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ObjectiveSystemic sclerosis (SSc) is a systemic autoimmune disease with high morbidity and significant mortality. There is a great need of predictors that would allow risk stratification of patients with SSc and ultimately initiation of treatment early enough to ensure optimal clinical results. In this study, we evaluated whether a history of digital ulcers (HDU) at presentation may be a predictor of vascular outcomes and of overall clinical worsening and death in patients with SSc.MethodsPatients from the EULAR Scleroderma Trials and Research (EUSTAR) database, satisfying at inclusion the 1980 American College of Rheumatology classification criteria for SSc, who had a follow-up of at least 3 years since baseline or who have died, were included in the analysis. HDU at presentation as a predictor of disease worsening or death was evaluated by Cox proportional hazards regression analysis.Results3196 patients matched the inclusion criteria (male sex 13.2%, 33.4% diffuse subset). At presentation, 1092/3196 patients had an HDU (34.1%). In multivariable analysis adjusting for age, gender and all parameters considered potentially significant, HDU was predictive for the presence of active digital ulcers (DUs) at prospective visits (HR (95% CI)): 2.41 (1.91 to 3.03), p<0.001, for an elevated systolic pulmonary arterial pressure on heart ultrasound (US-PAPs):1.36 (1.03 to 1.80), p=0.032, for any cardiovascular event (new DUs, elevated US-PAPs or LV failure): 3.56 (2.26 to 5.62), p<0.001, and for death (1.53 (1.16 to 2.02), p=0.003).ConclusionsIn patients with SSc, HDU at presentation predicts the occurrence of DUs at follow-up and is associated with cardiovascular worsening and decreased survival.

Digital ulcers (DUs) occur in up to half of patients with systemic sclerosis (SSc) and may lead to infection, gangrene and amputation with functional disability and reduced quality of life. This study has elucidated the burden of SSc-associated DUs through identification of four patient categories based on the pattern of DU recurrence over a 2-year observation period. Patients with SSc-associated DUs enrolled in the Digital Ulcers Outcome Registry between 1 April 2008 and 19 November 2013, and with ≥2 years of observation and ≥3 follow-up visits during the observation period were analysed. Incident DU-associated complications were recorded during follow-up. Work and daily activity impairment were measured using a functional assessment questionnaire completed by patients after the observation period. Potential factors that could predict incident complications were identified in patients with chronic DUs. From 1459 patients, four DU occurrence categories were identified: 33.2% no-DU; 9.4% episodic; 46.2% recurrent; 11.2% chronic. During the observation period, patients from the chronic category had the highest rate of incident complications, highest work impairment and greatest need for help compared with the other categories. Independent factors associated with incident complications included gastrointestinal manifestations (OR 3.73, p=0.03) and previous soft tissue infection (OR 5.86, p=0.01). This proposed novel categorisation of patients with SSc-associated DUs based on the occurrence of DUs over time may help to identify patients in the clinic with a heavier DU burden who could benefit from more complex management to improve their functioning and quality of life.

In this review, we discuss sympathetic regulation in normal and diabetic wound healing. Experimental denervation studies have confirmed that sympathetic nerve endings in skin have an important and complex role in wound healing. Vasoconstrictor neurons secrete norepinephrine (NE) and neuropeptide Y (NPY). Both mediators decrease blood flow and interact with inflammatory cells and keratinocytes. NE acts in an ambiguous way depending on receptor type. Beta2-adrenoceptors could be activated near sympathetic endings; they suppress inflammation and re-epithelialization. Alpha1- and alpha2-adrenoceptors induce inflammation and activate keratinocytes. Sudomotor neurons secrete acetylcholine (ACh) and vasoactive intestinal peptide (VIP). Both induce vasodilatation, angiogenesis, inflammation, keratinocytes proliferation and migration. In healthy skin, all effects are important for successful healing. In treatment of diabetic ulcers, mediator balance could be shifted in different ways. Beta2-adrenoceptors blockade and nicotinic ACh receptors activation are the most promising directions in treatment of diabetic ulcers with neuropathy, but they require further research.

Evaluating the predictive role of endothelial dysfunction in the development of vasculopathy-mediated complications in patients with limited cutaneous systemic sclerosis (lcSSc). 38 patients with lcSSc who were naïve for vasculopathy-mediated complications, defined as absent pre-existing digital ulcers (DU), pulmonary hypertension (PH) and symptomatic atherosclerotic cardiovascular diseases, were prospectively observed during a 3-years follow-up period. At study enrolment, functional and laboratory parameters of endothelial dysfunction were assessed. Microvascular events, defined as the development of DU and PH, macrovascular events, defined as newly symptomatic atherosclerotic cardiovascular diseases, and clinical events, defined as additional interstitial lung disease (ILD), renal crisis and esophageal dysfunction, were recorded annually. 33 patients (86.8%) completed all follow-up study visits. During the follow-up period, DU, PH, carotid and vertebral artery disease and ILD occurred in eight (24.2%), one (3.0%), one (3.0%) and two patients (6.1%), respectively, without recorded renal crisis and esophageal dysfunction. Number of pathologic FMD, NMD and/or PWV values was significantly associated with the development of clinical events ( p  = 0.035), but was not a significant predictor for microvascular events. Number of pathologic FMD, NMD and/or PWV values was a significant predictor for disease activity assessed by EUSTAR index ≥ 2.5 at last study visit (OR 5.47 [95% CI 1.01–29.03], p  = 0.049). Distinct endothelial dysfunction may promote the development of disease complications and disease activity in patients with lcSSc.

Diabetes mellitus disrupts wound repair and leads to the development of chronic wounds, likely due to impaired angiogenesis. We previously demonstrated that human proinsulin C-peptide can protect against vasculopathy in diabetes; however, its role in impaired wound healing in diabetes has not been studied. We investigated the potential roles of C-peptide in protecting against impaired wound healing by inducing angiogenesis using streptozotocin-induced diabetic mice and human umbilical vein endothelial cells. Diabetes delayed wound healing in mouse skin, and C-peptide supplement using osmotic pumps significantly increased the rate of skin wound closure in diabetic mice. Furthermore, C-peptide induced endothelial cell migration and tube formation in dose-dependent manners, with maximal effect at 0.5 nM. These effects were mediated through activation of extracellular signal–regulated kinase 1/2 and Akt, as well as nitric oxide formation. C-peptide-enhanced angiogenesis in vivo was demonstrated by immunohistochemistry and Matrigel plug assays. Our findings highlight an angiogenic role of C-peptide and its ability to protect against impaired wound healing, which may have significant implications in reparative and therapeutic angiogenesis in diabetes. Thus, C-peptide replacement is a promising therapy for impaired angiogenesis and delayed wound healing in diabetes.

Objective:To assess the impact of digital ulcers (DUs) on disability and health-related quality of life (HRQoL) in systemic sclerosis (SSc).Methods:Two hundred and thirteen patients with SSc were evaluated at four annual meetings of a patient society between 2004 and 2007 (n = 177) or during hospital stay (n = 36). HRQoL was assessed by the SF-36, global disability by the health assessment questionnaire (HAQ), hand disability by the Cochin Hand Function Scale (CHFS) and global hand and wrist mobility by the Kapandji index.Results:Sixty-seven patients (31.4%) had at least one DU at the time of evaluation. Patients with DUs showed significantly more pitting scars (p<0.001) and calcinosis (p<0.0001) than others. Patients with DU had significantly greater HAQ (mean (SD) 1.218 (0.723) vs 0.930 (0.717), p = 0.008), CHFS (mean (SD) 27.38 (20.68) vs 16.73 (18.19), p<0.0001) and aesthetic prejudice (mean (SD) 6.1 (2.2) vs 3.9 (2.5), p<0.0001) scores than others. Hand and wrist mobility were significantly diminished in patients with DU (mean (SD) Kapandji score 75.3 (22.8) vs 81.7 (19.2), p<0.0001). The presence of a DU did not significantly alter the physical component but influenced the mental component (mean (SD) 43.38 (12.53) vs 39.58 (9.54), p = 0.026) of the SF36.Conclusion:Patients with SSc with DUs have reduced wrist and hand mobility, increased global and hand disabilities and decreased mental component of HRQoL.

•This cohort reveals a severe HSAN IV phenotype in Jordanian patients.•All patients manifested global developmental delay, microcephaly and poor weight gain.•The most common mutation in our series is (c.1860_1861insT; p.Pro621fs).•A new mutation variant in c.2170 G > A is reported with probably a milder phenotype. To present the clinical picture, the associated complications and the genetic findings of Jordanian patients diagnosed with Congenital insensitivity to pain with anhidrosis (CIPA). This is a retrospective study including 7 patients diagnosed with CIPA presenting to Jordan University Hospital neurology clinic between 2001 and 2017. Among five families, seven patients were diagnose with CIPA and followed for a period ranging from one month to 6 years. The initial symptom observed in all patients was high fever in the first few days after birth, decreased sensation to pain and decreased sweating were later noted. Poor weight gain, microcephaly and global developmental delay were present in most cases. All patients had tongue ulcerations. Fingers/toes ulcerations were present in 6/7 (86.0 %), hip joint dislocation in 3/7 (43.0 %), chronic arthritis and joint swelling in 6/7 (86.0 %), corneal ulcers in 4/7 (57.1 %) and kidney amyloidosis in 1/7 (13.0 %) of all patients. Death occurred in 4/7 (57.1 %) patients. Consanguinity was present in all families. Mutation analysis revealed three variants in NTRK1 gene. The frameshift (c.1860_1861insT; p.Pro621fs) mutation was common in our series. One patient carried a novel missense mutation (c.2170 G > A; p.Gly724Ser). The third missense mutation (C2125 G > T; p.Val709Leu) was reported in a previous study in one patient. This cohort reveals a severe CIPA phenotype necessitating thorough multidisciplinary care and follow up.

In this study, we aimed to investigate the association of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) with clinical manifestations in patients with systemic sclerosis (SSc). We conducted a cross-sectional analysis of data collected from a cohort study of 114 female patients with SSc and of 304 age-matched, healthy, female controls recruited from a tertiary rheumatology center. Patients with digital ulcers (DU) included those with either active or healed ulcers. Interstitial lung disease (ILD) was diagnosed on detection of diffuse ground-glass opacity or pulmonary fibrosis on chest X-ray or on high-resolution computed tomography. Patients with SSc had significantly higher PLR and NLR than ealthy controls. Of 114 patients with SSc, 35 (30.7%) and 54 (47.4%) patients had DU (active: 12, healed: 23) and ILD, respectively. PLR and NLR in SSc patients with concurrent DU or ILD were significantly higher than that in those without these respective complications. The PLR (OR = 1.008, 95% CI 1.002–1.015), but not the NLR, was independently associated with the presence of DU in SSc patients, based on multivariable logistic regression models. Additionally, both PLR (OR = 1.008, 95% CI 1.001–1.014) and NLR (OR = 1.515, 95% CI 1.066–2.155) correlated independently with the presence of ILD. However, both the PLR and NLR showed no significant association with the modified Rodnan skin score, pulmonary arterial hypertension, and gastrointestinal involvement. Our results suggest that PLR and NLR could be considered as potential biomarkers of DU and ILD, in patients with SSc.

To determine if high-voltage pulsed current (HVPC) electrotherapy augments ischemic wound healing and increases periwound microcirculation. A prospective, randomized, single-blinded, sham-controlled clinical trial was conducted on a homogenous subset of quasi-stable ischemic wounds. Active HVPC or sham HVPC was applied to wounds for a 14-week period. Wounds were monitored every 4 weeks, except 2 weeks between weeks 12 and 14, for wound area, wound appearance, and microcirculation, which was measured by transcutaneous oxygen (TcPO2) levels and laser Doppler flow. Ischemic wounds treated with active HVPC decreased in size, contrary to the expected increase in ischemic wound size that was observed in wounds in the control group (P <.05, Student t test; week 4). A trend toward smaller wound area occurred in wounds in the HVPC group compared with wounds in the control group (week 14). Among the HVPC group, an improvement in periwound microcirculation occurred at weeks 8 (P <.05, TcPO2; P <.01, laser Doppler) and 12 (P <.05, laser Doppler). These increases suggest that HVPC promotes arteriolar vasodilation and dermal capillary formation. HVPC was well tolerated. The results of this study demonstrate that HVPC decreased the area of ischemic wounds, reversing the expected increase in wound size, and improved microcirculation. The promising results of this pilot study require a larger Phase II study to confirm and generalize these findings. Electrotherapy may prove to be a relatively safe and effective complement to surgical revascularization to improve the odds of healing ischemic wounds and promoting limb salvage.

We developed a novel mouse model of human refractory cutaneous ulcers that more faithfully reflects pathology and evaluated the effects of mixed cell sheets comprising peripheral blood mononuclear cells and fibroblasts, which we previously developed for treating refractory cutaneous ulcers. Model development involved sandwiching the skin between two magnets, one of which was implanted under the skin for 7 consecutive days. This magnet-implanted ulcer model produced persistently large amounts of exudate and induced the infiltration of the ulcer with inflammatory cells. The model mice had a thicker epidermis and impaired transforming growth factor-β (TGF-β) signaling followed by SMAD2 down-regulation, which causes epidermal hyperplasia in chronic ulcers. Impaired TGF-β signaling also occurred in the ulcers of critical limb ischemia patients. Mixed cell implantation in this ulcer model reduced TNF-α and IL-6 levels in the tissues surrounding the mixed cell sheet-treated ulcers compared with controls or mice treated with trafermin (FGF2). Seven days after commencing therapy, the epidermis was thinner in mice treated with the mixed cell sheets than in controls. This model may therefore serve as a clinically relevant model of human ulcers, and our mixed cell sheets may effectively relieve chronic inflammation and inhibit refractoriness mechanisms.