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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.)

Skin ulcers in Werner's syndrome often arise from hyperkeratotic lesions and trauma to pressure points such as the plantar region, and are more difficult to treat than wound healing in healthy individuals. Multiple factors contribute to the intractable skin ulcers in Werner's syndrome, including skin thinning, sclerosis, fatty tissue loss, impaired blood flow, calcification, and excessive pressure due to osteoarticular deformity. Treatment includes topical application of a keratolytic agent for keratosis around the ulcer. Treatment of ulcers is the same as for normal ulcers, and if the ulcer is associated with infection and necrotic tissue, surgical debridement with a scalpel or scissors should be performed as much as possible after washing with saline or mildly warm water or with an antibacterial agent. Topical medications that promote softening and debridement of the necrotic tissue are used with careful control of moisture in the wound. Topical agents that promote granulation should be used in wounds where necrotic tissue has been removed without infection. Dressings to maintain a moist environment in the wound may also be useful. If the wound does not improve with conservative treatment, surgical treatment should be considered. Geriatr Gerontol Int 2021; 21: 160-162., (© 2020 Japan Geriatrics Society.)

Aim: To provide guidelines on the diagnosis, treatment, and prevention of skin ulcers in Werner syndrome., Methods: This article was based on literature from 1996, when WRN was identified as a gene responsible for Werner syndrome, and we evaluated several authentic clinical cases of genetically diagnosed patients. There were 63 patients with Werner syndrome in the Japanese reports retrieved from Medical Online between January 1996 and December 2017. There were 56 patients with Werner syndrome in English reports written by Japanese authors and retrieved from PubMed during the same period., Results: Records on skin ulcers were found in 27 (43%) out of 63 patients and 22 (40%) out of 56 patients from the Japanese and English reports, respectively. The reported ulcers were often located at the distal one-third of the lower legs. There were 8 patients with callosities in the foot in the Japanese reports and 9 patients in the English reports. A skin ulcer in Werner syndrome is generally intractable. Weight-bearing ulcers or callosity should be critically assessed in surgical procedures because they have effects on patient pain and gait. By adopting a recently advanced technique to facilitate wound healing, the cases of ulcers that were difficult to treat and those requiring major operations can be closed with minimally invasive surgery., Conclusions: Skin ulcers in Werner syndrome are refractory, and they lead to reduced quality of life of patients. A callosity in Werner syndrome is an important therapeutic target for the prevention of ulcers. Geriatr Gerontol Int 2021; 21: 153-159., (© 2020 Japan Geriatrics Society.)

Patients with systemic sclerosis (SSc) develop various vasculopathy-induced vascular disorders such as Raynaud's phenomenon, abnormal nail-fold capillaries, persistent digital ischemia, digital ulcers (DU), and sometimes develop renal crisis and pulmonary artery hypertension (PAH), affecting prognosis. Earlobe crease (ELC), also known as Frank's sign, is a wrinkle extending from the tragus to the outer border of the earlobe and is generally recognized as the sign of cardiovascular events. However, no previous study analyzed the association between ELC and SSc. In this study, we examined the prevalence and clinical characteristics of ELC in SSc patients. We analyzed 145 Japanese SSc patients and found that the prevalence of ELC in SSc patients was 23.4% (43/145), similar to that previously reported in the general population without SSc. Using univariate analysis, we found that SSc patients with ELC were characterized by old age, high incidence of DU, ILD and PAH, and high complication of coronary artery diseases (CAD) compared with SSc patients without ELC. In multivariate analysis, ELC was significantly associated with old age and incidence of DU. PAH tended to correlate with ELC without statistical significance. These results suggest that ELC may be associated with vascular disorders in SSc patients. This is the first report concerning the prevalence and clinical characteristics of ELC in patients with SSc. ELC is very easy to detect in clinical practice and helps physicians to identify SSc patients at risk of developing vascular disorders such as DU and PAH., (© 2020 Japanese Dermatological Association.)

We recently identified the efficacy and safety of a botulinum toxin (BTX)-A/B in Raynaud's phenomenon (RP) and digital ulcers (DU) in Japanese patients with systemic sclerosis (SSc). Detailed assessments of peripheral vascular disorder using angiography and dermoscopic images of nail fold capillaries have not been performed previously. This study aimed to evaluate the effect of BTX-B on SSc-associated peripheral vascular disorder. Two SSc patients who suffered with RP and DU were treated with a BTX-B injection, and thereafter the symptoms of RP were improved and DU healed in both patients. Furthermore, angiography showed an increased blood flow to the palm and fingers, and dermoscopic images of nail fold capillary changes showed improvement. These results suggest that a BTX-B injection may increase peripheral blood flow and improve RP and DU in SSc patients., (© 2017 Japanese Dermatological Association.)

The efficacy and safety of botulinum toxin B (BTX-B) for treatment of Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis was assessed. A total of 45 patients with systemic sclerosis who had Raynaud's phenomenon were blinded and divided randomly into 4 groups: a no-treatment control group, and 3 treatment groups, using 250, 1,000 or 2,000 international units (U) of BTX-B injections in the hand with more severe symptoms. Four weeks after injection, pain/numbness visual analogue scale scores and Raynaud's score in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group and the group treated with 250 U BTX-B. These beneficial effects were sustained until 16 weeks after the single injection. At 4 weeks after injection skin temperature recovery in the group treated with 2,000 U BTX-B was significantly improved. The numbers of digital ulcers in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group. In conclusion, 1,000 and 2,000 U BTX-B injections significantly suppressed the activity of Raynaud's phenomenon and digital ulcers in patients with SSc without serious adverse events.

Background: Diabetic wounds are intractable due to complex factors, such as the inhibition of angiogenesis, dysfunction of phagocytosis by macrophages and abnormal inflammatory responses. It is recognized that mesenchymal stem cells (MSCs) promote wound healing in diabetic mice. We previously demonstrated that MSCs produce large amounts of MFG-E8., Object: The objective was to ascertain the role of MSCs-derived MFG-E8 in murine diabetic wounds., Methods: MFG-E8 WT/KO MSCs or rMFG-E8 were subcutaneously injected around the wound in diabetic db/db mice, and wound areas were analyzed. Quantification of angiogenesis, infiltrating inflammatory cells, apoptotic cells at the wound area was performed by immunofluorescence staining and real-time PCR. Phagocytosis assay was performed using peritoneal macrophages from WT or db/db mice., Results: MFG-E8 expression in granulation tissue in diabetic mice was significantly reduced compared with that in non-diabetic mice. We next examined the effect of subcutaneous injection of MFG-E8 WT/KO MSCs around the wound. Diabetic wound healing was significantly accelerated by the injection of MSCs. Diabetic wound healing in MFG-E8 KO MSCs-injected wounds was significantly delayed compared to that in WT MSCs-injected wounds. The numbers of CD31 + EC and NG2 + pericytes, as well as M2 macrophages in wounds in KO MSCs-injected mice were significantly decreased. MFG-E8 WT MSCs treatment suppressed the number of apoptotic cells and TNF-α + cells in wounds. In an in vitro assay, MFG-E8 WT MSCs-conditioned medium enhanced phagocytosis of apoptotic cells by peritoneal macrophages from diabetic mice., Conclusion: MSCs-derived MFG-E8 might accelerate diabetic wound healing by promoting angiogenesis, the clearance of apoptotic cells, and the infiltration of M2 macrophages, and by suppressing inflammatory cytokines in wound area., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

A multicenter, open-label study was performed to investigate the safety and tolerability of bosentan in Japanese patients with systemic sclerosis (SSc) and secondary digital ulcers. Twenty-eight patients were enrolled. The safety and tolerability of bosentan was monitored over 52 weeks of study treatment (primary end-point), while incidence and healing of digital ulcers were also assessed up to week 16. The following adverse events occurred in 5% or more of patients during the 52-week treatment period: upper respiratory tract infection (50.0%), abnormal liver function tests (42.9%), digital ulcers (25.0%), anemia (17.9%), peripheral edema (14.3%), diarrhea (10.7%), urinary tract infection (7.1%), arthralgia (7.1%), constipation (7.1%) and herpes zoster (7.1%). Eight patients experienced at least one serious adverse event, including drug-related serious adverse events in two patients, which were abnormal liver function tests and fluid retention (pericardial effusion) in one patient each. During the 16-week observation period, seven out of 28 patients (25%) developed new digital ulcers. In this study, adverse events were comparable with those previously reported with bosentan. Approximately half of the patients had adverse events associated with abnormal liver function tests, thus we conclude that liver function should be monitored regularly during treatment with bosentan., (© 2016 Japanese Dermatological Association.)