Portuguese Recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological and pharmacological management of Raynaud's phenomenon (RP) and digital ulcers (DUs) in patients with systemic sclerosis and other immune-mediated connective tissue diseases (CTDs). METHODS: A task force comprising 21 rheumatologists, two surgeons (vascular and plastic), two nurses, and one patient representative was established. Following a systematic literature review performed to inform the recommendations, statements were formulated and discussed during two meetings (one online and one in-person). Levels of evidence, grades of recommendation (GoR), and level of agreement (LoA) were determined. RESULTS: Five overarching principles and 13 recommendations were developed. GoR ranged from A to D. The mean ± standard difference (SD) LoA with the overarching principles and recommendations ranged from 7.8±2.1 to 9.8±0.4. Briefly, the management of RP and DUs in patients with CTDs should be coordinated by a multidisciplinary team and based on shared decisions with patients. Nifedipine should be used as first-line therapy for RP and/or DUs. Sildenafil, tadalafil, and/or iloprost IV are second-line options for severe and/or refractory patients with RP and/or DUs. Sildenafil, tadalafil and/or Iloprost IV, should be prescribed for healing and prevention (also including bosentan) of DUs. In patients with RP and/or DUs, non-pharmacological interventions might be considered as add-ons, but there is limited quality and quantity of scientific evidence supporting their use. CONCLUSIONS: These recommendations will inform rheumatologists, specialist nurses, other healthcare professionals, and patients about a comprehensive and personalized management of RP and DUs. A research agenda was developed to address unmet needs, particularly for non-pharmacologic interventions.

Efficacy of plasma rich in growth factors for healing chronic skin ulcers: a systematic review of randomized controlled trials with meta-analysis.

BACKGROUND: Chronic skin ulceration is a serious pathological condition for which the adjuvant use of platelet-rich plasma (PRP) has been indicated. However, evidence for the use of PRP in patients with chronic skin ulcers remains insufficient due to a large heterogeneity in experimental designs, PRP composition, and preparation protocols. OBJECTIVE: To assess previously published reports of the clinical effect of plasma rich in growth factors (PRGF) on chronic skin wounds. METHODS: A comprehensive search of the PubMed, Cochrane Library, and Scopus databases was performed to identify randomized controlled trials (RCTs) assessing the effect of PRGF on chronic ulcer healing, with no limitation regarding publication date (up to September 1, 2022). Percentage area reduction and probability of complete healing in chronic ulcers, pain reduction, infection risk, and cost savings were analyzed. A meta-analysis was performed, and the overall evidence was qualified using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. RESULTS: A total of 113 studies were identified. After full-text screening, 5 RCTs met the inclusion criteria. The meta-analysis showed a significant effect of PRGF on both wound area reduction (mean difference, 56.90% [95% CI, 52.28-61.51], I² = 0%; P = .56) and on the probability of complete healing (RR, 7.07 [95% CI, 1.84-27.16], I² = 0%; P = .53) in chronic ulcers. The overall risk of bias rating was "some concerns," whereas the certainty of evidence was high for both outcomes. A qualitative analysis suggested that PRGF did not increase infection risk and was able to reduce wound pain. CONCLUSION: The use of PRGF significantly enhances wound area reduction and also the probability of complete healing in chronic ulcers. More studies are needed to assess the effect of PRGF on pain and infection, as well as its cost-effectiveness.

Treatment of Chronic Parastomal Ulceration with Silver Sulfadiazine and Hyaluronic Acid: Two Case Reports.

ABSTRACT: Skin complications in individuals with an ostomy are widely reported and can cause physical and emotional challenges in everyday life. Chronic parastomal skin complications can be difficult to heal and cause significant pain.Two patients presented to the stomal therapy clinic for treatment and were diagnosed with chronic parastomal skin ulceration. Following standard treatment of wound management, topical corticosteroid ointment, and appliance review, the ulcers either were not improving or had reoccurred. Treatment with a combination cream consisting of 0.2% hyaluronic acid and 1% silver sulfadiazine was initiated, and both patients demonstrated complete healing.Treatment of parastomal skin ulceration with dual-action cream 0.2% hyaluronic acid and 1% silver sulfadiazine was successful for these two patients, with a reduction in pain and purulent fluid noted throughout treatment, in addition to a reduced cost of treatment when compared with standard protocols.

Multimodality management of locoregionally extensive Marjolin ulcer: a case report and review of the literature.

BACKGROUND: Marjolin ulcer (MU) is an aggressive cutaneous malignancy that commonly occurs in those with a chronic wound such as post-burn scar. CASE REPORT: A 20-year-old male who sustained a flame burn over the scalp at 3 months of age developed a nonhealing ulcer over the burn scar 20 years later, which was treated with adequate surgical margins with adjuvant mold brachytherapy. Two months after completion of that treatment, he developed parotid nodal metastasis with positron emission tomography (PET)-positive bilateral cervical, supraclavicular, right suboccipital, and mesenteric lymph nodes that were treated with concurrent chemoradiation. One month later, the patient developed an ulcerative lesion involving the left parotid region with PET showing infiltration of the parotid gland, but with resolution of other previous sites of uptake. The patient was treated surgically with radical parotidectomy with elective neck dissection and reconstruction with locoregional flap. At 6-month follow-up, the patient developed extensive locoregional recurrence and distant metastasis and was started on oral metronomic therapy. The patient was alive with stable disease at 3-month follow-up after initiation of palliative chemotherapy. CONCLUSION: Despite timely multimodality therapy, MU may present with a hostile clinical course with a short disease-free interval and early recurrence.

Efficacy of Local Autologous Platelet-Rich Plasma in the Treatment of Chronic Ulcer.

Chronic non-healing ulcers present significant challenges in diabetic, dermatological and surgical patients. Platelet-Rich Plasma (PRP), enriched with bioactive factors, offers promise for wound healing enhancement. The prospective observational study was done in the Department of Transfusion Medicine at AIIMS Bhopal for a period of two years, from April 2020 to 2022. This study evaluates PRP's efficacy, prepared via the single spin method, in non healing chronic ulcers. Aseptically, 100 ml of blood was drawn into CPDA (citrate-phosphate-dextrose-adenine) bags. PRP was prepared by centrifuging blood at 3400 rpm for 10 minutes, yielding PRP and buffy coat. Patient serum and 10.0% calcium gluconate were added to fibrin gel. PRP was injected around the ulcer and then dressed. Dressings were changed on the 5th, 15th and 20th days with PRP. The evaluation was done on day 30 using surface area and volume assessments. Thirteen patients aged 18-65 participated. The patients treated with single spin PRP (four females, nine males) had mean hemoglobin of 10.79±2.22gm/dL. Initial lesions (14.72cm²) significantly reduced to (8.78cm²) after application of single Spin PRP sessions (p=0.005). The PRP showed a mean platelet count of 1,527.00±192.26 × 109/L. Ulcer surface area decreased from 9.87cm² to 7.56cm²; lesion volume reduced from 14.72cm³ to 8.78cm³. Platelet count differences between whole blood and PRP were significant (p<0.05). The single-spin PRP method exhibited considerable improvements in healing parameters, showcasing its potential for chronic ulcer management.

The role of split-thickness skin grafting in the treatment of vasculitic and pyoderma gangrenosum ulcers in a multidisciplinary wound centre.

Vasculitic and pyoderma gangrenosum ulcers are traditionally treated with immunosuppressants, and the role of surgery in the treatment of these atypical ulcers remains unclear. This study aimed to investigate the need for surgical intervention as well as the outcome and safety of skin grafting in the treatment of 46 patients with vasculitic ulcers and 34 with pyoderma gangrenosum ulcers using data recorded in the validated Wound Registry. Of the 80 patients with atypical ulcers, 14% (n = 11) were treated surgically; these patients were older (p = 0.039), had lower mobility status (p = 0.002), and more often pulmonary diseases, rheumatoid arthritis, and previous arterial procedures (p = 0.007; p = 0.031; p = 0.031, respectively) than those treated conservatively. Of 181 ulcers, 15% (n = 27) were surgically treated, 78% once and 22% multiple times. During follow-up, 92.3% of both surgically and conservatively treated ulcers with available data healed. Of the surgically treated ulcers, median healing time after first surgical procedure was 96 days, and post-surgical complications were considered mild or unrelated to surgery. Our results suggest that if surgery is indicated, skin grafting is a safe and efficient treatment method provided that multidisciplinary approach is applied.

A randomised Trial of Autologous Blood products, leukocyte and platelet-rich fibrin (L-PRF), to promote ulcer healing in LEprosy: The TABLE trial.

INTRODUCTION: Autologous blood products like Platelet Rich Plasma (PRP) and Leukocyte and Platelets Rich Fibrin (L-PRF) have been used for many years across many types of skin ulcers. However, the effectiveness of autologous blood products on wound healing is not well established. METHODS: We evaluated the 'second generation' autologous product- Leukocyte and Platelet- Rich Fibrin (L-PRF). Our trial was undertaken on patients suffering from neuropathic leprosy ulcers at the Anandaban hospital which serves the entire country of Nepal. We conducted a 1:1 (n = 130) individually randomised trial of L-PRF (intervention) vs. normal saline dressing (control) to compare rate of healing and time to complete healing. Rate of healing was estimated using blind assessments of ulcer areas based on three different measurement methods. Time to complete healing was measured by the local unblinded clinicians and by blind assessment of ulcer images. RESULTS: The point estimates for both outcomes were favourable to L-PRF but the effect sizes were small. Unadjusted mean differences (intervention vs control) in mean daily healing rates (cm2) were respectively 0.012 (95% confidence interval 0.001 to 0.023, p = 0.027); 0.016 (0.004 to 0.027, p = 0.008) and 0.005 (-0.005 to 0.016, p = 0.313) across the three measurement methods. Time to complete healing at 42 days yielded Hazard Ratios (unadjusted) of 1.3 (0.8 to 2.1, p = 0.300) assessed by unblinded local clinicians and 1.2 (0.7 to 2.0, p = 0.462) on blind assessment. CONCLUSION: Any benefit from L-PRF appears insufficient to justify routine use in care of neuropathic ulcers in leprosy. TRIAL REGISTRATION: ISRCTN14933421. Date of trial registration: 16 June 2020.

Cutaneous Crohn disease presenting as "knife-edged" ulcers: a case report.

BACKGROUND: CCD presents as non-caseating granulomas within the skin at a site distant from the GI tract. CCD is a debilitating extraintestinal sequela of CD that can sometimes precede its GI manifestations. In the absence of GI symptoms, the histopathologic and clinical features of CCD can present as a variety of inflammatory skin conditions that can range from ruptured follicle-associated granulomas to cutaneous ulcerations. While a variety of therapeutic options for patients with CCD and concurrent luminal CD have been described in the literature, there is no standard treatment algorithm for the management of refractory CCD with limited or covert GI involvement. CASE REPORT: The authors discuss the case of a 33-year-old female who presented to the wound care clinic with multiple "knife-edged" cutaneous ulcerations involving the intertriginous spaces, found to be consistent with CCD. Her original cutaneous symptoms and diagnosis manifested with minimal GI involvement and responded to IVIG treatment. CONCLUSIONS: This case supports the inclusion of CCD in the differential diagnosis in patients with knife-edged granulomatous skin lesions in intertriginous locations. This clinical condition may present in the setting of no or limited GI symptoms. The management of CCD and a proposed treatment algorithm are also presented.

The Application of Umbilical Cord Blood-derived Platelet Gel for Skin Ulcers Associated With Chronic Graft-Versus-Host Disease in Pediatrics: A Randomized Trial.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative strategy against a variety of malignant and nonmalignant disorders. However, acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) commonly complicate this approach, culminating in substantial morbidities and mortalities. The integumentary system is the preponderant organ involved in cGVHD, and its response to existing treatments, including well-versed immunosuppressants and novel targeted therapies, is not desirable. Despite the rarity, ulcers of sclerotic skin cGVHD are treatment-refractory and associated with significant morbidities and an exaggerated risk of infectious complications. Platelet-rich plasma (PRP) and its derivatives are endowed with growth factors and proangiogenic molecules and hold regenerative potential. This study aimed to assess the safety and efficacy of the application of platelet gel-containing dressing against ulcerative skin cGVHD in pediatric patients. This randomized trial is conducted at the hematopoietic stem cell transplantation unit of the Children's Medical Center Hospital in Tehran, Iran. Twenty-one pediatric patients (aged between 5 and 15 years) were initially enrolled, and 16 met the inclusion criteria. All cases (4 females) were recipients of allo-HSCT who had been complicated with symmetrically or near-symmetrically ulcerative sclerotic skin cGVHD. Fresh umbilical cord blood (UCB) was obtained from healthy donors and underwent centrifugation using a novel PRP preparation kit in a single-step process. Platelet gel was produced by adding thrombin to the isolated buffy coat layer. Two similar ulcers of each patient were randomized to receive either conventional dressing or platelet gels up to 6 times. At each time point evaluation, ulcer size and its relative reduction compared to the basal size were recorded. Included patients received a total of 80 platelet gel-containing dressings. While the mean sizes of randomized ulcers at the beginning of the study were similar, their differences became significant 15 days after the initiation of intervention (P = .019). In addition, the mean reduction in the ulcers' surface area (in comparison to their baseline values) was significantly higher for the intervention arm at all evaluation points (P = .001 for day 5 and P < .001 for subsequent time points). At the end of the trial, the number of ulcers with a more than 50% reduction in size was 14 (87.5%) in the intervention arm (including 6 completely healed ulcers) versus 1 (6.25%, which was not completely healed) in the control arm (P < .001). None of the patients exhibited any localized or systemic treatment-related adverse events. In this study, using a relatively large number of cases, we showed that UCB-derived platelet gel is a safe, feasible, and effective curative approach for skin ulcers of sclerotic skin cGVHD in pediatric patients. Designing upcoming trials on the efficacy of this therapeutic approach for ocular, mucosal, and acute skin GVHD is prudent. Retrospectively registered at the Iranian Registry of Clinical Trials (registration number IRCT20190101042197N1) on August 24, 2020.

The Management of Chronic Graft-Versus-Host Disease Skin Ulcers after Hematopoietic Stem Cell Transplantation: A Case Report.

ABSTRACT: The comprehensive management of a patient with chronic graft-versus-host disease skin ulcers after hematopoietic stem cell transplantation is challenging. This report describes the case of a 53-year-old woman who presented with ulcers on her right leg 140 weeks after a bone marrow transplant. The patient received wound assessment and management based on the Triangle of Wound Assessment and Wound Bed Preparation 2021, respectively. Hydrogel and antibacterial protease dressings were applied along with systemic oral administration of moxifloxacin hydrochloride (two capsules, two times daily) and JiXueGanPian tablets (classic Chinese herbal formula; two capsules, two times daily), hospital-community-home continuous care, and patient-centered education. Finally, after 133 days of nursing, the patient's wound was completely healed without complications or other skin issues. The use of hydrogel combined with the antibacterial protease dressing was a promising technique for handling this type of wound, enhanced by multidisciplinary collaboration. Of course, providing patients with education that focuses on prevention is necessary.

Systematic literature review to inform the Portuguese recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. METHODS: A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. RESULTS: Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. CONCLUSION: The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

Healing refractory livedoid vasculopathy-related skin ulcers by ozone therapy: a case-based review.

Chronic skin wounds represent a prominent etiological factor in the occurrence of non-traumatic foot amputations on a global scale and pose a substantial threat to the patient's well-being and mortality in the absence of effective treatment strategies. There exists a subset of patients that exhibit an insufficient response to different treatment options, comprising antibiotics, dressings, gauze bandages, debridement, rehabilitation, collagen patch, and vacuum-assisted closure. In this patient group, distinct treatment strategies emerge before surgery and amputation. Ozone therapy is one of them. Ozone exhibits a wide variety of effects such as antimicrobial, anti-inflammatory, antioxidant, and trophic. Its trophic effect is mediated by disinfection, stimulation of granulation tissue, acceleration of the angiogenesis process, and detoxification mechanisms. In this article, we presented the beneficial effect of ozone therapy in a case of chronic skin ulcer associated with livedoid vasculopathy. In this context, we aimed to discuss the role of ozone therapy in the management of chronic skin ulcers. Finally, we focused on ozone therapy as a promising method in inflammatory rheumatic diseases.

Autologous blood products: Leucocyte and Platelets Rich Fibrin (L-PRF) and Platelets Rich Plasma (PRP) gel to promote cutaneous ulcer healing - a systematic review.

OBJECTIVE: To summarise evidence on the effectiveness of Platelet-Rich Plasma (PRP) gel and Leucocyte and Platelet Rich Fibrin (L-PRF) gel as agents promoting ulcer healing compared with the standard wound dressing techniques alone. DESIGN: Systematic review. ELIGIBILITY CRITERIA: Individual patient randomised controlled trials on skin ulcers of all types excluding traumatic lesions.Intervention group: treatment with topical application of L-PRF gel or PRP gel to the wound surface. CONTROL GROUP: treatment with standard skin ulcer care using normal saline, normgel or hydrogel dressings. INFORMATION SOURCES: Medline (Ovid), Excerpta Medica Database (EMBASE), Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science and manual search of studies from previous systematic reviews and meta-analyses. The papers published from 1946 to 2022 with no restriction on geography and language were included. The last date of the search was performed on 29 August 2022. DATA EXTRACTION AND SYNTHESIS: Independent reviewers identified eligible studies, extracted data, assessed risk of bias using V.2 of the Cochrane risk-of-bias tool for randomised trials tool and assessed certainty of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. MAIN OUTCOME MEASURES: Time to complete healing, proportion healed at a given time and rate of healing. RESULTS: Seven studies met the inclusion criteria, five using PRP gel and two using L-PRF gel. One study showed a better proportion of complete healing, three reported reduced meantime to complete healing and five showed improved rate of healing per unit of time in the intervention group. The risk of bias was high across all studies with one exception and the GRADE showed very low certainty of evidence. CONCLUSION: The findings show potential for better outcomes in the intervention; however, the evidence remains inconclusive highlighting a large research gap in ulcer treatment and warrant better-designed clinical trials. PROSPERO REGISTRATION NUMBER: CRD42022352418.

Treatment of dermal ulcer with autologous fibrin glue: Two case reports of an exploratory prospective pilot study.

INTRODUCTION: The healing of recurrent and refractory skin ulcers requires a long time, during which there is risk of infection, and hospital admission is occasionally required for surgical or daily conservative treatment. Therefore, the development of promising treatments that promote faster, uneventful healing is a must. Composed of cryoprecipitate and thrombin, fibrin glue has a history of surgical use for preventing bleeding and spinal fluid leakage. Moreover, in-house cryoprecipitates contain higher concentrations of coagulation factors and cytokines that may enhance wound healing than commercially available products. However, the efficacy of completely autologous fibrin glue (AFG) in tissue repair has not yet been fully demonstrated. PATIENT CONCERNS: This study aimed to evaluate the efficacy of AFG in the treatment of refractory skin ulcers in comparison with the conventional treatment. DIAGNOSIS: Two patients with skin ulcer on their lower extremities due to trauma or scleroderma who showed resistance to conventional treatment were included in the study. Both study participants were diagnosed with refractory skin ulcer and were ineligible for autologous skin transplantation. INTERVENTIONS: AFG was prepared following autologous blood donation using a Cryoseal® system. Subsequently, AFG was administered to 50% of the area of each ulcer and observed for 4 weeks in comparison with recombinant basic fibroblast growth factor with bucladesine sodium treatment that was administered to the rest of the ulcer. OUTCOMES: The skin ulcer after trauma in participant 1 showed better improvement in the AFG-treated area. Although AFG did not show superiority regarding the ulcer area of a patient with scleroderma, it guarded the continuous exudation from the edge of the swollen skin surrounding the ulcer. CONCLUSION: AFG showed effective and beneficial results for wound healing of refractory skin ulcer and prevented exudation without any severe adverse events.

Non-surgical local treatments of digital ulcers in systemic sclerosis: a systematic literature review.

INTRODUCTION: Digital ulcers (DUs) are difficult to treat in patients with systemic sclerosis (SSc) and systemic (i.e., pharmacological) therapy is currently considered the 'standard of care'. Our aim was to examine the safety and efficacy of local, non-surgical treatment for SSc-DUs. METHODS: A systematic literature review (SLR) of original research articles up to August, 29 2022 was performed according to the PICO framework. References were independently screened by two reviewers and risk of bias was assed using validated tools. Due to study heterogeneity narrative summaries are used to present data. RESULTS: Among 899 retrieved references, 14 articles were included (2 randomised trials (RTs), and 12 observational (OBS) studies). The most frequently studied procedure (5 studies) was botulin A toxin (hand or single finger) injection with a reported healing rate (HR) of 71%-100%. Amniotic and hydrocolloid membranes were examined in one study each and associated with a good HR. Tadalafil 2% cream was studied in a single study with a reduction in the number of DUs. Vitamin E gel was associated with a reduction in ulcer healing time. Low-level light therapy, hydrodissection and corticosteroid injection, extracorporeal shock wave (ESW) and photobiomodulation were evaluated in a single study each and showed a positive trend. Dimethyl sulfoxide was associated with significant local toxicity. CONCLUSIONS: A range of non-surgical, local treatments for SSc-DUs have been explored and showed efficacy to some extent. We have identified methodological flaws that should be avoided in the design of future studies to explore locally-acting treatments for SSc-DUs.

Treatment of systemic sclerosis-associated digital ulcers: recommendations of the Turkish Society for Rheumatology.

OBJECTIVES: Digital ulcers (DUs) are associated with a significant burden in systemic sclerosis (SSc) by leading to severe pain, physical disability, and reduced quality of life. This effort aimed to develop recommendations of the Turkish Society for Rheumatology (TRD) on the management of DUs associated with SSc. METHODS: In the first meeting held in December 2020 with the participation of a task force consisting of 23 rheumatologists the scope of the recommendations and research questions were determined. A systematic literature review was conducted by 5 fellows and results were presented to the task force during the second meeting. The Oxford system was used to determine the level of evidence. The preliminary recommendations were discussed, modified, and voted by the task force and then by members of TRD via e-mail invitation allowing personalised access to a web-based questionnaire [SurveyMonkey®]. RESULTS: A total of 23 recommendations under 7 main headings were formulated covering non-pharmacological measures for the prevention of DUs and pharmacological treatments including vasodilators, anti-aggregants, antibiotics, wound care, pain control, and interventions including sympathectomy, botulinum toxin, and surgery. Risk factors, poor prognostic factors, prevention of DU and adverse effects of medical treatments were reported as 4 overarching principles. CONCLUSIONS: These evidence-based recommendations for the management of SSc-associated DUs were developed to provide a useful guide to all physicians who are involved in the care of patients with SSc, as well as to point out unmet needs in this field.

Immersion Ultrasound Therapy in Combination with Manual Therapy in the Treatment of Ischemic Digital Ulcers in Systemic Sclerosis.

Background and Objectives: Digital ulcers (DUs) are the most common complication in patients with Systemic Sclerosis (SSc). They cause pain with hand dysfunction and negatively impact activities of daily and working life. Our study aims to evaluate the efficacy of a combined treatment of manual therapy and ultrasound therapy in SSc patients with ischemic DU (IDU) compared to manual therapy alone. Materials and Methods: We conducted a before-and-after study (non-randomized study). We enrolled a consecutive series of IDU patients undergoing rehabilitation treatment and divided them into two groups: a treatment group consisting of patients undergoing a combination of manual therapy and US water immersion and a standard care group consisting of patients subjected to manual therapy alone. At the time of the first visit (T0) and at the end of the 4-week rehabilitation period (T1), we evaluated functional capacity, pain intensity, ulcer evolution, and quality of life. Results: In the treatment group, we observed a statistically significant improvement in the functional capacity of the hand (DHI: 28.15 ± 11.0 vs. 19.05 ± 8.83; p < 0.05), pain (NRS: 5.55 ± 1.2 vs. 2.9 ± 1.09; p < 0.05), and PSST score (24.4 ± 4.0 vs. 16.2 ± 2.36; p < 0.05). In the standard care group, we observed a statistically significant improvement only for the functional capacity of the hand (DHI: 28.85 ± 9.72 vs. 22.7 ± 7.68; p < 0.05). Finally, from the comparison between the treatment group and the standard care group, we observed statistically significant improvements in pain (2.9 ± 1.09 vs. 4.5 ± 1.07; p < 0.05) and in the PSST scale (16.2 ± 2.36 vs. 20.4 ± 4.02; p < 0.05). Furthermore, at the end of treatment in the treatment group, 15 ulcers (62.5%) were completely healed, while in the standard care group, only 3 ulcers were completely healed (14.3%). Conclusions: Combined treatment with manual therapy and ultrasound therapy appears to be useful in the management of IDU in patients with scleroderma.

Treatment of Vascular Complications in Systemic Sclerosis: What Is the Best Approach to Diagnosis and Management of Renal Crisis and Digital Ulcers?

Vasculopathy as exemplified by scleroderma renal crisis (SRC) and digital ulcers (DUs) is a cardinal feature of systemic sclerosis (SSc) and is associated with significant morbidity, including in patients with early disease. Prompt recognition and management is required to alleviate potentially irreversible damage from SSc-associated vasculopathy. Both SRC and DUs share many etiopathogenic drivers which inform the therapeutic strategy. The aim of our review was to describe the diagnosis and management of SRC and DUs in SSc, and to discuss unmet needs for future research.

Calciphylaxis and skin ulcers: a diagnostic and therapeutic challenge.

INTRODUCTION: Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare and severe disorder that presents with skin ischemia and necrosis. Diagnosis is challenging, and even if the condition is diagnosed in the early stages, the mortality rate is exceptionally high, ranging from 45% to 80%. CASE REPORT: A 55-year-old male with chronic kidney disease secondary to diabetic nephropathy presented with painful, severe, necrotic ulcers in the lower legs and underwent treatment with sodium thiosulfate, debridement of necrotic tissue, and topical oxygen therapy. Complete healing of the ulcers was achieved within 3 months. CONCLUSION: This case report raises awareness of this rare condition and details successful treatment in 1 patient.

Endothelial progenitor cell derived exosomes mediated miR-182-5p delivery accelerate diabetic wound healing via down-regulating PPARG.

Diabetic wound is one of the most common and serious complications of diabetes, which is characterized by abnormal number and quality of wound repair related cells. Previous studies have shown that human endothelial progenitor cells derived exosomes (EPCs-EXO) can promote diabetic wound healing through modulating vascular endothelial cell function. The purpose of this study was to investigate the biological effects and molecular mechanisms of EPCs-EXO on diabetic wound healing. The regulation of EPCs-EXO on human immortalized epidermal cell line HaCaT in high glucose (HG) environment was evaluated. Our data showed that EPCs-EXO promoted the proliferation, migration, while inhibited apoptosis of HaCaTs challenged by HG via elevating miR-182-5p expression level in vitro. Skin wound healing was significantly enhanced by EPCs-EXO in diabetic mice. Moreover, bioinformatics analyses and luciferase reporter assay indicated that exosomal miR-182-5p was bound to PPARG 3' UTR sequence and inhibited the expression of PPARG. Collectively, our findings provided a new role of EPCs-EXO in the clinical treatment of diabetic skin wounds. Diabetic wound is one of the most common and serious complications of diabetes, which is characterized by abnormal number and quality of wound repair related cells. Previous studies have shown that human endothelial progenitor cells derived exosomes (EPCs-EXO) can promote diabetic wound healing through modulating vascular endothelial cell function. The purpose of this study was to investigate the biological effects and molecular mechanisms of EPCs-EXO on diabetic wound healing. The regulation of EPCs-EXO on human immortalized epidermal cell line HaCaT in high glucose (HG) environment was evaluated. Our data showed that EPCs-EXO promoted the proliferation, migration, while inhibited apoptosis of HaCaTs challenged by HG via elevating miR-182-5p expression level in vitro. Skin wound healing was significantly enhanced by EPCs-EXO in diabetic mice. Moreover, bioinformatics analyses and luciferase reporter assay indicated that exosomal miR-182-5p was bound to PPARG 3' UTR sequence and inhibited the expression of PPARG. Collectively, our findings provided a new role of EPCs-EXO in the clinical treatment of diabetic skin wounds.