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Cutaneous angiosarcoma (CAS) is a rare soft-tissue sarcoma of vascular endothelial origin. Paclitaxel (PTX) and docetaxel (DTX) are used as systemic chemotherapy; however, chemoresistance often occurs in CAS. Switching one taxane to the other (i.e., PTX to DTX, or vice versa) is an option when the first taxane is no longer effective in malignant cancers such as ovarian or breast cancer. However, the efficacy of the same strategy in CAS has not been reported. Herein, we report the clinical response of switching one taxane-based chemotherapy to the other in CAS patients with resistance to the first taxane. Twelve CAS patients were included for analyses. In all patients, the median overall survival from the start of the first taxane treatment was 29.0 months (range, 6.47-58.5). During the first taxane, the median PFS for all patients was 5.96 months (1.81-47.1). Similarly, the median (range) PFS for all patients during the second taxane was 5.87 months (1.60-18.2). Furthermore, the median OS was 22.7 months (PTX to DTX) and 39.5 months (DTX to PTX) (p = 0.307). The median PFS during the first taxane was 5.14 (PTX to DTX) and 12.5 months (DTX to PTX), respectively (p = 0.380). The median PFS during the second taxane was 3.5 (PTX to DTX) and 7.1 months (DTX to PTX), respectively (p = 0.906). The objective response rate, defined as the sum of complete response (CR) and partial response (PR) rates, was 16.7%. The disease control rate, defined as the sum of CR, PR, and stable disease rates, was 50%. The frequency of adverse events during the second taxane was the same between the two groups (p > 0.999). Our report suggests that CAS patients could benefit from the second taxane treatment if the tumor is resistant to the first taxane., (© 2023 Japanese Dermatological Association.)

Patients with systemic sclerosis (SSc) develop various vascular disorders, including digital ulcers (DUs), which are sometimes intractable. Bosentan is a dual endothelin receptor antagonist expected to suppress the development of new DUs. The objective of this study was to analyze retrospectively Japanese SSc patients treated with bosentan and investigate its efficacy and safety. We analyzed 40 patients who visited our department from 2009 to 2022 and were treated with bosentan. Of the 25 patients who were able to continue bosentan, 64% (16 patients) were cured by 16 weeks . New DUs occurred in 5.9% (2/34) of patients and the number of new DUs per person was 0.1. Adverse events occurred in 45% (18/40), and hepatic dysfunction was occurred most frequently at 32.5% (13/40). In univariate analysis, hepatic dysfunction was significantly high in patients with low modified Rodnan total skin thickness score. Antimitochondria-antibody-positive patients were more likely to develop liver dysfunction. Hepatic dysfunction was improved without the reduction or discontinuation, dose reduction, discontinuation, or concomitant use of ursodeoxycholic acid. These results suggest that bosentan can be selected as an additional treatment for DU, which is difficult to treat with existing therapies, while carefully monitoring hepatic function., (© 2023 Japanese Dermatological Association.)

Pseudoxanthoma elasticum (PXE) is a progressive hereditary disease that affects tissues such as the skin, retina, blood vessels, and gastrointestinal tracts. Therefore, comprehensive medical care across clinical departments specialized in specific organs is needed to provide the best clinical practices to PXE patients. The Japanese version of clinical guidelines developed by the Japanese Dermatological Association was published in 2017, and aimed to promote equal accessibility of PXE-related medical care. Here, the English version of Japanese guideline is reported, and is intended to be worldwide reference for medical care of PXE., (© 2022 Japanese Dermatological Association.)

A 37-year-old Japanese man with a 3-year history of diffuse cutaneous systemic sclerosis was admitted to our hospital with high fever, arthralgia, myalgia, and muscle weakness. A physical examination revealed facial erythema, Gottron's sign, and mechanic's hands in addition to skin sclerosis. Laboratory data revealed significantly elevated levels of creatine kinase and decreased complement. Anti-RNP, anti-Smith, anti-DNA, anti-β 2 -glycoprotein 1, anti-polymyositis (PM)/Scl75, and anti-PM/Scl100 antibodies were detected. He also had urinary protein, interstitial lung disease, pericarditis, multifocal cerebral infarctions, and leukoencephalopathy. Thus, a diagnosis of overlap syndrome of diffuse cutaneous systemic sclerosis, dermatomyositis, and systemic lupus erythematosus with antiphospholipid syndrome was made. Because of the intractable course, he was treated with multiple immunosuppressive and immunomodulatory drugs, including three rounds of 1000 mg methylprednisolone pulse therapy. This is the first case report of anti-PM/Scl antibody-positive overlap syndrome of three major connective tissue diseases., (© 2021 Japanese Dermatological Association.)

Pachydermoperiostosis (PDP) is a genetic disease characterized by digital clubbing, periostosis, and pachydermia caused by mutated HPGD or SLCO2A1. Plasma prostaglandin (PG)E 2 levels are increased in these patients. However, other eicosanoids have not been quantitated. We aimed to quantitate plasma eicosanoid levels in four patients carrying SLCO2A1 mutations by high-performance liquid chromatography-tandem mass spectrometry. PGE 2 level was elevated in all patients; PGD 2 and 11β-PGF 2 α levels were also increased in some patients, whereas eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels were decreased in all patients. Our data indicate a dysfunctional eicosanoid homeostasis and varied levels of PG in patients with a complete form of PDP carrying SLCO2A1 mutations. PGE 2 levels seem to mostly affect the symptoms, with other eicosanoids possibly having a minor effect., (© 2021 Japanese Dermatological Association.)

Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of central and peripheral vascular disorders, including carotid, coronary and peripheral arterial diseases, and Raynaud's phenomenon. Recently, associations of plasma homocysteine levels with autoimmune diseases such as systemic lupus erythematodes and systemic sclerosis have been reported. However, no study analyzed the association between plasma homocysteine levels and dermatomyositis (DM). The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with DM. Plasma homocysteine levels in 28 Japanese patients with DM and 22 healthy controls were examined. We found that the plasma homocysteine levels in DM patients were significantly higher than those in healthy individuals (15.8 ± 1.1 vs 8.5 ± 0.5 µmol/L, P < 0.01). Presence of mechanic's hand, complication of interstitial lung disease (ILD), high serum Krebs von den Lungen-6 (KL-6), surfactant protein-D and creatine kinase levels, and anti-aminoacyl-tRNA synthetase (ARS) antibody (Ab) positivity were significantly more prevalent among DM patients with elevated plasma homocysteine levels. The plasma homocysteine levels in DM patients with mechanic's hand, ILD and anti-ARS Ab were significantly higher than those in DM without those features. Furthermore, the plasma homocysteine levels were positively correlated with serum KL-6 levels. These results suggest that the pathogenesis of elevated plasma homocysteine levels may be associated with ILD in DM patients, especially with anti-ARS Ab, and further examination is required., (© 2020 Japanese Dermatological Association.)

Dermatomyositis (DM) patients are known to have various infectious complications, such as cytomegalovirus (CMV) reactivation, due to immune dysfunction caused by DM itself and immunosuppressants used for treatment. Although CMV reactivation has been known to be a major cause of mortality in immunocompromised hosts, there has not been sufficient study of CMV reactivation in DM patients. The objective of this study was to examine the frequency of CMV reactivation in DM patients and to investigate risk factors potentially associated with development of CMV reactivation. We analyzed 52 Japanese DM patients, and CMV reactivation was observed in 21 (40.4%). The mean duration from the initiation of prednisolone (PSL) to the diagnosis of CMV reactivation was 6.1 ± 0.5 weeks. The total amount of oral PSL before the diagnosis of CMV reactivation was 2000.3 ± 169.3 mg. Using a univariate analysis, we found that the prevalence of interstitial lung disease and the frequency of diabetes mellitus complications in DM patients with CMV reactivation was significantly higher than that in DM patients without CMV. We identified that low lymphocytes (<900/μL) in DM patients was significantly associated with developing CMV reactivation. The use of immunosuppressants, including tacrolimus, cyclosporin and/or i.v. cyclophosphamide, was significantly associated with CMV reactivation in DM patients. Using a multivariate analysis, low lymphocytes at the time of DM diagnosis was found to be a risk factor for CMV reactivation. In addition, there was a tendency for diabetes mellitus to be a risk factor for CMV reactivation in DM patients. There was no difference in the prognosis for those with or without CMV reactivation in this study. These results suggest that in the DM patients with risk factors such as low lymphocytes and diabetes mellitus complications, regularly monitoring CMV reactivation and adequate treatment with antiviral agents may be necessary to prevent a poor prognosis., (© 2020 Japanese Dermatological Association.)

Subcutaneous granuloma annulare is a rare variant of granuloma annulare. It mostly presents as painless subcutaneous nodule(s) with or without annular lesions on the lower legs and scalp of children. We herein report a case of a 5-year-old Japanese girl with subcutaneous granuloma annulare on the right heel. The lesions improved in 15 months without any therapy. We also review 85 reported cases of subcutaneous granuloma annulare between 1 and 85 years of age in the Japanese published work. The most susceptible age was 5 years and below; however, a small peak occurred from the 40s to 60s. Subcutaneous granuloma annulare was more frequent in females (male : female ratio, 6:11). Sixty-five cases (76.4%) had multiple lesions; the average number of lesions was 4.8 ± 5.8. The most affected site was the lower legs (28 cases), followed by the dorsum of the foot (21 cases) and scalp (17 cases). The heel was an unusual location; only two cases of sole subcutaneous granuloma annulare have been reported. Twenty-one cases revealed a classical dermal change along with a subcutaneous change. Patients with classical dermal lesions were younger (P < 0.0001) and had a smaller number of lesions (P < 0.05) than those without the lesions. The lesion(s) resolved in 24 of the 44 untreated cases within 1 week to 19 months. Refractory or recurrent lesion(s) were seen in four of 21 treated cases and in four of 44 untreated cases. Because subcutaneous granuloma annulare lesions often resolve spontaneously without treatment, invasive treatments should be avoided., (© 2020 Japanese Dermatological Association.)

Pulse corticosteroid therapy is effective for alopecia areata (AA) in the early stage. The risk and efficacy of this therapy for patients with several backgrounds, however, remains controversial. To explore the predictive factors of the response and risk factors of this therapy, data from 105 AA patients treated with methylprednisolone (500 mg) i.v. for 3 days consecutively in our facility were retrospectively analyzed. Among good responders, longer time from the onset to therapy was correlated with longer time required for hair regrowth (P = 0.037, n = 27). Multivariate models demonstrated that "severity", "relapse" and longer "duration from the latest onset" were significantly and independently associated with poorer outcome (P < 0.01). "History of atopic dermatitis (AD)" was also associated with poorer outcome, but this correlation could be explained by the effect that duration from the latest onset of AA was longer among participants with AD. We propose that earlier initiation of pulse corticosteroid therapy is preferable for better outcome of AA, particularly among patients with AD. Clinicians should be mindful of the occurrence of mild adverse effects in the elderly patients., (© 2019 Japanese Dermatological Association.)

Histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile or adult xanthogranuloma (AXG) and Rosai-Dorfman disease (RDD), are rare disorders characterized by the proliferation of cells derived from monocyte/macrophage lineages. A few cases of LCH coexisting with xanthogranuloma or RDD have been reported. The etiology of these diseases remains unclear. However, oncogenic BRAF V 600E mutations have been identified in LCH. Here, we report the case of a 26-year-old Japanese man with a 3-month history of a solitary occipital nodule. No abnormality was detected in his other organs, and a total resection of the nodule was performed. Histopathological examination revealed the coexistence of LCH and AXG with prominent emperipolesis characteristic of RDD. Immunohistochemistry showed that most of the large histiocytes were positive for CD68, weakly positive or negative for S100, and negative for CD207 and CD1a, supporting the diagnosis of AXG. The tumor cells with emperipolesis did not show S100-positive findings characteristic of RDD. The focally aggregated oval histiocytic cells were positive for CD1a, CD207, CD68 and S100, and were compatible with the immunophenotype of LCH cells. In addition, these cells were positive for BRAF V 600E mutation. The tumor cells in our patient exhibited a cellular morphology characteristic of multiple histiocytoses in a solitary cutaneous nodule, which may imply an etiological association among LCH, AXG and RDD. To our knowledge, this is the first report of a BRAF V 600E mutation-positive case of LCH coexisting with AXG. Because patients with BRAF V 600E mutation have higher risks of multisystemic LCH and recurrence, we should carefully follow up the patient., (© 2018 Japanese Dermatological Association.)

Chronic oral ulcers are induced by various causative factors. Biopsy from an active site around ulceration is critical for both the definitive diagnosis and proper treatment. We report two cases of chronic oral ulcers, circumorificial plasmacytosis (CP) and traumatic ulcerative granuloma with stromal eosinophilia (TUGSE). A 65-year-old man presented with a mucosal ulcer on the right half of the lower lip. The dense plasmacytic inflammatory infiltration was histologically consistent with CP. A 32-year-old woman presented with a mucosal ulcer on the right mouth commissure. The dense mixed inflammatory cell infiltrates composed of eosinophils, lymphocytes and histiocytes extending from the submucosal tissue to underlying striated muscle fibers were histologically consistent with TUGSE. p.o. administration of corticosteroid was effective in both cases. A broad differential diagnosis is required for chronic oral ulcers. If the oral ulcer did not respond to the first therapy, clinical re-evaluation and biopsy is essential., (© 2018 Japanese Dermatological Association.)

Pseudoxanthoma elasticum (PXE) is a hereditary disease, causing calcification and degeneration of elastic fibers, which affects the skin, eye, cardiovascular systems and gastrointestinal tract. PXE is caused by mutations in the ABCC6 gene. Neither detailed nor large-scale analyses have been accomplished in Japanese patients with PXE. We, therefore, investigated clinical symptoms and ABCC6 gene mutations in 76 Japanese patients. Japanese PXE patients (n = 76) had a significantly lower incidence of vascular lesions than 505 PXE patients in the Leiden Open Variation Database (LOVD) (38.7% vs 65.1%, respectively; P = 1.34E-06); however, the incidences of the skin, eye, cardiac and gastrointestinal lesion symptoms were not significantly different. Symptom severity scores for skin, eye and vascular lesions, calculated using the Phenodex™ system, were significantly lower in Japanese PXE patients than in LOVD PXE patients. Genetic analysis revealed three nonsense, four frame-shift, one exon deletion and 13 missense mutations in ABCC6 in 73 patients; however, we were unable to detect pathogenic mutations in three patients. Frequent mutations differed between Japanese and LOVD PXE patients. In Japanese PXE patients, the top five mutations accounted for more than 60% of all pathogenic changes, suggesting the presence of founder effects. Consistent with previous reports, no obvious correlations between genotypes and phenotypes were identified in this study. In conclusion, we consider that the milder clinical phenotypes, observed even in older Japanese PXE patients, could be attributed to environmental factors such as dietary habits and lifestyle, as well as genetic background., (© 2017 Japanese Dermatological Association.)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and life-threatening cutaneous adverse drug reactions. While there is no established therapy for SJS/TEN, systemic corticosteroids, plasma exchange and i.v. immunoglobulin (IVIG) have been used as treatment. The efficacy of IVIG is still controversial because total doses of IVIG used vary greatly from one study to another. The aim of this study was to evaluate the efficacy of IVIG, administrated for 5 days consecutively, in an open-label, multicenter, single-arm study in patients with SJS or TEN. IVIG (400 mg/kg per day) administrated for 5 days consecutively was performed as an additional therapy to systemic steroids in adult patients with SJS or TEN. Efficacy on day 7 of IVIG was evaluated. Parameters to assess clinical outcome were enanthema including ophthalmic and oral lesions, cutaneous lesions and general condition. These parameters were scored and recorded before and after IVIG. We enrolled five patients with SJS and three patients with TEN who did not respond sufficiently to systemic steroids before IVIG administration. All of the patients survived and the efficacy on day 7 of the IVIG was 87.5% (7/8 patients). Prompt amelioration was observed in skin lesions and enanthema in the patients in whom IVIG therapy was effective. Serious side-effects from the use of IVIG were not observed. IVIG (400 mg/kg per day) administrated for 5 days consecutively seems to be effective in patients with SJS or TEN. IVIG administrated together with steroids should be considered as a treatment modality for patients with refractory SJS/TEN. Further studies are needed to define the therapeutic efficacy of IVIG., (© 2015 Japanese Dermatological Association.)

Juvenile or childhood onset systemic sclerosis (SSc) is rare. In our department, we encountered three juvenile SSc patients among the overall 206 SSc patients. All three cases were diffuse cutaneous type SSc (dSSc) with positive antinuclear antibodies. In this report, we report the three patients and analyze clinical and serological features of 58 Japanese patients with juvenile SSc. Forty-eight patients (92.3%) were classified as dSSc and 21 out of 35 patients (60%) had anti-topoisomelase I antibodies, while anticentromere antibodies were not detected in any patients. Prevalence of lung fibrosis and scleroderma renal crisis was low, however, the rate of cardiac involvement was higher than that in adult patients.

A 34-year-old woman with adult-onset Still's disease (AOSD) developed prurigo pigmentosa-like lesions on her chest and upper back in addition to the typical rash of AOSD. A biopsy specimen taken from the upper back showed characteristic features of prurigo pigmentosa. The eruption and fever subsided immediately after the administration of 40 mg/day prednisolone, but arthralgia persisted even after intravenous pulse methylprednisolone therapy in combination with immunosuppressive drugs. Various atypical skin rashes, including prurigo pigmentosa-like lesions, have been reported in association with AOSD. Therefore, one should carefully follow the clinical course of a patient in order not to overlook these atypical cutaneous manifestations of AOSD.