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Scleredema adultorum, also known as scleredema of Buschke, is a rare connective tissue disease with unknown etiology, which is characterized by diffuse skin induration of face, neck, upper chest, back, shoulders and arms. Although there is no established treatment for this disease, the efficacy of phototherapy has been reported. We herein describe a case of scleredema adultorum successfully treated with narrow-band ultraviolet B and discuss a potential mechanism explaining its efficacy for fibrotic skin diseases.

The clinical use of adalimumab and infliximab, human anti-tumor necrosis factor (TNF)-α monoclonal antibodies, for psoriasis began in January 2010. In January 2011, ustekinumab, a human anti-interleukin-12/23p40 (IL-12/23p40) monoclonal antibody, was newly approved as the third biologic with an indication for psoriasis. While all of these biologics are expected to exhibit excellent therapeutic effect for psoriasis and to contribute to the improvement of quality of life in patients, these drugs require careful safety measures to prevent adverse drug reactions, such as serious infections. The new guidance, an English version prepared by revising the Japanese Guidance/Safety Manual for Use of Biologics for Psoriasis 2011 (in Japanese), is intended to provide up-to-date, evidence-based recommendations and safety measures on the use of biologics, and describes the optimal use of the three biologics, medical requirements for facilities for using biologics, details of safety measures against reactivation of tuberculosis and hepatitis B virus infection, and recommendable combination therapies with biologics.

This study evaluates the effect of ustekinumab on health-related quality of life (HRQoL) in Japanese patients with moderate-to-severe plaque psoriasis through 64 weeks. A total of 158 patients were randomized to receive subcutaneous injections of ustekinumab 45 mg (n = 64) or 90 mg (n = 62) at weeks 0, 4, and every-12-weeks, or placebo (n = 32) with crossover to ustekinumab at week 12. Secondary study endpoints included change in Dermatology Life Quality Index (DLQI) at week 12. Other assessments included the 36-item Short Form health survey to assess Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, and Psoriasis Disability Index (PDI), a psoriasis-specific instrument to assess HRQoL. Baseline demographic and disease characteristics were similar across randomized treatment groups. Ustekinumab-treated patients had significantly greater mean improvements in DLQI from baseline to week 12 (45 mg: 8.0 ± 6.5; 90 mg: 7.4 ± 6.5) than placebo-treated patients (0.3 ± 5.3; P < 0.0001 for each), and these improvements were maintained through week 64. Also at week 12, significant improvements from baseline in PDI scores were observed in ustekinumab-treated patients (45 mg: 8.6 ± 9.6; 90 mg: 12.0 ± 11.8) compared with placebo-treated patients (-0.1 ± 4.2). Improvements in the PCS (45 mg: 7.8 ± 14.5; 90 mg: 5.1 ± 12.0) and MCS (45 mg: 5.3 ± 9.8; 90 mg: 5.8 ± 10.5) scores were also observed in ustekinumab-treated patients at week 12. Placebo-treated patients who crossed-over to ustekinumab achieved improvements in HRQoL comparable to those observed in patients originally randomized to ustekinumab. Ustekinumab significantly improves HRQoL in Japanese patients with moderate-to-severe plaque psoriasis through week 64.

Objective To identify the 140-kd autoantigen recognized by anti-155/140 autoantibodies that are associated with adult cancer-associated dermatomyositis (DM) and juvenile DM and to determine the clinical relevance of anti-155/140 antibodies in a large cohort. Methods Sera from 456 DM patients were assessed for the presence of anti-155/140 antibodies by immunoprecipitation using K562 cell extracts as substrate. Using immunoprecipitation and Western blotting, we then examined whether anti-155/140–positive sera recognized transcription intermediary factor 1α (TIF-1α), TIF-1β, and TIF-1γ. The clinical associations of antigen reactivity were also evaluated. Results Anti-155/140–positive sera reacted with 140-kd TIF-1α in addition to 155-kd TIF-1γ. Among sera from 456 DM patients, 52 were reactive with both TIF-1α and TIF-1γ, while another 25 were reactive with TIF-1γ alone. Additionally, 7 were reactive with TIF-1β. Malignancy was more frequently found in adult patients with both anti–TIF-1α and anti–TIF-1γ antibodies than in those with anti–TIF-1γ antibodies alone (73% versus 50%; P < 0.05). In addition to juvenile DM patients and middle-aged and older DM patients with high percentages of malignancy, 8 “young adult” DM patients without malignancy had these autoantibodies. Conclusion Anti-155/140 antibodies target TIF-1 family proteins, TIF-1α and TIF-1β, in addition to TIF-1γ. Since TIF-1 proteins have significant roles in oncogenesis, these antibodies may be produced during misdirected antitumor immunity.

ObjectivesMyositis-specific autoantibodies (MSAs) are useful tools for identifying clinically homogeneous subsets and predicting prognosis of patients with idiopathic inflammatory myopathies (IIM) including polymyositis (PM) and dermatomyositis (DM). Recent studies have shown that anti-NXP2 antibody (Ab) is a major MSA in juvenile dermatomyositis (JDM). In this study the frequencies and clinical associations of anti-NXP2 Ab were evaluated in adult patients with IIM.MethodsClinical data and serum samples were collected from 507 adult Japanese patients with IIM (445 with DM and 62 with PM). Eleven patients with JDM, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with idiopathic pulmonary fibrosis were assessed as disease controls. Serum was examined for anti-NXP2 Ab by immunoprecipitation and western blotting using polyclonal anti-NXP2 Ab.ResultsSeven patients (1.6%) with adult DM and one (1.6%) with adult PM were positive for anti-NXP2 Ab. Except for two patients with JDM, none of the disease controls were positive for this autoantibody. Among eight adult patients with IIM, three had internal malignancies within 3 years of diagnosis of IIM. Another patient with DM also had a metastatic cancer at the diagnosis. All of the carcinomas were at an advanced stage (stage IIIb–IV).ConclusionsWhile less common than in juvenile IIM, anti-NXP2 Ab was found in adult IIM. Anti-NXP2 Ab may be associated with adult IIM with malignancy.

Nephrogenic systemic fibrosis (NSF) is a fibrotic disease that presents with a history of renal dysfunction. The differential diagnosis generally includes scleromyxedema, systemic sclerosis, and morphea. Especially, scleromyxedema can be extremely difficult to distinguish microscopically. Although the fibrocytes in NSF are often positive for CD34 and procollagen-I, this is not specific for NSF. We identified positive iron staining in the skin of a patient with NSF and investigated whether this was a specific feature among 9 patients with NSF reported in Japan. We found that 6 of 9 patients showed positive iron staining in the dermal fibrocytes. The amount of iron deposition seemed to have no correlation with the degree of fibrosis or duration of the skin lesions but correlated with apparent history of the use of gadolinium-based contrast agents. As controls, skin biopsies from patients with scleromyxedema, morphea, and systemic sclerosis were evaluated by iron staining. None of these control patients showed iron deposition, indicating that positive iron staining may be specific to NSF and can be a useful tool for NSF diagnosis.

Basic fibroblast growth factor (bFGF) has been shown to promote wound healing. The present trial evaluated the clinical efficacy of bFGF for diabetic ulcer, a type of refractory skin ulcer, and the dose-response relationship. This was designed as a randomized, double-blind, dose-ranging, placebo-controlled trial. A total of 150 patients with non-ischaemic diabetic ulcers measuring 900 mm2 or less were randomized into a placebo group (n = 51), a 0.001% bFGF group (n = 49) and a 0.01% bFGF group (n = 50), and 148 of these patients received treatment for 8 weeks or less. The efficacy evaluation was carried out on 139 patients who met the protocol in this trial. The primary outcome was the percentage of patients showing 75% or greater reductions in the area of ulcer. The area of ulcer decreased by 75% or more in 57.5% (27/47), 72.3% (34/47), and 82.2% (37/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively, and differences were significant between the 0.01% bFGF and placebo groups (p = 0.025). The cure rate was 46.8% (22/47), 57.4% (27/47), and 66.7% (30/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively. The findings obtained in this trial showed wound healing accelerating effects of bFGF on diabetic ulcers.

To determine the current status of psoriatic arthritis, we conducted a retrospective survey by sending questionnaires. The newly visited psoriatic arthritis patients accounted for 10.5% (95% confidence interval, 7.9-13%) of all newly visited psoriasis patients (n = 2581) between April 2014 and March 2015 in 73 institutes. Additionally, questionnaires on detailed patients' information were returned by 92 institutes (response rate, 70.8%), where 1282 patients with psoriatic arthritis were identified. There was a male predominance. The mean onset age of psoriatic arthritis was 44.9 years, and mean onset age for cutaneous psoriasis (36.4 years) was lower than that for arthritis (45.1 years). The mean duration in patients who developed psoriasis prior to arthritis was 11.2 years, while that in patients preceded by arthritis was 4.4 years. According to the Moll and Wright criteria, polyarthritis type was most common (36%), followed by distal interphalangeal type (26%) and oligoarthritis type (22%). Peripheral joint pain was 61.5%, back pain such as lumbago and neck pain was 34.3%. Enthesitis and dactylitis were observed in 28.3% and 59.2%, respectively. Biologics were used in 55.5% of psoriatic arthritis patients, and 31% used disease-modifying antirheumatic drugs. In conclusion, the ratio of psoriatic arthritis in Japan is increasing, and nearly 10% of new psoriasis patients had psoriatic arthritis. This study shows the current status of psoriatic arthritis in Japan, including several unexpected findings such as male predominance, longer duration between the onset of cutaneous psoriasis and arthritis, and dominance of polyarthritis.

Desmoplastic trichoepithelioma is a rare tumor that usually exhibits the distinct clinical features of a solitary granuloma annulare-like growth on the face. We experienced two cases of desmoplastic trichoepithelioma, one of which showed unusual clinical features and the other of which was a typical case. The first case was a 20-year-old female who presented with a five year history of a solitary yellowish nodule, 5 mm in diameter, centrally between the eyebrows. There was no central dimple or elevated border. The other case was a 40-year-old female who presented with a ten year history of a solitary nodule, 6 mm in diameter on her left cheek. The latter lesion had a typical depressed area in the center of the nodule with elevated borders and could be clinically diagnosed as desmoplastic trichoepithelioma. The histopathological examination revealed that both of them were desmoplastic trichoepithelioma. Histopathological comparison of the two specimens suggested that the clinical dimple in the center of the first tumor might be the result of stromal dystrophic changes induced by the tumor.

A 61-year-old man was admitted to our hospital because of edematous erythema on his upper eyelids and dry cough. No subjective nor objective findings suggestive of skeletal muscle involvement, such as muscle weakness and elevated levels of aldolase and creatine phosphokinase were noted. Chest high-resolution computed tomography revealed a ground glass opacity and consolidation of his lower lung. Skin biopsy findings were compatible with dermatomyositis. Therefore, he was diagnosed as amyopathic dermatomyositis (ADM) with acute interstitial pneumonia and treatment with steroid pulse therapy was started. Since histological evaluation showed diffuse alveolar damage during the initial treatment, the treatment was changed into the combination therapy of prednisolone and cyclosporine. However, his acute interstitial pneumonia did not respond to this treatment and passed away by aggravation of a breathing state and concurrence of disseminated intravascular coagulation. Japanese patients with ADM have been shown to be more frequently associated with intractable acute interstitial pneumonia than Caucasian patients, suggesting that the racial difference influences the occurrence of acute interstitial pneumonia in ADM. Since autoantibodies specific for ADM have not been detected, we performed immunoprecipitation analysis using 35S methionine-labeled K562 cells to identify them. His sera immunoprecipitated a polypeptide of 140 kDa. The 140 kDa polypeptide might be one of autoantibodies specific for ADM with acute interstitial pneumonia, although future analysis using a larger number of patients with ADM will be required to confirm this result.

Generalized pustular psoriasis (GPP) is a rare but notoriously recalcitrant cutaneous diseases. Therefore, there have been few reports of more than ten patients with GPP who were treated at the same institution. The severity of this disease and its response to each therapeutic modality vary among patients. In some GPP is life-threatening, but in others it may show a benign, chronic course for a long period of time. Before starting treatment, a knowledge of the therapeutic efficacy and side effects of each drug used in the treatment of GPP is necessary. In our multicenter study, we compared the effectiveness of and adverse reactions to several systemically administered drugs. Following the development of a unique classification of the disease severity based on scoring the clinical symptoms and the laboratory findings, we propose here therapeutic guidelines for the treatment of GPP.

Background: The Japanese Society for Psoriasis Research has conducted an annual survey of psoriasis patients in Japan from 1982 to 2001. Objective: To perform the epidemiological study about a survey of psoriasis patients conducted in Japan for twenty years. Methods: A sample of 28628 cases was collected from 148 dermatology centers throughout Japan. The reports from each center were analyzed. Results: Males (65.8%) were predominant over females (34.2%) in number. The vast majority of cases (86.0%) had plaque-form of psoriasis vulgaris, and 812 cases (2.8%) showed guttate psoriasis. Psoriatic erythroderma (0.8%), generalized pustular psoriasis (0.9%), and localized pustular psoriasis (0.5%) were rare. Three hundred of the patients (1.0%) manifested psoriatic arthritis. Local corticosteroids (67.8%) were the most used modalities, whereas local vitamin D 3 preparations (2.4%) were rarely used. For phototherapeutical treatments, topical (12.1%) and systemic (7.5%) PUVA were predominant over UVB therapy (0.5%). In systemic treatments, drugs from the herbal medicine was the first (14.2%), followed by etretinate (7.6%), nonsteroidal anti-inflammatory drugs (4.4%), oral corticosteroids (4.1%), methotrexate (2.8%), cyclosporine (1.6%), and anti-cancer drugs (1.4%). Conclusion: This survey was the first epidemiological study throughout Japan.

Summary Background JTE-052 is a novel Janus kinase inhibitor presently under clinical development for the topical treatment of atopic dermatitis (AD). Objectives To evaluate the efficacy and safety of JTE-052 ointment in Japanese adult patients with AD. Methods Patients with moderate-to-severe AD were randomized (2: 2: 2: 2: 1: 1) to receive JTE-052 ointment at 0·25%, 0·5%, 1% or 3%, the vehicle ointment or tacrolimus 0·1% ointment (reference) twice daily for 4 weeks. The primary efficacy end point was the percentage change in modified Eczema Area Severity Index (mEASI) score from baseline at the end of treatment (EOT). Secondary efficacy end points included change from baseline in the pruritus numerical rating scale (NRS) score. Results In total, 327 patients were enrolled. At EOT, the least-squares mean percentage changes from baseline in mEASI score for JTE-052 at 0·25%, 0·5%, 1% and 3% and the vehicle ointment were −41·7%, −57·1%, −54·9%, −72·9% and −12·2%, respectively. All JTE-052 groups showed significant reductions of mEASI score vs. the vehicle group (P < 0·001 for all). In the tacrolimus group, the mean percentage change in mEASI score was −62·0%. The JTE-052 groups also showed significant improvement in other parameters; notably, the pruritus NRS score was reduced as early as day 1 night-time. JTE-052 ointment at doses up to 3% was safe and well tolerated. Conclusions Topical JTE-052 markedly and rapidly improved clinical signs and symptoms in Japanese adult patients with moderate-to-severe AD, with a favourable safety profile. The study results indicate that topical JTE-052 is a promising therapeutic option for AD. The trial registration number is JapicCTI-152887.

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SUMMARYTo determine the prevalence and the characterization of antibodies to endothelial cells in patients with SSc, serum samples from 80 patients with SSc, 20 patients with systemic lupus erythematosus (SLE), and 20 healthy control subjects were examined by ELISA using cultured human umbilical vein endothelial cells (HUVEC), indirect immunofluorescence analysis (IIF), and immunoblotting using cytoplasmic extract of HUVEC. IgG and/or IgM isotype anti-endothelial cell antibodies (AECA) were demonstrated by ELISA in 43 of 80 patients with SSc (54%), in 15 of 20 patients with SLE (75%), and in none of 20 healthy control subjects. Immunofluorescence analysis on HUVEC substrate showed homogeneous cytoplasmic staining. Immunoblotting demonstrated that these patients had antibodies directed to one or several antigens of approximately 60, 90, 110 and 140 kD, and the most common responses were to the 90-kD antigen. By the immunofluorescence method using HUVEC, affinity-purified anti-90-kD antibodies showed identical cytoplasmic staining to that produced by sera positive for AECA. Furthermore, AECA were closely correlated with pulmonary fibrosis in patients with SSc. These findings suggest that patients with SSc have abnormal antibodies to endothelial cell antigens, and support the hypothesis that endothelial dysfunction is involved in the development of this disease.

Skin fibrotic disorders are understood to develop under the influence of some growth factors, such as transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), or connective tissue growth factor (CTGF). To establish an appropriate animal model of skin fibrosis by exogenous application of growth factors, we investigated the in vivo effects of growth factors by injecting TGF-beta, CTGF, and bFGF into the subcutaneous tissue of newborn mice. A single application of TGF-beta or bFGF resulted in the formation of transient granulated tissue that disappeared despite 7 days of consecutive injections. A single CTGF injection also caused slight granulation. However, injecting TGF-beta plus CTGF produced long-term fibrotic tissue, which persisted for at least 14 days. Also, fibrotic tissue was observed when CTGF was injected from 4 to 7 days after TGF-beta injections for the first 1-3 days. In situ hybridization analysis revealed the expression of CTGF mRNA in the fibroblasts at least in a few fibrotic conditions. These findings suggest that either CTGF mRNA or an application of exogenous CTGF protein is required for the development of persistent fibrosis. From our study, it appears that interaction of several growth factors is required for persistent fibrotic tissue formation, with TGF-beta causing the induction and CTGF needed for maintenance of skin fibrosis. The animal model on skin fibrosis by exogenous application of growth factors developed in this study may prove useful for future studies on fibrotic disorders.

This study investigated the prevalence and clinical significance of anti-ribosomal P protein (anti-P) antibodies in patients with systemic sclerosis (SSc). Serum samples from 150 patients with SSc were examined by indirect immunofluorescence, ELISA and immunoblotting. Anti-P antibodies were detected in four (3%) patients with SSc. Three of the four patients showed SSc/SLE (systemic lupus erythematosus) overlap syndrome, but psychiatric disorders were not observed in these patients. By longitudinal immunoblotting analysis one patient, who was initially diagnosed with SSc, later developed anti-P antibodies along with clinical manifestations of SLE. Our data suggest that anti-P antibodies are uncommon in SSc and that the presence of anti-P antibodies in patients with SSc indicates an overlap with SLE.

We investigated the responses of normal and scleroderma fibroblasts to various growth factors, especially transforming growth factor-beta 1 (TGF-beta 1). The effects of various growth factors on [3H]thymidine incorporation in normal and scleroderma fibroblasts were examined. [125I]-labeled platelet-derived growth factor (PDGF)-BB binding in scleroderma and normal fibroblasts was examined both in the presence and absence of TGF-beta 1 (1 ng/ml). Cytoplasmic protein was isolated and analyzed by Western blotting. Total RNA from fibroblasts was also isolated and analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) using specific primer sets. Mitogenic responses to TGF-beta 1 (0.33-1 ng/ml) in seven scleroderma fibroblast strains were significantly greater than those in normal controls. [125I]-PDGF-BB binding to scleroderma fibroblasts was increased after TGF-beta 1 stimulation. The increased response to TGF-beta 1 was shown to be mediated through PDGF-like protein induction; TGF-beta 1-treated scleroderma fibroblasts produced greater amounts of 36-kD PDGF-like protein, which was reported previously as connective tissue growth factor (CTGF), than did TGF-beta 1-treated normal fibroblasts. TGF-beta 1 treatment also upregulated PDGF-alpha receptor expression in scleroderma fibroblasts but not in normal dermal fibroblasts. mRNA expression of CTGF and PDGF-alpha receptor was correlated with the above protein expression. These observations suggest that the increased growth response to TGF-beta 1 in scleroderma fibroblasts is mediated through the induction of CTGF and PDGF-alpha receptor.

Sclerotic skin change in systemic sclerosis (SSc) usually accompanies increased skin thickness. In order to quantify the cutaneous changes and to clarify the changes in the 'uninvolved' skin in systemic sclerosis (SSc), we measured the skin thickness on the chest, the forearms and the hands of 79 patients with SSc and 81 healthy controls with a B-mode ultrasound (30 MHz) apparatus. The thickness of the 'uninvolved', as well as the 'involved' skin in patients with SSc was significantly greater than that of healthy controls. Increased skin thickness on the forearms and/or the hands showed a 64.6% sensitivity and a 100% specificity for SSc. These results indicated that the skin which appears to be 'uninvolved' in patients with SSc is already pathologic, as shown by increased thickness. Moreover, measurement of skin thickness may be beneficial in the diagnosis of this disease at an early stage.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare neoplasm of eccrine sweat gland origin that typically presents as a mass on the distal extremities. It is associated with high rates of local recurrence and distal metastasis. Presented here is the case of a 61-year-old male who developed ADPA on his distal sole just above the head of the first metatarsal bone. Wide excision of the tumor involving a 3-cm skin margin from previous surgical scar of biopsy was performed, and sentinel lymph node biopsies were taken from the popliteal fossa and inguinal regions. During this wide excision surgery, the pedicle for the reverse medial plantar flap had to be removed along with the tumor. Reconstructive surgery was performed with a medial plantar flap that was vascularized with a lateral plantar artery in a reverse fashion. This flap successfully covered the defect and the patient can walk without any problems. However, the pedicle crossed the donor site somewhat tightly and the flap became congested for a while. Therefore, it is important to ensure careful handling of the donor site when performing this procedure.

This study evaluates the effect of ustekinumab on health-related quality of life (HRQoL) in Japanese patients with moderate-to-severe plaque psoriasis through 64 weeks. A total of 158 patients were randomized to receive subcutaneous injections of ustekinumab 45 mg (n = 64) or 90 mg (n = 62) at weeks 0, 4, and every-12-weeks, or placebo (n = 32) with crossover to ustekinumab at week 12. Secondary study endpoints included change in Dermatology Life Quality Index (DLQI) at week 12. Other assessments included the 36-item Short Form health survey to assess Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, and Psoriasis Disability Index (PDI), a psoriasis-specific instrument to assess HRQoL. Baseline demographic and disease characteristics were similar across randomized treatment groups. Ustekinumab-treated patients had significantly greater mean improvements in DLQI from baseline to week 12 (45 mg: 8.0 ± 6.5; 90 mg: 7.4 ± 6.5) than placebo-treated patients (0.3 ± 5.3; P0.0001 for each), and these improvements were maintained through week 64. Also at week 12, significant improvements from baseline in PDI scores were observed in ustekinumab-treated patients (45 mg: 8.6 ± 9.6; 90 mg: 12.0 ± 11.8) compared with placebo-treated patients (-0.1 ± 4.2). Improvements in the PCS (45 mg: 7.8 ± 14.5; 90 mg: 5.1 ± 12.0) and MCS (45 mg: 5.3 ± 9.8; 90 mg: 5.8 ± 10.5) scores were also observed in ustekinumab-treated patients at week 12. Placebo-treated patients who crossed-over to ustekinumab achieved improvements in HRQoL comparable to those observed in patients originally randomized to ustekinumab. Ustekinumab significantly improves HRQoL in Japanese patients with moderate-to-severe plaque psoriasis through week 64.

Nephrogenic systemic fibrosis is a fibrosing disorder that affects patients with advanced renal dysfunction and is associated with gadolinium-based contrast media. As the number of reports increase, it is becoming clear that its clinical course and symptoms are various. We describe a 14-year-old boy and 71-year-old man with nephrogenic systemic fibrosis and review the Japanese cases documented thus far. In Japan, there are only 10 cases definitely associated with gadolinium, whereas over 500 cases have been recorded worldwide. We found a remarkable difference in clinical signs among Japanese cases. Some cases showed keratotic papules or plaques on the extremities. This group tended to develop symptoms after a shorter interval following gadolinium exposure. The remainder of the cases presented glossy and smooth surfaces, with symptoms tending to develop after a longer interval following their last gadolinium exposure. The discrepancies between the actual and the estimated number of patients, and the various clinical manifestations can be explained by the comparatively smaller dosage of gadolinium-based contrast agents commonly administrated in Japan, in contrast to the higher dosages administrated in the USA and Europe.

This phase 2/3, double-blind, placebo-controlled study was designed to assess the safety and efficacy of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis. Overall, 158 patients were randomized to receive ustekinumab 45 or 90 mg at weeks 0, 4, and every 12 weeks, or placebo with cross-over to ustekinumab at week 12. The primary end-point was the proportion of patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 12. Physician's Global Assessment (PGA), Dermatology Life Quality Index (DLQI), Nail Psoriasis Severity Index and joint pain Visual Analog Scale (VAS) were also measured. At week 12, 59.4% and 67.7% of ustekinumab 45 and 90 mg patients achieved PASI 75, respectively, compared with 6.5% in the placebo group (P0.0001 each). PASI 75 responses were maintained through week 64 in 65.0% and 78.6% of the ustekinumab-treated patients, respectively. Placebo cross-over patients had similar responses to ustekinumab-treated patients. Significant improvements in PGA, DLQI and VAS scores were observed at week 12 and generally maintained over time. Adverse events during the placebo-controlled period were similar among groups (45 mg, 65.6%; 90 mg, 59.7%; placebo, 65.6%). Serious adverse events were observed in 0%, 4.8% and 6.3% of patients, respectively. Through week 72, similar rates and types of adverse events and serious adverse events were reported in patients receiving 45 and 90 mg. Rates of injection site reactions and antibodies to ustekinumab were low. Ustekinumab was efficacious and generally well-tolerated in Japanese patients with moderate-to-severe plaque-type psoriasis through 72 weeks. These results are consistent with those reported in the global, phase 3 studies.

抗nRNP抗体陽性の膠原病例は混合性結合組織病(MCTD)を含む多様な病態および経過をとることが知られている。今回われわれは慢性関節リウマチ(RA)と診断されていたMCTDの2例を報告した。症例1は関節痛で初発し, RA因子陽性のためRAと診断されたが, 手指の変形を伴わない関節痛が長期に持続していたため, 抗核抗体を測定したところ抗nRNP抗体陽性と判明した。手指には軽度腫脹がみられ, 胸部X線上肺線維症が認められた。プレドニン®10mg/日内服にて関節痛は著明に軽減した。症例2も関節痛で初発し, RA因子陽性のためRAと診断されたが, レイノー現象が出現してきたため抗核抗体を測定したところ, 抗nRNP抗体陽性と判明した。手指には軽度腫脹がみられたが, 内臓病変の合併は認められなかった。両者ともRAをはじめとする古典的膠原病の診断基準のいずれをも満たさず, 症例1はMCTD, 症例2はMCTD不全型と診断した。抗nRNP抗体陽性52例の初発症状を解析したところ, 関節痛で初発するものが19.2%を占めた。したがって, 抗nRNP抗体陽性例において, 関節炎で初発しRA因子が陽性である場合, 発病初期にはRAと診断される危険性があると考えられた。

The effects of sera and of platelet-poor plasma from patients with scleroderma on endothelial cell survival in vitro were studied. The survival ratio of rat heart endothelial cells was studied both in 10% test serum and in 10% platelet-poor plasma. Sera from patients with scleroderma decreased the survival ratio significantly when compared with sera from normal controls. In contrast, there was no significant difference between platelet-poor plasma from patients with scleroderma and that from normal controls. Our data indicate that platelets in the patients with scleroderma may cause vascular damage by affecting endothelial cell survival.

© 2014 The Authors. doi: 10.2340/00015555-1675 Journal Compilation © 2014 Acta Dermato-Venereologica. ISSN 0001-5555 Patients with mycosis fungoides (MF) typically have a prolonged clinical course. A small proportion of cases progress over years through patch, plaque and tumour stages, followed by lymph node and visceral involvement (1). Some cases of MF are difficult to distinguish from other skin diseases, such as psoriasis and atopic dermatitis. Currently, tumour necrosis factor (TNF)-α inhibitors, such as infliximab, adalimumab, and etanercept, are widely used for treating patients with moderate to severe psoriasis (2). Blockade of TNF-α, however, is profoundly immuno suppressive, resulting in reactivation of tuberculosis and histoplasmosis, as well as the emergence of malignant lymphomas (3). In fact, some cases with MF manifested by treatment with TNF-α inhibitors have been reported (4–7). We describe here a 60-year-old woman diagnosed with psoriasis who showed exacerbation of MF with large cell transformation during treatment with infliximab.

Antiphospholipid antibodies (aPL) have been reported to occur in several conditions other than antiphospholipid syndrome, including infections. We herein report the case of a 21-year-old Japanese woman with Parvovirus B19 infection, who developed multiple pulmonary emboli associated with aPL, a lupus anticoagulant and IgM anticardiolipin antibody. Eight weeks later, antiphospholipid antibodies spontaneously disappeared and normal pulmonary flow was observed. Considering the high prevalence of Parvovirus B19 infection, we should be aware of thrombosis associated with transient aPL antibodies in this infectious disease.

Finasteride is a type 2 5 alpha-reductase inhibitor that inhibits conversion of testosterone to dihydrotestosterone, a key mediator of male pattern hair loss (androgenetic alopecia). The objective of this study was to identify the optimal dosage of finasteride and to evaluate its efficacy and safety in the treatment of Japanese men with male pattern hair loss. In this double- blind randomized study, 414 Japanese men with male pattern hair loss received finasteride 1 mg (n = 139), finasteride 0.2 mg (n = 137), or placebo (n = 38) once daily for 48 weeks. Efficacy was evaluated by global photographic assessment, patient self-assessment, and investigator assessment. All efficacy endpoints showed significant improvement with finasteride therapy by 12 weeks (p0.05 versus placebo). At 48 weeks, 58%, 54%, and 6% of men in the finasteride 1 mg, finasteride 0.2 mg, and placebo groups, respectively, had improved based on assessments of global photographs. All efficacy endpoints were numerically superior for the 1 mg dose over the 0.2 mg dose at 48 weeks. Finasteride treatment was generally well tolerated. Finasteride 1 mg\day slows hair loss and improves hair growth in Japanese men with male pattern hair loss.

© 2010 The Authors. doi: 10.2340/00015555-0857 Journal Compilation © 2010 Acta Dermato-Venereologica. ISSN 0001-5555 Primary idiopathic cutaneous pustular vasculitis (PICPV) is a rare clinical entity, which was first reported by McNeely et al. in 1986 (1). The disease is characterized by tender, purpuric pustules that recur several times over a period of 3–4 months, histological findings of Sweet’s-like vasculitis, the presence of circulating immune complexes, deposit of immune complex in blood vessels, and the absence of other diseases associated with pustular lesions. We report here a second case with clinical manifestations compatible with this disease.

Connective tissue growth factor (CTGF) is a member of a family of immediate early gene products that may play an important role during tissue regeneration, wound repair and skin fibrosis. In this study, CTGF gene expression in mesenchymal tumors was investigated by in situ hybridization and CD34 antigen expression was studied by means of immunohistochemical staining. CTGF mRNA was expressed in fibroblasts of all nine dermatofibromas examined, but five of seven dermatofibrosarcoma protuberans (DFSP) or two cases of malignant fibrous histiocytoma were negative for its expression. In contrast, CD34 antigen was expressed only in DFSP. In vascular tumors, CTGF mRNA was expressed in pyogenic granuloma but not in angiosarcoma. In addition, the endothelial cells in angiolipoma and angioleiomyoma, but not in venous lake, expressed CTGF mRNA. These vascular lesions were all positive for CD34 expression. Tumors of other origins were negative for CTGF mRNA. Our findings indicated that benign fibroblasts and/or vascular endothelial cells have the capability to express CTGF mRNA when activated, but these cells lose this ability when they achieve malignant potency. Thus, examination of CTGF gene expression may be useful for differentiating between benign and malignant mesenchymal tumors, or to determine the origin of the tumors in connective tissue.

We report a 64-year-old male with granulocytopenia and dermatitis due to cyanamide treatment. We administered cyanamide for alcoholism. After about one month he suffered from scaly erythema over his whole body and granulocytopenia (granulocyte; 140/μl) with maturation arrest in bone marrow. After cessation of cyanamide and the start of granulocyte colony-stimulating factor administration, the skin eruption ameliorated gradually, and the peripheral blood granulocyte counts increased. Cyanamide showed positive results in the drug lymphocyte stimulation test (198%) and the patch test led to the diagnosis of granulocytopenia and dermatitis induced by cyanamide. After restarting glibenclamide and diazepam administration, his granulocytopenia did not reoccur. To our knowledge, this is the first report of a case with granulocytopenia induced by cyanamide.(Internal Medicine 36: 640-642, 1997)

In order to determine the prevalence and clinical significance of β2-GPI-dependent anticardiolipin antibodies (β2-GPI/aCL) in patients with systemic sclerosis (SSc), serum samples from 80 patients with SSc, 20 patients with systemic lupus erythematosus (SLE), and 120 healthy control subjects were examined by ELISA using purified β2-GPI. IgG isotype β2-GPI/aCL was present in eight of 80 patients with SSc (10%), and the presence of β2-GPI/aCL IgG was significantly correlated with the presence of isolated pulmonary hypertension (PH). Furthermore, levels of β2-GPI/aCL IgG were significantly correlated with levels of mean pulmonary arterial pressure. These data suggest that IgG isotype β2-GPI/aCL might be a serological indicator of the severity of PH in patients with SSc.

The role of some growth factors and cytokines in the pathogenesis of systemic sclerosis (SSc) has been suggested. In particular, the contribution of transforming growth factor beta in the progression of skin sclerosis is suspected. Connective tissue growth factor (CTGF) was originally identified in human umbilical vein endothelial cells, and a recent study has revealed that human skin fibroblasts produce CTGF after stimulation with transforming growth factor beta. In the present study, the distribution of CTGF gene expression in tissue sections from patients with SSc was investigated by digoxigenin-labeled in situ hybridization. Strong CTGF mRNA signals were observed in the fibroblasts in sclerotic lesions, especially in the deep dermis, of the skin specimens from patients with SSc, whereas there was no expression in the skin from normal controls. The number of fibroblasts with positive hybridization signals was more abundant in the dermis from the sclerotic stage than in that from the inflammatory stage. Our findings indicate a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-beta plays an important role in the pathogenesis of SSc, because transforming growth factor beta is the only inducer for CTGF identified to date.

Background: Intercellular adhesion molecule-1 (ICAM-1) is important in immune-mediated mechanisms, and its circulating form (cICAM-1) may be an indicator of immune activation. Localized scleroderma is accompanied by various immunologic abnormalities. Objective: We investigated whether the serum level of cICAM-1 in patients with localized scleroderma was elevated and was correlated with the clinical or serologic features of this disease. Methods: Serum cICAM-1 levels were determined by an enzyme-linked immunosorbent assay in 48 patients with localized scleroderma, in 20 patients with systemic sclerosis, and in 20 healthy control subjects. Results: Serum levels of cICAM-1 were significantly higher in patients with localized scleroderma than in the healthy control subjects. These levels correlated with the number of lesions, the number of involved areas, levels of antihistone antibody IgM, and levels of soluble interleukin 2 receptor. Conclusion: The results suggest that immune activation may be a factor in localized scleroderma.

The serum level of procollagen type I carboxyterminal propeptide (P1CP), which has been used as an index of collagen synthesis in patients with various fibrotic diseases during the active stage, was measured using enzyme-linked immunosorbent assay in 61 patients with systemic sclerosis (SSc) and in 21 control subjects. The mean P1CP level in the SSc patients was significantly higher than in the normal controls (mean +/- SD, 326 +/- 319 vs 128 +/- 87 ng/ml; p0.005). In 36% of the SSc patients, the serum P1CP level was significantly elevated more than two standard deviations above the mean control value. The mean serum P1CP level in patients with diffuse SSc was significantly higher than in those with limited SSc (411 +/- 373 vs 255 +/- 199 ng/ml; p0.05). In addition, the SSc patients with elevated serum P1CP levels showed a significantly greater incidence of lung fibrosis and joint involvement than those with normal P1CP levels (p0.005 and p0.05, respectively). These results suggest that the serum P1CP level is a useful indicator of the severity of disease in SSc patients.

Objective. To study the prevalence and antigen specificity of antihistone antibodies (AHA) in localized scleroderma. Methods. Forty-nine serum samples from patients with localized scleroderma were examined by an enzyme-linked immunosorbent assay (ELISA) and by immunoblottin. Results. By ELISA, AHA were demonstrated in 47% (23 of 49) of patients with localized scleroderma and in 87% (13 of 15) of patients with generalized morphea. Immunoblotting revealed that the predominant antigens were histones H1 and H3. The presence of AHA correlated with that of anti–single-stranded DNA antibody. Conclusion. Some of the major antigens for antinuclear antibodies in patients with localized scleroderma are histones.

While the association of morphea and systemic sclerosis (SSc) is considered to be a rare condition, we observed well-demarcated sclerotic skin changes indistinguishable from morphea in 9 of 135 SSc patients who visited our clinic during the last decade. We consider this rate of incidence (6.7%) to be high enough to consider morphea to be one of the skin involvements of SSc. There was a significantly (p0.01) higher incidence of morphea in males (3 of 5) than in females (6 of 130). Only 3 of 111 SSc patients positive for antinuclear antibody (ANA) also showed morphea, whereas 6 of 9 patients negative for ANA showed morphea (p0.01). Although the mechanism underlying the development of morphea in SSc patients remains unknown, our observations suggest a heterogeneous pathogenesis related to SSc gender and ANA type.

We have compared the biological and biochemical properties of recombinant PDGF AA, AB, and BB using three types of fibroblastic cells: NIH/3T3, human skin fibroblast, and fetal bovine aortic smooth muscle. PDGF binding, receptor autophosphorylation, phosphatidyl inositol hydrolysis, as well as chemotactic and mitogenic responses of the cells were analyzed. PDGF-AB and PDGF-BB showed similar receptor binding, receptor autophosphorylation, and potent biological activity for all three of the cell types tested. In contrast, PDGF-AA was biologically active only for the NIH/3T3 cells in which binding sites for PDGF-AA were abundant, but was inactive for bovine aortic smooth muscle cells and human skin fibroblasts in which binding sites for PDGF-AA were absent. PDGF-AA could not induce any biochemical changes in the human skin fibroblasts or smooth muscle cells. Western blot studies with anti-Type alpha and beta PDGF receptor antibodies indicate that the NIH/3T3 cells contained both PDGF alpha and beta receptors, whereas the human skin fibroblasts and bovine smooth muscle cells contained only detectable levels of beta receptors. These results indicate that cells possessing high levels of PDGF beta receptors only are capable of responding equally well to either PDGF AB or BB.

Abnormal growth regulation in lesional skin fibroblasts may be related to scleroderma pathogenesis. We report on the abnormal response of cultured fibroblasts derived from sclerotic lesions to various growth factors. We investigated the responses of skin fibroblasts (10 strains) and normal fibroblasts (9 strains) to the growth factors as PDGF, TGF-beta 1, EGF and basic FGF. Experiments were conducted during the proliferation and confluent stages. PDGF, EGF and basic FGF stimulated fibroblast growth during the proliferation and confluent stages, but the response of scleroderma fibroblasts was significantly lower than that of normal fibroblasts. TGF-beta 1 slightly stimulated confluent fibroblast growth and inhibited proliferating fibroblasts, and the response of scleroderma fibroblasts exceeded that of normal fibroblasts. The decreased response to growth-stimulating factors observed in scleroderma fibroblasts suggests that cultured fibroblasts derived from scleroderma lesions were already senescent because they have been activated by growth-stimulating factors and repeatedly divided in vivo. Thus, abnormal growth regulation of skin fibroblasts may be partially related to the pathogenesis of scleroderma.

To the Editor.— Localized scleroderma differs from systemic sclerosis because of the difference in the distribution of skin sclerosis and the lack of Raynaud's phenomenon, acrosclerosis, and internal involvement. In localized scleroderma, the lesions are usually limited to the skin and to the subcutaneous tissue beneath the cutaneous lesions. However, it has been suggested that the disease has an immunologic basis because the serum samples of patients frequently contain antinuclear antibody (ANA). Recent reports on ANAs by indirect immunofluorescence methods using monolayer cultured cells showed greater frequencies than those by previous standard tests using frozen tissue sections. We first reported that 72% of the patients with localized scleroderma have positive ANAs when HeLa cells served as the test substrate. 1 Recently, Falanga et al 2-4 have reported elevated levels of anti-single-stranded DNA (anti-ss-DNA) antibody in localized scleroderma. They have also shown a positive correlation between anti-ss-DNA antibody and joint contracture

The authors have previously reported that dipyridamole decreased platelet-derived growth factor levels in human serum by lowering the release of this factor during blood clotting. In the present study, we have shown that this effect is specific to dipyridamole, and does not occur with other antiplatelet drugs such as aspirin, trapidil or ticlopidine. In addition, dipyridamole has been shown to decrease the PDGF level selectively, but not the levels of other factors from α granules in platelets (β-thromboglobulin and platelet factor 4). These data indicate that dipyridamole may be an effective drug for the prevention of PDGF-related disorders.