Shinichi Imafuku

Efficacy and safety of secukinumab in patients with generalized pustular psoriasis: A 52-week analysis from phase III open-label multicenter Japanese study.

Generalized pustular psoriasis (GPP) is a severe inflammatory skin disease characterized by the presence of sterile pustules covering almost the entire body and systemic symptoms such as fever. Secukinumab, a fully human‐recombinant anti‐interleukin‐17A monoclonal antibody was indicated for psoriasis vulgaris and psoriatic arthritis in Japan but is not yet investigated for GPP. In this phase III, open‐label multicenter single arm study, the efficacy and safety of secukinumab as monotherapy or with co‐medication was evaluated in 12 Japanese patients with GPP. All the patients received secukinumab 150 mg s.c. at baseline, week 1, 2, 3 and 4, and then every 4 weeks. Two non‐responders were up‐titrated to 300 mg. Change in GPP severity from baseline was evaluated by clinical global impression (CGI) categorized as “worsened”, “no change”, “minimally improved”, “much improved” or “very much improved”. Treatment success was achieved by 83.3% (n = 10) of patients at week 16 (primary end‐point) with CGI evaluated as “very much improved” (n = 9) and “much improved” (n = 1). Moreover, the area of erythema with pustules improved as early as week 1 and resolved by week 16 in most of the patients. The improvements were sustained throughout 52 weeks. Over the 52‐week treatment period, secukinumab was well tolerated with no unexpected safety signals. Nasopharyngitis, urticaria, diabetes mellitus and arthralgia were the frequent adverse events reported. The data from this study shows that secukinumab can become one of the potent treatment options for GPP.

Topical vitamin D3 analogues induce thymic stromal lymphopoietin and cathelicidin in psoriatic skin lesions

Summary Background  Psoriasis is a chronic inflammatory skin disease of unknown aetiology, and an active form of vitamin D3 (1α,25‐dihydroxyvitamin D3) and its analogues (VD3As) are widely used topical reagents for psoriasis treatment. Besides their well‐known calcium homeostasis functions, VD3As have been shown to have various immune‐modulating effects including the induction of thymic stromal lymphopoietin (TSLP), a master cytokine for inducing Th2 inflammation, in mouse models, but not yet in human psoriasis. VD3As also have been shown to induce cathelicidin, an antimicrobial peptide and strong inducer of innate immunity. Cathelicidin is overexpressed in psoriatic skin lesions; however, its role in this disease seems as yet inconclusive.

Profile of patients with psoriasis associated with hepatitis C virus infection

Psoriasis is a chronic inflammatory skin disease associated with various complications such as arthritis, diabetes mellitus and hypertension. Hepatitis C is caused by chronic infection of hepatitis C virus (HCV), and eventually leads to liver cirrhosis and hepatocellular carcinoma. Although an association between psoriasis and HCV has been reported, there have been no large case series to date. The aim of the present study was to outline the profiles of HCV‐positive psoriatic patients. Patients with a diagnosis of psoriasis who visited Fukuoka University from 1991–2011 were sought in the database, and their medical records were manually checked for detailed information about serum liver enzymes, anti‐HCV antibodies, medical history, and treatments and outcomes of both psoriasis and hepatitis. There were 54 (7.5%) anti‐HCV antibody‐positive patients among the 717 psoriatic patients detected. Male predominance (male/female ratio, 44:10) and late onset (median age, 55 years) were the characteristics of the 54 patients. HCV infection preceded the onset of psoriasis definitely in 80% and probably in 11%. Interferon therapy exacerbated 70% of pre‐existing psoriasis cases, and induced de novo psoriasis in eight patients. Complication with diabetes mellitus was found in 35% of the patients. Our observations suggest that HCV infection can be an inducing factor for psoriasis. In hepatitis C patients, elevated tumor necrosis factor‐α is known to cause progression of hepatic disease and possibly induces psoriasis in patients with a certain predisposition.

Oral tofacitinib efficacy, safety and tolerability in Japanese patients with moderate to severe plaque psoriasis and psoriatic arthritis: A randomized, double-blind, phase 3 study.

Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis and psoriatic arthritis. Japanese patients aged 20 years or more with moderate to severe plaque psoriasis and/or psoriatic arthritis were double‐blindly randomized 1:1 to tofacitinib 5 or 10 mg b.i.d. for 16 weeks, open‐label 10 mg b.i.d. for 4 weeks, then variable 5 or 10 mg b.i.d. to Week 52. Primary end‐points at Week 16 were the proportion of patients achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75) and Physicians Global Assessment of “clear” or “almost clear” (PGA response) for psoriasis, and 20% or more improvement in American College of Rheumatology criteria (ACR20) for patients with psoriatic arthritis. Safety was assessed throughout. Eighty‐seven patients met eligibility criteria for moderate to severe plaque psoriasis (5 mg b.i.d., n = 43; 10 mg b.i.d., n = 44), 12 met eligibility criteria for psoriatic arthritis (5 mg b.i.d., n = 4; 10 mg b.i.d., n = 8) including five who met both criteria (10 mg b.i.d.). At Week 16, 62.8% and 72.7% of patients achieved PASI75 with tofacitinib 5 and 10 mg b.i.d., respectively; 67.4% and 68.2% achieved PGA responses; all patients with psoriatic arthritis achieved ACR20. Responses were maintained through Week 52. Adverse events occurred in 83% of patients through Week 52, including four (4.3%) serious adverse events and three (3.2%) serious infections (all herpes zoster). No malignancies, cardiovascular events or deaths occurred. Tofacitinib (both doses) demonstrated efficacy in patients with moderate to severe plaque psoriasis and/or psoriatic arthritis through 52 weeks; safety findings were generally consistent with prior studies.

Poor adherence to medication as assessed by the Morisky Medication Adherence Scale-8 and low satisfaction with treatment in 237 psoriasis patients

Previously we assessed the medication adherence for oral and topical remedies by a translated Japanese version of the Morisky Medication Adherence Scale‐8 (MMAS‐8) together with socioeconomic backgrounds in 3096 Japanese dermatological patients, and found the medication adherence, especially to topical drugs, was poor in these patients. In order to elucidate the disease‐specific sociomedical factors, we further sub‐analyzed the medication adherence in 237 psoriasis patients and compared it with that in other dermatological diseases such as atopic dermatitis, urticaria or tinea. This study was conducted among patients registered in monitoring system and 3096 eligible patients were enrolled. Our web‐based questionnaire included the following items such as age, sex, annual income, main health‐care institution, experience of effectiveness by oral or topical medication, overall satisfaction with treatment, and MMAS‐8 for oral or topical medication. Mean adherence score by MMAS‐8 was 5.2 for oral and 4.3 for topical medication. More patients with psoriasis used a university hospital and fewer used a private clinic compared with those with the other skin disease patients. Experience of drug effectiveness by oral medication and overall satisfaction with treatment was lower in psoriasis patients than in other patients. In oral medication, significantly better adherence was observed in those of higher age and with higher annual income. The adherence to medication, especially to topical drugs, was poor in 237 psoriasis patients. We speculated that some severe psoriasis patients were not sufficiently treated systemically and were resistant to topical therapy, leading to poor adherence.

Vitamin D-dependent cathelicidin inhibits Mycobacterium marinum infection in human monocytic cells

BACKGROUND 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) up-regulates the production of human cathelicidin antimicrobial peptide (CAMP) from monocytes/macrophages infected with Mycobacterium tuberculosis (M. tbc). CAMP facilitates the co-localization of autophagolysosomes with M. tbc, promoting the antimicrobial activity of monocytes. Mycobacterium marinum (M. marinum) is an acid-fast bacillus that causes less severe granulomatous skin lesions compared with M. tbc. OBJECTIVE We investigated whether autophagic antimicrobial activity is promoted by 1,25(OH)2D3 or C-terminal of cathelicidin LL-37 in human monocytes upon infection with M. marinum. METHODS Human monocytes (THP-1) were infected with M. marinum. Effects of simultaneous treatments of 1,25(OH)2D3, exogenous LL-37 peptide, autophagolysosome inhibitors, 3-methyladenine or chloroquine, were examined. RESULTS CAMP was strongly induced by adding 1,25(OH)2D3 to the culture of THP-1 cells. In the absence of 1,25(OH)2D3 M. marinum infection alone did not induce CAMP, however, simultaneous addition of 1,25(OH)2D3 to M. marinum infection accelerated CAMP production more than 1,25(OH)2D3 alone. Proliferation of M. marinum was markedly decreased in the presence of 1,25(OH)2D3 or exogenous LL-37 in THP-1 cells. Co-localization of CAMP with autophagolysosome was evident in 1,25(OH)2D3 and LL-37 treated THP-1 cells after M. marinum infection. Autophagolysosome inhibitors abrogated the antimicrobial effects of 1,25(OH)2D3 and exogenous LL-37 against M. marinum infection in THP-1 cells. CONCLUSIONS Human monocytic cells, whose CAMP production is up-regulated by 1,25(OH)2D3-vitamin D receptor pathway, accelerate antimicrobial function of autophagolysosome in M. marinum infection.

Possible association of hepatitis C virus infection with late‐onset psoriasis: A hospital‐based observational study

Psoriasis is a chronic inflammatory disease mainly involving the skin and joints, mediated by pro‐inflammatory cytokine tumor necrosis factor (TNF)‐α. In hepatitis C, continuous inflammation mediated by TNF‐α leads to liver cirrhosis and diabetes mellitus. Hence, psoriasis and hepatitis C have pathophysiological factors in common. An epidemiological association between the two conditions has been reported, but no detailed research has yet been performed. Frequency of hepatitis C virus (HCV) infection was assessed in 717 patients with psoriasis and 38 057 with all other dermatological diseases who visited Fukuoka University Hospital in 1998–2011. HCV+ and HCV− psoriatic patients were further compared. Frequency of HCV infection was significantly higher in psoriasis (7.5%) than in controls (3.3%) in overall ages. When stratified by age at the first visit, the frequency was significantly higher in patients with psoriasis than in controls aged in their 60s (11.8% vs 6.6%, respectively, P = 0.0215) and 70s (19.5% vs 7.3%, P < 0.0001). HCV+ psoriatic patients were significantly older at onset than HCV− ones (median, 54 vs 39 years), stronger male predominance (male/female ratio, 4.4:1), similar family history of psoriasis, higher association of diabetes mellitus and hypertension, and significantly lower body mass index (22.4 ± 2.73 vs 24.2 ± 4.61), in age‐stratified (≥40 years) analysis. HCV+ psoriatic patients were less obese, but still had a higher frequency of diabetes mellitus and hypertension, possibly due to chronic inflammation in the liver and other organs. HCV infection may trigger psoriasis, especially late‐onset psoriasis, possibly via overproduction of TNF‐α, a common mediator of the two conditions.

Cutaneous pseudolymphoma induced by adalimumab and reproduced by infliximab in a patient with arthropathic psoriasis

pet., palladium chloride 1% pet., ammonium tetrachloroplatinate 0Æ15% pet. and ammoniated mercury 1% pet.) and the dental technicians series (including acrylates, all in pet.) of the DKG. In addition, a specimen of the patient’s own dental prosthesis was also tested. Contact allergens were supplied by Almirall Hermal (Reinbek, Germany) and were applied to the patient’s upper back for 48 h using Finn Chambers on Scanpor tape (Epitest, Tuusula, Finland). In the test area of the patient’s own denture, readings at 48 and 72 h showed an erythema, palpable infiltration and papules, as well as an erosion probably as a result of ruptured vesicles (see Fig. 1). This test reaction was assessed as moderate positive allergic according to the ICDRG and DKG guidelines. Furthermore, an allergic patch test reaction to propolis was detected, which had no current clinical relevance. We were surprised that the patient had no itching in the dental prosthesis test area of her back. Even though there were no visible intraoral abnormalities, we decided to exclude an infectious cause of the test reaction. We performed smears from the oral mucosa and dental prosthesis, as well as skin scrapings from the patch test area. The microscopic examination of all native preparations showed mycelia. Afterwards colonies of Candida were cultivated on agar plate chromID Candida (bioMérieux, Marcy l’Etoile, France). The intraoral burning pain disappeared within 1 week following topical antifungal treatment of the oral mucosa and denture with miconazole. Dental materials are very seldom responsible for intraoral allergic reactions when considering the extent of their use. Allergic factors seem to be of minor relevance in most cases of BMS, but may be related to the symptoms in a few patients. Patch testing is the diagnostic method to assess or exclude an intraoral contact allergy. It is noteworthy that cutaneous and intraoral contact allergic reactions are not always analogous. The morphological and immunological characteristics of the oral mucosa may produce tolerance to substances in the oral cavity but which evoke a positive patch test reaction on the skin. Furthermore, saliva plays an important role by quickly diluting and eliminating allergens in the oral cavity. The pathogenesis of BMS is poorly understood and many cases are idiopathic. For patient treatment it is important to distinguish between primary BMS, obviously related to neuropathic disorders and resistant to therapy, and secondary BMS associated with local and systemic factors. For the latter condition, eliminating these precipitating factors may lead to improvement of the pain. BMS is most prevalent in postmenopausal women and can occur at any site of the oral cavity, with the tongue as the most frequently affected site. Oral candidiasis is a relatively common, incompletely understood, opportunistic infection with a variety of clinical manifestations and classifications. Our case report supports the results of previous studies, that BMS, particularly glossodynia, may be caused by oral candidiasis without visible manifestations. Subclinical intraoral Candida colonization may lead to ‘falsepositive’ patch test reactions to the patient’s dental prosthesis. The misdiagnosis of intraoral contact allergy may result in expensive replacement of dental materials and may cause discomfort for the patient. The first diagnostic step in evaluating a doubtful contact allergy to the patient’s denture should be an exclusion of a Candida infection, particularly in patients without visible intraoral abnormalities and with intermittent oral burning sensations.

Kasabach-Merritt syndrome associated with angiosarcoma of the scalp successfully treated with chemoradiotherapy.

Sir, Kasabach-Merritt syndrome (KMS) is a condition of consumption coagulopathy in patients bearing vascular tumours and malformations. KMS is seen not only in infants bearing large haemangiomas, but has also been observed in various vascular diseases, such as bluerubber-bleb nevus syndrome (1) and Osler-Weber-Rendu disease (2). Angiosarcoma is a rare malignancy of vascular or lymphatic endothelial cell origin. Angiosarcoma has a poor prognosis and association with KMS, usually seen at advanced stage, makes the patients’ clinical course worse (3). KMS with early stage angiosarcoma of the scalp has not been reported previously. We report here a case of a now 70-year-old patient with KMS associated with angiosarcoma of the scalp and disseminated intravascular coagulation, which was successfully controlled by anti-cancer treatment.

Sentinel node biopsy for high-risk cutaneous squamous cell carcinoma

AIM The use of sentinel node biopsy (SNB) has not been established for cutaneous squamous cell carcinoma (SCC), and its clinical significance has not been clarified. We investigated the usefulness of and indication criteria for SNB for cutaneous SCC. MATERIALS AND METHODS Twenty-six patients with high-risk cutaneous SCC that had undergone SNB were retrospectively reviewed. SNB was performed with either the dye method or a combined dye and radioisotope method. RESULTS Of the 26 patients, recurrence or metastasis was observed in 5 cases (19.2%). Six cases (23.1%) were sentinel node (SN) metastasis-positive. All cases that were SN metastasis-negative survived, and 4 of 6 SN metastasis-positive (66.7%) cases died of the original disease. The 3-year survival rates of all cases, SN metastasis-negative cases, and SN metastasis-positive cases were 82.2%, 100%, and 20.8%, respectively. Tumour thickness was a significant risk factor for SN metastasis (p = 0.049). Recurrence occurred in 4 of 7 cases involving external genitalia, 3 of which died. The 3-year survival rates of external genitalia and nongenital cases were 47.6% and 94.1%, respectively (p = 0.016). CONCLUSIONS SNB aided the early discovery and treatment of latent lymph node metastasis and helped predict whether SN metastasis had occurred, and therefore helped predict patient prognosis. These results suggest that thickness of the primary lesion is an indication criterion for the use of SNB in cases of cutaneous SCC. SNB should be considered in cases where tumour thickness is ≥2 mm and actively performed in cases ≥5 mm.