U/mL, using a quartile point. Patients with more than 6000 U/mL sIL-2R were categorized into the high-risk group, less than and equal to 1000 U/mL into the low-risk group, and the others into the intermediate-risk group, and MSTs were 1.6 years, not reached, and 5.5 years, respectively (P < .0001). iATL-PI has potential as a novel tool for a risk-adapted therapeutic approach.

Treatment satisfaction, willingness to pay and quality of life in Japanese patients with psoriasis.

There is a range of psoriasis treatments available, from topical applications to biologic therapy, with corresponding cost variations. The efficacy of each treatment is usually evaluated by objective measures such as the Psoriasis Area and Severity Index (PASI) or subjective measures such as the Dermatology Life Quality Index (DLQI). However, the social and economic impacts of psoriasis, including cost-effectiveness, have not been assessed in Japan. The EuroQol 5-Dimension (EQ-5D) is a generic instrument used worldwide to calculate quality-adjusted life years, on which calculations of treatment cost-effectiveness are based. We conducted a pilot study to determine the cost-effectiveness of psoriasis treatment in Japan. We administered a questionnaire to 133 patients with psoriasis (105 men and 28 women) who visited four university hospitals in Fukuoka Prefecture. The questionnaire covered medical costs, satisfaction and willingness to pay (WTP), and we investigated the relationships between these items. PASI was evaluated by physicians. More participants indicated satisfaction with treatment in the group paying less than ¥5000/month. WTP, PASI and EQ-5D showed little correlation. However, the DLQI and EQ-5D showed a moderate correlation (r = 0.472). WTP seemed more dependent on participants' economic backgrounds. We found that it was difficult to reflect the PASI with the EQ-5D. However, the DLQI may be used to estimate the cost-benefit relationship in patients with psoriasis. This is the first study to evaluate the EQ-5D in patients with psoriasis in Japan.

Treatment and survival among 1594 patients with ATL.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes caused by human T-lymphotropic virus type I. Intensive combination chemotherapy and allogeneic hematopoietic stem cell transplantation have been introduced since the previous Japanese nationwide survey was performed in the late 1980s. In this study, we delineated the current features and management of ATL in Japan. The clinical data were collected retrospectively from the medical records of patients diagnosed with ATL between 2000 and 2009, and a total of 1665 patients' records were submitted to the central office from 84 institutions in Japan. Seventy-one patients were excluded; 895, 355, 187, and 157 patients with acute, lymphoma, chronic, and smoldering types, respectively, remained. The median survival times were 8.3, 10.6, 31.5, and 55.0 months, and 4-year overall survival (OS) rates were 11%, 16%, 36%, and 52%, respectively, for acute, lymphoma, chronic, and smoldering types. The number of patients with allogeneic hematopoietic stem cell transplantation was 227, and their median survival time and OS at 4 years after allogeneic hematopoietic stem cell transplantation was 5.9 months and 26%, respectively. This study revealed that the prognoses of the patients with acute and lymphoma types were still unsatisfactory, despite the recent progress in treatment modalities, but an improvement of 4-year OS was observed in comparison with the previous survey. Of note, one-quarter of patients who could undergo transplantation experienced long survival. It is also noted that the prognosis of the smoldering type was worse than expected.

Post-mastectomy benign lymphangioendothelioma of the skin following chronic lymphedema for breast carcinoma: a teaching case mimicking low-grade angiosarcoma and masquerading as Stewart-Treves syndrome.

Benign lymphangioendothelioma (BL) represents a very rare lymphatic vascular proliferation. Our aim is to be aware that owing to its characteristic features, pathologists can easily misinterpret it as cutaneous low-grade angiosarcoma when examining only small specimens. In the present case, multiple small and yellowish to reddish soft nodules were noticed in the edematous left arm of a 54-year-old Japanese female 4 years after the radical mastectomy with axillary lymph nodes dissection and following radiotherapy to the chest for the left breast carcinoma. The biopsy specimen showed an ill-defined lesion composed of a proliferation of irregular and sometimes anastomosing vascular structures in the dermis, lined by endothelial cells having mildly hyperchromatic and pleomorphic nuclei, but no mitotic figures. As the lesion grew within deeper dermis, these proliferating vessels dissected dermal collagenous bands, occasionally arranged in low-papillary projections and/or characteristic hobnail cytomorphology. We first interpreted it as low-grade angiosarcoma following chronic lymphedema due to the operation, i.e., the so-called Stewart-Treves syndrome. Although additional treatments were performed for 7 years, she had neither local invasion nor metastases of these tumors, respectively, and was alive and well. Retrospective immunohistochemical findings demonstrated that these mildly atypical endothelial cells were strongly positive for lymphatic vessel endothelial hyaluronan receptor (LYVE)-1 as well, and MIB-1 labeling index was less than 1%. Therefore, we finally made a diagnosis of BL of the skin. MIB-1 labeling index might be useful and adjunctive aids for reaching the correct diagnosis of cutaneous BL, especially in case of small or inadequate specimens.Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_197.

Induction of cytotoxic T cells as a novel independent survival factor in malignant melanoma with percutaneous peptide immunization.

BACKGROUND: Malignant melanoma (MM) often shows multiple chemo-resistance, leading to poor prognosis of the patients. Therapeutic anti-cancer vaccination may be a feasible way to prolong the survival of patients. We have demonstrated that application of antigenic peptides via the tape-stripped, horny layer-removed skin, known as percutaneous peptide immunization (PPI), induces tumor cell-specific cytotoxic T lymphocytes (CTLs) in rodents and humans. OBJECTIVE: To evaluate clinical significance of PPI in advanced MM patients. METHODS: We performed PPI in 59 patients undergoing advanced MM with Melan-A, tyrosinase, MAGE-2, MAGE-3 and gp-100 peptides based on HLA typing in individuals. The induction of CTLs was assessed by the tetramer or pentamer flow cytometry in 35 patients. Patients showing positive CTL responses to all antigens were defined as complete responder (n=18), and those showing negative responses to at least one applied antigen were classified as incomplete responder (n=17). The primary endpoint of the study was overall survival (OS). For statistical analysis, log-rank test, univariate and multivariate Cox proportional hazard model were used. RESULTS: OS of the complete responders was longer than that of the incomplete responders (median survival time: 55.8 vs 20.3 months, log rank P=0.089). A hazard ratio for the complete responders relative to the incomplete responders was 0.23 (95% confidence interval: 0.06-0.93, P=0.039) in a multivariate Cox proportional hazard model. CONCLUSION: The induction of CTLs was a novel independent survival factor, and the induction of peptide-specific CTLs by PPI contributes to the prolonged survival and represents an impact on therapeutic approaches in MM. Unique trial number: UMIN000005706.

Combination of skin-directed therapy and oral etoposide for smoldering adult T-cell leukemia/lymphoma with skin involvement.

Approximately 50% of patients with adult T-cell leukemia/lymphoma (ATLL) have skin involvement, and the smoldering, skin lesion-bearing cases are often treated with various skin-directed therapies, such as phototherapy and radiation therapy. Daily oral administration of etoposide plus prednisolone (EP) is also used for smoldering-type ATLL. However, it remains unclear whether these therapies improve patients' survival. We retrospectively analyzed the prognosis of patients with smoldering, skin lesion-bearing ATLL (n = 62), who were treated, as first therapy, with one skin-directed therapy (n = 29), oral EP alone (n = 14) or a combination of skin-directed therapy and oral EP (n = 19). Multivariate analysis revealed that the hazard ratios (HRs) for the overall survival (OS) and progression-free survival (PFS) with the combination therapy were significantly lower than those with the skin-directed therapy (HR 0.1, p = 0.001; HR 0.2, p = 0.002, respectively). These results suggest that the combination of skin-directed therapy and oral EP improves the clinical outcome of patients with smoldering, skin lesion-bearing ATLL.

A group of atopic dermatitis without IgE elevation or barrier impairment shows a high Th1 frequency: possible immunological state of the intrinsic type.

BACKGROUND: Atopic dermatitis (AD) can be classified into the major extrinsic type with high serum IgE levels and impaired barrier, and the minor intrinsic type with normal IgE levels and unimpaired barrier. OBJECTIVE: To characterize the intrinsic type of Japanese AD patients in the T helper cell polarization in relation to the barrier condition. METHODS: Enrolled in this study were 21 AD patients with IgE<200kU/L (IgE-low group; 82.5±59.6kU/L) having unimpaired barrier, and 48 AD patients with IgE>500kU/L (IgE-high group; 8.050±10.400kU/L). We investigated filaggrin gene (FLG) mutations evaluated in the eight loci common to Japanese patients, circulating Th1, Th2 and Th17 cells by intracellular cytokine staining and flow cytometry, and blood levels of CCL17/TARC, IL-18, and substance P by ELISA. RESULTS: The incidence of FLG mutations was significantly lower in the IgE-low group (10.5%) than the IgE-high group (44.4%) (normal individuals, 3.7%). The percentage of IFN-γ-producing Th1, but not Th2 or Th17, was significantly higher in the IgE-low than IgE-high group. Accordingly, Th2-attracting chemokine CCL17/TARC, was significantly lower in the IgE-low than the IgE-high group. There were no differences between them in serum IL-18 levels, or the plasma substance P levels or its correlation with pruritus. CONCLUSION: The IgE-low group differed from the IgE-high group in that it had much less FLG mutations, increased frequency of Th1 cells, and lower levels of CCL17. In the intrinsic type, non-protein antigens capable of penetrating the unimpaired barrier may induce a Th1 eczematous response.