Real-world effectiveness and safety of bosentan in Japanese patients with systemic sclerosis: A single-center retrospective study.

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.

Tofacitinib in the treatment of skin and musculoskeletal involvement in patients with systemic sclerosis, evaluated by ultrasound.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by fibrosis of the skin and internal organs, autoimmunity-driven damage and vasculopathy. The current approved disease-modifying treatments have limited efficacy, and treatment is guided toward alleviating organ complications. Thus, there is an unmet need for discovering new effective treatment options. There is recent evidence that the JAK/STAT signaling pathway is markedly activated in SSc patients. To assess the efficacy and safety of tofacitinib (TOF) on skin and musculoskeletal involvement as compared to methotrexate (MTX) in systemic sclerosis (SSc). In this 52-week pilot study, 66 patients with SSc were enrolled: 33 patients received 5 mg of oral TOF twice a day; 33 received 10 mg of MTX weekly. The proportion of dcSSc and lcSSc patients was similar (dcSSc: 42% TOF group and 36% MTX group; lcSSc: 58% TOF group and 64% MTX group). The primary outcome was the change in the modified Rodnan skin score (mRSS). Secondary outcomes included ultrasound (US) skin thickness and musculoskeletal involvement (US10SSc score). Digital ulcers (DUs) and adverse events (AEs) were documented through the treatment. Both groups had similar characteristics and medians on the outcome measures at baseline. At week 52, the TOF median mRSS was significantly lower than the MTX (p < 0.001) with a mean reduction of 13 points versus MTX 2.57. The mean percent improvement in the TOF group was 44% higher than in the MTX group. TOF median US skin thickness was significantly lower than MTX (p < 0.001), with a mean reduction of 0.31 mm versus 0.075 mm in the MTX group. The US10SSc median score was significantly lower in the TOF group (p = 0.002); mean reduction of 10.21 versus 5.27 in the MTX group. Healing of DUs with no new occurrences was observed in the TOF group. There was no significant difference between the groups in the number of AEs from baseline to week 52. TOF showed greater efficacy than MTX in reducing mRSS, skin thickness and musculoskeletal involvement in SSc and a satisfactory safety profile.

NLRP3 protects mice from radiation-induced colon and skin damage via attenuating cGAS-STING signaling.

In the present study, the effects of NLRP3 on radiation-induced tissue damage, including colon and skin damage in mice, and the possible mechanisms were explored in vivo and in vitro. The mice were subjected to whole abdomen radiation by timed exposure to X-ray at a cumulative dose of 14 Gy. The survival rate showed that NLRP3 deficiency increased the mortality rate in mice. Furthermore, colon damage, evaluated by H&E staining and barrier function analysis, were significantly aggravated by NLRP3 deficiency. Enhanced phosphorylation of p-TBK1 and p-IRF3 in colonic tissue as well as elevated IFN-ß levels in the serum indicated hyperactivation of cGAS-STING signaling. Moreover, radiation-induced expression of p-TBK1, p-IRF3, and IFN-ß in BMDMs increased in vitro after NLRP3 knockout. Thus, our study outcomes suggest that NLRP3 may protect mice from radiation-induced tissue damage via attenuating cGAS-STING signaling.

The incidence rate of pulmonary arterial hypertension and scleroderma renal crisis in systemic sclerosis patients with digital ulcers on endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i).

INTRODUCTION: Endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i) are beneficial in pulmonary arterial hypertension (PAH) and digital ulcers (DU) and prevent from DU recurrences. Our study aimed to determine the difference in the incidence rate of PAH and scleroderma renal crisis (SRC) in patients with SSc and DU (SSc-DU) under ERAs/PDE5i or without treatment. METHODS: We conducted a retrospective cohort study including SSc-DU patients from the Spanish Scleroderma Registry (RESCLE). The primary outcome was the incidence rate of PAH and SRC in patients under ERAs/PDE5i or not. RESULTS: Some 544 patients out of 1817 (29.9%) in the RESCLE database had DU, 221 (40.6%) under ERAs/PDE5i and 323 (59.4%) not. The incidence rate (95% CI) difference between patients under treatment or not under did not reach statistical significance in PAH [-0.1 (-4.8, 4.69), P = 0.988] or in SRC [0.7 (-2.2, 3.7), P = 0.620]. However, the time from the first DU to the diagnosis of SRC was delayed in treated patients [mean (s.d.) 7.6 (5.8) years vs 2.9 (5.3); P = 0.021]. The dcSSc subset was more prevalent in the treatment group (36 vs 26%; P = 0.018), along with anti-topoisomerase I antibodies (34 vs 18%; P < 0.001) and tendon friction rubs (12 vs 6%; P = 0.038), whereas the lcSSc subset was more prevalent in the no-treatment group (57 vs 66%; P = 0.031) along with ACA (37 vs 46%; P = 0.031). CONCLUSION: There was no difference in the incidence rate of PAH and SRC between groups. However, treatment with ERAs and/or PDE5i appeared to delay the occurrence of SRC.

Management guideline for Werner syndrome 2020. 6. Skin ulcers associated with Werner syndrome: Prevention and non-surgical and surgical treatment.

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.

Ulcer metastasis? Anatomical locations of recurrence for patients in diabetic foot remission.

BACKGROUND: The "cancer analogy" is powerful for communicating risk to and organizing care for patients with diabetic foot syndrome. One potentially underappreciated similarity between cancer and foot ulcers is that both can recur at anatomical locations distinct from the primary occurrence, albeit with different physiological mechanisms. Few studies have characterized the location of diabetic foot ulcer recurrence, and these have been limited by considering only the first recurrent wound following a recent-healed wound. We therefore characterized the anatomical locations at which diabetic foot ulcers are likely to recur considering multiple wounds during follow-up and the locations of all prior wounds documented in the participant's history. METHODS: We completed a secondary analysis of existing data from a 129 participant multi-center study of participants in diabetic foot remission. The primary outcome was plantar foot ulceration, and each participant was followed for 34 weeks or until withdrawing consent, allowing characterization of all wounds occurring. We stratified the anatomical locations of wounds prior to the trial by the following outcome categories during the trial: no recurrence, recurrence to the same anatomical location, recurrence to a different anatomical location on the same foot, and recurrence to the contralateral foot. RESULTS: A large percentage (48%) of wounds recurred to the contralateral foot, and the proportion of subsequent foot ulcer to the contralateral limb was largely unaffected by the anatomical location of foot ulcer prior to the study. Only 17% of prior diabetic foot ulcers were followed by recurrence to the same anatomical location. Rates of recurrence remained high during treatment of a wound (0.41 foot ulcer/ulcer-year). Participants had documented wounds to 2.2 distinct anatomical locations on average, and more than 60% of participants had wounds to more than one plantar location by the end of the study. CONCLUSIONS: Given the significant morbidity, mortality, and resource utilization associated with foot ulcer recidivism, quality and evidenced-based preventive care is essential. Our results better characterize the burden of recurrence and to what anatomy recurrence is most likely. These insights may benefit providers and patients alike for the provision of high-quality preventive care thereby resulting in reduced morbidity, mortality, and cost. TRIAL REGISTRATION: The study providing the data for this secondary analysis was registered on ClinicalTrials.gov (NCT02647346) on January 6, 2016. The study was retrospectively registered.

Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade.

Skin ulcers resulting from impaired wound healing are a serious complication of diabetes. Unresolved inflammation, associated with the dysregulation of both the phenotype and function of macrophages, is involved in the poor healing of diabetic wounds. Here, we report that topical pharmacological inhibition of the mineralocorticoid receptor (MR) by canrenoate or MR small interfering RNA can resolve inflammation to improve delayed skin wound healing in diabetic mouse models; importantly, wounds from normal mice are unaffected. The beneficial effect of canrenoate is associated with an increased ratio of anti-inflammatory M2 macrophages to proinflammatory M1 macrophages in diabetic wounds. Furthermore, we show that MR blockade leads to downregulation of the MR target, LCN2, which may facilitate macrophage polarization toward the M2 phenotype and improve impaired angiogenesis in diabetic wounds. Indeed, diabetic LCN2-deficient mice showed improved wound healing associated with macrophage M2 polarization and angiogenesis. In addition, recombinant LCN2 protein prevented IL-4-induced macrophage switch from M1 to M2 phenotype. In conclusion, topical MR blockade accelerates skin wound healing in diabetic mice via LCN2 reduction, M2 macrophage polarization, prevention of inflammation, and induction of angiogenesis.

Skin considerations for older adults with wounds.

Ageing leads to a number of skin changes that not only place an older adult at risk of tissue damage, but can present as peri-wound problems for those with existing wounds, for example, incontinence-associated and moisture-associated dermatitis in individuals with pressure ulcers. Older adults with venous disease experience skin changes concomitant with venous hypertension, making the skin more at risk of breakdown, specifically the common complications of lipodermatosclerosis and venous eczema. In individuals with diabetic foot disease, skin changes related to autonomic neuropathy mean patients can experience dry skin that cracks easily, placing them at higher risk of infection. Common to all individuals with wounds requiring some sort of dressing is the risk of medical adhesive-related skin injury, where dressing application and removal need to be of the utmost priority to reduce the risk of injury. This article discusses some of the common peri-wound skin considerations in patients with chronic wounds.

Management of wounds in the community: five principles.

The care of any wound in the community requires multidisciplinary working between healthcare professionals. In this article, the authors offer five generalisable principles that colleagues providing community care can apply in order to achieve timely wound healing: (1) assessment and exclusion of disease processes; (2) wound cleansing; (3) timely dressing change; (4) appropriate (dressing choice; and (5) considered antibiotic prescription. High-quality wound care is an essential aspect of healthcare practice but lacks an evidence base and standardised practice at present. The practice and teaching of wound care should be more greatly emphasised in healthcare training for all disciplines.

A clinically effective primary wound dressing that supports self-care for chronic and acute wounds.

Wound care forms a large component of the ever-increasing workload of district and community nurses. The need for a cost-effective product that can be used on a variety of wounds and that meets multiple requirements (e.g. protease modulation, anti-microbial, peri-wound skin protection, maceration control and barrier function) is well recognised. The plethora of wound dressings available today all fulfil some, although not all, of these requirements. Choosing the correct dressing decreases healing time, provides cost-effective care and improves patient quality of life. This article looks at the important properties of wound care products, investigates the need to release nurse time and describes how patients with wounds can engage in effective self-care, with a focus on 1 Primary Wound Dressing® (1PWD), a cost effective, easy-to-use product that has already demonstrated clinical efficacy. Case studies showing the successful use of 1PWD are also presented to highlight the clinical application of this novel product.

Vitamin D serum levels and the risk of digital ulcers in systemic sclerosis: A longitudinal study.

AIM: Low levels of vitamin D (25OHD) have been found to associated with digital ulcers (DUs) in systemic sclerosis (SSc), although only cross-sectional studies have been performed. We aimed to investigate if variations in vitamin D serum levels over time affect DU in SSc. METHODS: This is a retrospective study on 65 patients. 25OHD was measured in 2011 and 2016 and its variations correlated with DU. RESULTS: The mean age of our cohort was 58 (SD 12) years with a mean disease duration of 9.5 (5.3) years. Most of our patients had a limited SSc (69.2%). At baseline 50.8% and 41.5% after 5 years had 25OHD <30 ng/mL. Patients receiving supplementation (8750 IU/wk) at baseline numbered 39 (60.0%) and 45 (69.2%) at the end of follow up. Nevertheless, 31 (47.7%) had a decrease of 25OHD in 5 years. In univariate analysis, patients with incident DU had a decrease in 25OHD as compared to patients with no incident DU (-17.4 [37.0] vs 13.0 [89.5], P = 0.018). No differences in 25OHD variations were found for other disease characteristics. In multivariate analysis correcting for previous DU and modified Rodnan Skin Score at baseline, patients with a decrease in 25OHD had an increased risk of developing DU (odds ratio 16.6; 95% CI 1.7-164.5, P = 0.017). CONCLUSIONS: A decrease in 25OHD is associated with the risk of developing DUs. In addition, vitamin D supplementation with the doses currently recommended may be insufficient in SSc. Further studies in wider cohorts are needed to confirm these results.

New Approach in Ulcer Prevention and Wound Healing Treatment using Doxycycline and Amoxicillin/LDH Nanocomposites.

Doxycycline (DOX) and amoxicillin (AMOX) are important Broad-spectrum antibiotics used in treating multiple human and animal diseases. For the sake of exploring novel medical applications, both antibiotics were loaded into magnesium aluminium layer double hydroxide (Mg-Al)/LDH nanocomposite through the co-precipitation method. The synthesized materials were characterized by XRD, FT-IR, particle size analysis, FESEM and HRTEM. Acute toxicological studies were conducted using median lethal dose LD50, where a total number of 98 rats (200-150 gm) of both sexes were used. An experimental wound was aseptically incised on the anterior-dorsal side of each rat, while 98% of pure medical ethanol was used for ulcer induction. Acute toxicity, wound closure rate, healing percentages, ulcer index, protective rate and histopathological studies were investigated. Antibiotic Nanocomposites has significantly prevented ulcer formation and improved wound healing process to take shorter time than that of the typical processes, when compared with that of same drugs in microscale systems or commercial standard drugs. These results were confirmed by the histopathological findings. By converting it into the Nanoform, which is extremely important, especially with commonly used antibiotics, novel pharmacological properties were acquired from the antibiotics. The safe uses of DOX/LDH and AMOX/LDH Nanocomposites in this study were approved for biomedical applications.

Technological features of advanced skin protectants and an examination of the evidence base.

Products that provide a protective skin barrier play a vital role in defending the skin against the corrosive effect of bodily fluids, including wound exudate, urine, liquid faeces, stoma output and sweat. There are many products to choose from, which can be broadly categorised by ingredients. This article describes the differences in mechanisms of action between barrier products comprising petrolatum and/or zinc oxide, silicone film-forming polymers and cyanoacrylates, and compares the evidence on them. The literature indicates that all types of barrier product are clinically effective, with little comparative evidence indicating that any one ingredient is more efficacious than another, although film-forming polymers and cyanoacrylates have been found to be easier to apply and more cost-effective. However, laboratory evidence, albeit limited, indicates that a concentrated cyanoacrylate produced a more substantial and adherent layer on a porcine explant when compared with a diluted cyanoacrylate and was more effective at protecting skin from abrasion and repeated exposure to moisture than a film-forming polymer. Finally, a silicone-based cream containing micronutrients was found to significantly reduce the incidence of pressure ulceration when used as part of a comprehensive prevention strategy.

Report of the proceedings of a UK skin safety advisory group.

Moisture-associated skin damage, especially incontinence-associated dermatitis, continues to present significant health challenges and requires multidisciplinary input to provide effective prevention and treatment. In the absence of mandatory reporting such damage is under- or wrongfully reported, resulting in a lack of accurate data on prevalence and costs of associated care. In March this year, a multidisciplinary team of experts met in the UK to seek to determine measures to improve patient skin care. They aimed to identify activities to increase awareness and education, collect data, and improve prevention and treatment regimes. This article describes that discussion and the conclusions made by the group, such as the key actions required to effect policy changes.