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As the clinical course of systemic sclerosis (SSc) varies widely, prognostic indicators have been sought to predict the outcomes of individual patients. Racial differences in SSc render it necessary to validate prognostic indicators in different patient cohorts. In this study, we aimed to assess clinical and laboratory parameters in Japanese patients with early‐stage SSc with diffuse cutaneous involvement and/or interstitial lung disease, and identify predictive factors for disease progression. We performed multivariate analyses of baseline clinical information to estimate symptoms 4 years later in Japanese patients with diffuse cutaneous SSc and/or SSc with interstitial lung disease. Patients were enrolled in the study within 5 years of disease onset at 10 Japanese SSc centers. Over 12 years, 115 patients followed up for 4 years were included in this study. The modified Rodnan skin score (mRSS) at 4 years correlated with the baseline mRSS and finger‐to‐palm distance, defined as the average length from the distal tip of the fourth finger to the distal palmar crease. The percentage predicted vital capacity (%VC) in year 4 positively and negatively correlated with initial %VC and the presence of anti‐topoisomerase I antibodies, respectively. The Health Assessment Questionnaire Disability Index (HAQ‐DI) at 4 years was positively and negatively associated with baseline HAQ‐DI and %VC, respectively. The occurrence of digital ulcers within 4 years was associated with the initial presence of digital ulcers, finger‐to‐palm distance, and the presence of digital pitting scars and anti‐topoisomerase I antibodies. This study identified several factors that may predict the progression of early‐stage SSc in Japanese patients. Finger‐to‐palm distance may be a useful tool for predicting the progression of skin thickening and the development of digital ulcers in the early stages of severe SSc, but larger, long‐term prospective studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Objective Semaphorin 3A (Sema3A) plays a regulatory role in immune responses. The aim of this study was to evaluate Sema3A levels in patients with systemic sclerosis (SSc), especially in major vascular involvements such as digital ulcer (DU), scleroderma renal crisis (SRC), pulmonary arterial hypertension (PAH), and to compare Sema3A level with SSc disease activity. Methods In SSc patients, patients with DU, SRC, or PAH were grouped as major vascular involvements and those without as nonvascular, and Sema3A levels were compared between the groups and with a healthy control group. The Sema3A levels and acute phase reactants in SSc patients, as well as their association with the Valentini disease activity index and modified Rodnan skin score, were evaluated. Results The Sema3A values (mean ± SD) were 57.60 ± 19.81 ng/mL in the control group (n = 31), 44.32 ± 5.87 ng/mL in patients with major vascular involvement SSc (n = 21), and 49.96 ± 14.00 ng/mL in the nonvascular SSc group (n = 35). When all SSc patients were examined as a single group, the mean Sema3A value was significantly lower than controls (P  = .016). The SSc with major vascular involvement group had significantly lower Sema3A levels than SSc with nonmajor vascular involvement group (P  = .04). No correlation was found between Sema3A, acute phase reactants, and disease activity scores. Also, no relationship was observed between Sema3A levels and diffuse (48.36 ± 11.47 ng/mL) or limited (47.43 ± 12.38 ng/mL) SSc types (P  = .775). Conclusion Our study suggests that Sema3A may play a significant role in the pathogenesis of vasculopathy and can be used as a biomarker in SSc patients with vascular complications such as DU and PAH. [ABSTRACT FROM AUTHOR]

ObjectivesThis study aimed to assess the effectiveness of iguratimod (IGU) as an alternative treatment for systemic sclerosis (SSc), especially in the prevention of ischemic digital ulcers (DUs).MethodsWe constructed two cohorts from the Renji SSc registry. In the first cohort, SSc patients receiving IGU were observed prospectively with effectiveness and safety. In the second cohort, we picked up all the DU patients with at least a 3-month follow-up to investigate the prevention of IGU on ischemic DU.ResultsFrom 2017 to 2021, 182 SSc patients were enrolled in our SSc registry. A total of 23 patients received IGU. With a median follow-up of 61 weeks (IQR: 15–82 weeks), the drug persistence was 13/23. In total, 91.3% of the patients (21/23) became free of deterioration in the last visit with IGU. Of note, 10 patients withdrew from the study due to the following reasons: two patients withdrew due to deterioration, three due to incompliance, and five due to mild-to-moderate side effects. All the patients with side effects recovered fully after stopping IGU. Of note, 11 patients had ischemic DU, and 8 out of 11 (72.7%) patients had no new occurrence of DU during the follow-up. In the second cohort of 31 DU patients receiving a combination of vasoactive agents with a median follow-up of 47 weeks (IQR, 16–107 weeks), IGU treatment was protective of new DU occurrence (adjusted risk ratio = 0.25; 95% CI, 0.05–0.94; adjusted odds ratio = 0.07; and 95% CI, 0.01–0.49).ConclusionOur study for the first time describes the potential of IGU possibly as an alternative treatment for SSc. To our surprise, this study provides a hint that IGU treatment can be used for the prevention of the occurrence of ischemic DU and merits further investigation.

Objectives: Systemic sclerosis (SSc) is a disease characterized by diffuse sclerosis of skin and organs and small vessel vasculopathy. Despite it, large vessels can also be involved with ulnar artery vasculopathy, revealing as a more frequent feature of SSc. The aim of this paper is to assess the macrovascular involvement of SSc patients through an ultrasound (US) evaluation of radial and ulnar arteries. Methods: Radial and ulnar resistance indices (RIs) and peak systolic velocity (PV) (cm/s) together with clinical features of SSc patients were evaluated. Raynaud phenomenon (RP) and healthy control (HC) groups were used for comparison. Results: Forty-three SSc patients were evaluated. Twelve patients (28%) had ulnar artery occlusions (UAOs). In nine cases (75%), UAOs were bilateral. A high UAO prevalence (42%) was found in SSc patients with late nailfold-video-capillaroscopy (NVC) pattern (p = 0.0264). Patients with UAOs had digital ulcers (DUs) in 10 cases (83.3%). Radial and ulnar PVs were lower in SSc and RP patients than the HC group. Radial and ulnar RIs were higher in SSc and RP patients than the HC group. A decision tree analysis led to the classification of 70% of SSc patients with an ulnar RI > 0.82 and ulnar PV > 2.8 cm/s. The most influential variables on UAO development were interstitial lung disease (ILD) (p = 0.002) and NVC pattern (p = 0.002). A positive correlation was shown between modified Rodnan skin score (mRSS) and ILD (p = 0.283; r = 0.033), mRSS and DU (r = 0.344; p = 0.012) and DU and ILD (r = 0.303; p = 0.024). Male sex was associated with increased UAO frequency (p = 0.042). Conclusions: UAO is a peculiar feature of severe SSc present in 28% of the cases, particularly associated with the presence of ILD and late NVC pattern. In 75% of the cases, UAOs are bilateral. DUs are very frequent in patients with UAOs (83%). The RI evaluated by US could be useful to distinguish SSc from HC patients. US could be a useful tool for assessing high-risk DU development in patients. [ABSTRACT FROM AUTHOR]

Introduction: Systemic sclerosis (SSc) represents a complex, multisystem rheumatologic disorder characterized by immune dysregulation, vascular dysfunction, and multi-organ fibrosis. This review discusses the efficacy of the available therapeutic options and the significance of developing effective strategies against its varied manifestations, pivotal to improving patient outcomes., Areas Covered: The review elaborates on the pharmacological treatments available for managing key manifestations of SSc, including skin and lung involvement, and vascular complications, as well as the most recent findings in the field. We evaluated recent literature and clinical trials from the past decade, as well as most recent guidelines from entities like EULAR and the ACR, to provide a comprehensive overview of current management strategies., Expert Opinion: Despite advancements in therapeutic options, SSc remains a challenging disease to manage due to its complexity, our relatively limited understanding of disease pathogenesis, and its severe impact on quality of life. The development of targeted therapies and the refinement of existing treatment protocols offer hope for better management. Future research should focus on personalized medicine approaches and refining treatment algorithms to optimize outcomes for patients.

Introduction: Digital ulcers represent a current public health issue, due to the relevant difficulties in their management and their tendency to become chronic, non-healing lesions. We present an observational study of 28 patients referred to our Wound Care Service, focused on multidisciplinary and dermatological management. Objectives: Our case series represents an opportunity to discuss the main comorbidities that affect these kinds of patients and to present an evidence-based protocol that has proved highly effective in our clinical practice. Methods: We collected the clinical data of 28 patients referred to our Wound Care Service at S.Orsola-Malpighi Hospital, where they were all clinically evaluated; subsequently a local treatment was set up with dressings and the application of topical medications, while for most of them a further multidisciplinary evaluation was required to control the underlying disease and to avoid relapses. Results: Digital ulcers were divided into 5 categories, based on the causative agent: peripheral artery disease, diabetes associated wounds, mixed wounds, pressure wounds and immune-mediated diseases associated with wounds. Each group received a specific management, based on the characteristics of the ulcer and the underlying comorbidities. Conclusions: The clinical evaluation of digital wounds requires a thorough knowledge of the possible causes behind the onset of these ulcerative forms. In case of suspicion, send the patient for a specialist evaluation, to carry out a proper management of the case. A multidisciplinary approach in the management of these wounds is necessary to achieve a precise diagnosis and a correct treatment.

Background/aim: Systemic sclerosis (SSc) is a chronic systemic disease characterized by vascular damage, autoimmunity, and fibrosis in the skin and internal organs. In this study, we tried to determine the causes of severe infection in patients with SSc and to reveal the factors associated with severe infection. Materials and methods: We retrospectively examined 214 SSc patients between January 2010 and August 2020. Forty-seven patients with at least one severe infection and 167 patients without severe infection were compared. Results: A total of 76 episodes of severe infections were detected in 47 (22%) patients. Common infections included pneumonia, infected digital ulcer, urinary tract infections, and osteomyelitis. Female patients had a higher frequency in the group without severe infection (91.6% vs. 80.9%, p = 0.035). Patients with severe infections had a higher frequency of digital ulcers (p < 0.001), cardiac (p = 0.002), and GIS involvement (p < 0.001). In multivariable analysis, digital ulcer presence (OR: 2.849 [1.356-5.898] (p = 0.006) and cardiac involvement (OR: 2.801 [1.248-6.285]) were associated with severe infection. Of the patients with severe infections, 34% had recurrent severe infections. There was no difference in demographic and clinical characteristics between patients with recurrent and nonrecurrent severe infections. Conclusion: The presence of digital ulcer and cardiac involvement seem to be associated with a severe infection in patients with systemic sclerosis. In patients with cardiac involvement and digital ulcers, more careful attention may be required for the development of severe infections. [ABSTRACT FROM AUTHOR]

Digital ulcer generally reflects the presence of focal ischemia related to a microangiopathy. Etiologies are dominated by connectivites in women and by diffuse arteriopathies such as Leo-Buerger disease in men, as well as emboligenic heart disease. This article describes the case of a 46-year-old chronic hemodialysis female patient with nephroangiosclerosis, who presented a progressive onset of intermittent cyanosis of the fingertips and toes. The symptomatology was worsened by the evolution toward necrosis at the amputation stage. Etiological workup was in favor of multiple myeloma, requiring the initiation of chemotherapy. [ABSTRACT FROM AUTHOR]

ObjectiveIschemic digital ulcers (DUs) are frequent and severe complications of systemic sclerosis (SSc). Treatment options for SSc-related digital vasculopathy are based on aggressive vasodilation, with the objective to improve blood flow in ischemic areas. Intravenous prostanoids are recommended to treat active DUs. However, the level of evidence for the duration of 5 days is low. Therefore, the aim of this study was to determine whether prolonging the infusion beyond 5 days increases the rate of healing of active DUs in SSc.MethodsThis is an observational longitudinal retrospective bicenter study from 2000 to 2017. The objective was to compare the healing rate and time (defined by a healing of at least 50% of DUs) between two durations of iloprost administration: 5 days or less, or more than 5 days.ResultsForty-one patients, with a mean age of 47 ± 15 years at diagnosis and 32 (78%) females have been included. Systemic sclerosis was diffuse in 10 (24%) cases and 13 (32%) had an interstitial lung disease. A total of 243 iloprost infusions for DUs were performed: 140 infusions for 5 days or less, and 103 infusions for more than 5 days (prolonged duration). Patients with active DUs which received >5 days of iloprost had higher modified Rodnan skin scale at the time of iloprost infusion (median 33 vs. 15; p < 0.05), more interstitial lung disease (44 vs. 27%; p < 0.05), more anti-topoisomerase I antibody positivity (59 vs. 44%; p < 0.05), and received more previous cyclophosphamide therapy (48 vs. 19%; p < 0.05). While the number of active DUs before iloprost infusion was not significantly different among those who received ≤5 days and >5 days of iloprost, the time to healing after iloprost infusion significantly decreased in SSc patients who received >5 days iloprost infusion: 48 [7–392] vs. 91 [9–365] days (p < 0.05). The proportion of SSc patients with healed DUs tended to increase in patients with >5 days iloprost infusion (log rank = 0.06). The number of patients with complete DU healing at day 90 was significantly increased in SSc who received >5 days of iloprost: 53 (51%) vs. 52 (37%) (p < 0.05). In addition, the time to healing was not significantly associated with the use of calcium channel blockers, endothelin receptor antagonists or a combination of PDE-5 inhibitors.ConclusionProlonging duration of iloprost >5 days could improve the healing rate and the time to healing of SSc-related DUs. Prospective randomized studies are needed to confirm these data and define the optimal duration of iloprost therapy.

Chronic non-healing wounds impose a huge burden on patients and health care providers. In spite of improvements in standards of care there are no effective and safe treatments that promote new tissue formation and wound closure in ailments such as diabetic foot ulcer, pressure ulcer, venous leg ulcer or digital ulcer in systemic sclerosis. Endothelial dysfunction, which associates with impaired endogenous nitric oxide formation is assumed to be a main disease mechanism in chronic, non-healing wounds in diabetic and elderly patients as well as in digital ulcers in systemic sclerosis. Topadur Pharma has invented small molecular weight nitric oxide-releasing PDE5 inhibitors, which by modulating a key enzyme system of intracellular signaling may address chronic non-healing wounds. The promising first drug candidate TOP-N53 is currently in early clinical development. Here we describe for the first time the design of TOP-N53 and the synthesis of the clinical GMP batch.

Objectives: Systemic sclerosis is characterised by ischaemic skin ulcers on the fingertips, and low-energy shock wave therapy is suggested as a novel treatment for ischaemic lesions with angiogenic effects. We aimed to investigate the efficacy and safety of shock wave therapy for skin ulcers in patients with systemic sclerosis., Methods: In this phase 3 pivotal study, we analysed 60 systemic sclerosis patients with digital ulcers that did not disappear after >4 weeks of existing treatment: 30 patients were treated with extracorporeal shock wave therapy and 30 with conventional treatment. The ulcer count reduction observed after an 8-week treatment period was compared between the shock wave therapy and conventional treatment groups., Results: After an 8-week treatment period, the mean reduction in the number of ulcers was 0.83 (standard deviation [SD] 2.79) in the conventional treatment group compared to a more pronounced reduction of 4.47 (SD 2.65) in the shock wave therapy group., Conclusions: The study findings indicate the efficacy of extracorporeal shock wave therapy for refractory digital ulcers associated with systemic sclerosis, which has limited therapeutic options. This therapy is non-invasive and safe and can be used without restriction in combination with other therapies, thus serving as a novel therapeutic method., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Introduction: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vascular abnormalities, often leading to the development of digital ulcers (DUs). DUs are painful and debilitating, significantly impacting patients' quality of life. Effective pain management during debridement is crucial, yet there is no consensus on the optimal approach. This study evaluates the efficacy and safety of digital nerve block (DNB) using lidocaine and mepivacaine for pain control during sharp debridement of DUs in SSc patients., Methods: This prospective observational study was conducted from September 2023 to May 2024 at the Rheumatology Operating Unit, University of Verona. Patients were randomized to receive either 1 mL of 2% lidocaine or 2% mepivacaine for DNB. Pain levels were assessed using a categorical grading scale during the injection and debridement. The outcomes were pain control and performance of lidocaine versus mepivacaine., Results: The cohort developed 46 ulcers. The pain was abolished in almost all patients. Lidocaine achieved faster anaesthesia (127.92 ± 34.32 s) compared with mepivacaine (252.65 ± 49.89 s, p  < 0.001). Mepivacaine resulted in less pain during injection ( p  = 0.006). No significant difference in pain levels during debridement was observed between the two anaesthetics. Three mild adverse effects (Raynaud's phenomenon) were reported. All procedures were completed successfully, and 35 ulcers healed with a mean time of 6.1 ± 7.77 weeks., Conclusions: DNB with mepivacaine provides effective pain control during DU debridement in SSc patients, with lower injection site pain and comparable efficacy to lidocaine. The procedure is safe, well-tolerated and facilitates successful ulcer healing. Further studies with larger cohorts are warranted to confirm these findings., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

Objectives: The digital ulcers of systemic sclerosis are disabling and frequent· Their pathogenesis involves a capillary microangiopathy and a digital arterial disease that few studies were able to quantify up to now. A multicentre observational study about the predictive value of capillaroscopy in systemic sclerosis offered us the opportunity to evaluate further the complementary information provided by both capillary and arterial evaluations., Methods: During the SCLEROCAP study, five out of the nine centers performed a systematic evaluation of the finger brachial pressure index (FBPI) in the last four fingers of both hands at baseline, using the same laser-doppler device. In the present work, FBPI measurements were compared between fingers with vs without digital ulcers or scars, before and after adjusting for the capillaroscopic pattern and systemic factors., Results: FBPI measurements were performed in 2537 fingers from 326 patients. Active ulcers or scars were found in 10·8% of those fingers, more often on the right hand, and in the second and third fingers. FBPI was lower than 0·70 in 26% of all fingers and in 57·5% of those with ulcers. A strong association was found between a low FBPI and the presence of digital ulcers, even after adjusting for capillaroscopic pattern, ulcer location and the patient himself., Conclusion: These results confirm the importance of digital arterial disease in the pathogenesis of digital ulcers of systemic sclerosis, which is independent from the microangiopathy. FBPI measurements complement the information provided by capillaroscopy and might have an important predictive value for subsequent digital ulcers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In conclusion, a few clinical trials support the efficacy of BTX local injections for RP/DU in SSc patients. Keywords: botulinum toxin; digital ulcer; Raynaud phenomenon; systemic sclerosis EN botulinum toxin digital ulcer Raynaud phenomenon systemic sclerosis 187 189 3 01/31/23 20230201 NES 230201 Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by tissue and organ fibrosis and vasculopathy.[1] Digital ulcers (DU) and Raynaud phenomenon (RP) are the presentations of vasculopathy found in SSc. Efficacy of botulinum toxin B injection for Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis. [Extracted from the article]

Introduction: Systemic sclerosis (SSc) is a systemic multi-organ disease. Raynaud's phenomenon (RP) and digital ulcers (DUs) in SSc patients can be resistant to usual treatments. We studied the clinical benefits, capillaroscopy changes, and cost-effectiveness of local injection of botulinum toxin-A (BTX-A) and intravenous prostaglandin analogs (iloprost/alprostadil) in patients with SSc with resistant DUs. Method: In a clinical trial study, we evaluated 26 patients fulfilling the ACR/EULAR SSc criteria with resistant DUs. Visual analog scale of pain and RP, skin color and type of ulcers, and capillaroscopy were assessed before and 1 month after treatment. In the first group, 20 units of BTX-A was injected at the base of each involved fingers by a dermatologist. In the second group, 20 µg iloprost or 60 µg alprostadil was infused daily. The cost of these treatments was compared. Result: In 26 patients (43 fingers), there were 16 patients (22 fingers) in the BTX-A and 10 patients (21 fingers) in the prostaglandin group. In 95.5% of the BTX-A and 90.5% of the prostaglandin group, the ulcers were healed. In both groups, a significant decrease in pain was seen (p < 0.0001). Capillaroscopy patterns in both groups were not changed although the microhemorrhages disappeared significantly (p value: BTX-A: 0.03 and prostaglandin: 0.002). The cost was significantly lower in the BTX-A injection group (p < 0.0001). Conclusion: Both BTX-A and prostaglandins helped in the healing and pain control of DUs. In capillaroscopy, microhemorrhages were significantly decreased in both groups. In the BTX-A group, the cost was significantly lower as an outpatient treatment and was more time-saving. Key messages: • BTX-A and prostaglandin analogs both contributed to the healing of digital tip ulcers and improving the pain • In capillaroscopy, microhemorrhages were significantly decreased or disappeared after both treatments • There was no significant side effect in both groups • Comparing both groups, in the BTX-A group, the cost was significantly lower when performed on an outpatient treatment and more time-saving. [ABSTRACT FROM AUTHOR]

Materials and Methods: The aim of the present systematic review and meta-analysis was to evaluate the therapeutic efficacy of bosentan, a dual endothelin receptor antagonist, for systemic sclerosis (SSc) patients with digital ulcers (DUs). Methods: A systematic search of MEDLINE, Embase, Web of Science, and Scopus was done using appropriate keywords till September 2021. Weighted mean difference (WMD) as the effect of therapeutic efficacy of bosentan on continuous outcomes was an estimate. Furthermore, the pooled prevalence of diffuse SSc and limited SSc was computed. Fixed or random effects models when appropriate were used for data synthesis. Results: Totally, 469 patients, with a mean age ranging from 48.1 to 63.7 years, from 8 studies were included in the systematic review and meta-analysis. The pooled frequency of diffuse SSc and limited SSc was 56% (95% confidence interval [CI]: 39%, 73%) and 44% (95% CI: 27%, 61%). The pooled prevalence of new DUs following bosentan treatment was 21% (95% CI: 10%, 33%). The results of the meta-analysis showed a pooled mean decrease of WMD: −0.09 (95% CI: −0.020, 0.02, P= 0.10), WMD: −2.82 (95% CI: −5.91, 0.27, P= 0.07), and WMD: −6.65 (95% CI: −9.49, −3.82, P< 0.001) in mean SSc-Health Assessment Questionnaire, pain, and Rodnan score, respectively. Our meta-analysis also indicated a significant pooled decrease in the number of new DUs in SSc patients compared to placebo subjects (WMD: −0.89 [95% CI: −1.40, −0.37; P= 0.001]) and baseline values (WMD: −1.34 (95% CI: −1.95, −0.73; P< 0.001). Conclusion: Bosentan possibly is an efficacious treatment option for SSc-related DUs. Although further large-scale randomized clinical trials are required to confirm the preliminary finding and underlying mechanisms of action.

Objectives To assess the efficacy of an endothelin receptor antagonist (ERA) and phosphodiesterase type5 inhibitors (PDE5is) for treating SSc-related digital ulcers (DUs). Methods This prospective, multicentre, observational cohort study recruited patients with active SSc-related DUs from 13 medical centres in South Korea. The primary outcome was time to cardinal ulcer (CU) healing. A secondary outcome was time to new DU occurrence. Patients were followed up 4, 8, 12 and 24 weeks after treatment initiation. Results Sixty-three patients were analysed. Their mean age was 49.9 years (s. d. 11.4) and 49 were female. Twenty-eight had limited SSc. Forty-nine patients received ERA, 11 received a PDE5i (9 sildenafil, 1 udenafil and 1 tadalafil) and 3 received other medication. The hazard ratio (HR) for time to CU healing in the ERA group vs the PDE5i group was 0.75 (95% CI 0.35, 1.64; P  = 0.47) in an unadjusted model and 0.80 (95% CI 0.36, 1.78; P  = 0.59) in a model adjusted for age, sex, use of calcium channel blockers (CCBs), total DU number and initial CU area. The HR for new DU development in the ERA group vs the PDE5i group was 0.39 (95% CI 0.16, 0.93; P  = 0.03) in an unadjusted model and 0.32 (95% CI 0.13, 0.81; P  = 0.02) in an adjusted model. No patients receiving CCBs developed new DUs at 24 weeks. Conclusion Time to CU healing is comparable for ERA and PDE5i. ERAs are more effective in reducing new DU occurrence than PDE5is. CCBs may be effective as a background medication. [ABSTRACT FROM AUTHOR]

Following periarterial sympathectomy, patients with recurrent digital ischemia due to vasospastic or vaso-occlusive disease have few remaining treatment options. We performed a retrospective review from 1997 to 2019 to determine the safety and efficacy of revision periarterial sympathectomy. Eleven patients were identified who underwent revision periarterial sympathectomy, performed on average 84 months after their initial procedure. Preoperatively, all patients had worsening ischemic pain and five had non-healing digital ulcers. Revision digital periarterial sympathectomy alone was performed in seven patients, while four had a more extensive sympathectomy. Mean follow-up after revision was 23 months (range 3 to 76). Eight patients had symptomatic improvement and four healed their digital ulcers. Three patients developed new ulcers during follow-up, of which two healed with conservative management and one required three digital amputations. Revision periarterial sympathectomy is effective in providing symptomatic improvement and digital ulcer healing with minimal postoperative complications. Level of evidence: IV [ABSTRACT FROM AUTHOR]

Objective: Quantitative Sensory testing (QST) is a non-invasive method used in the diagnosis and classification of peripheral neuropathies. This study aimed to evaluate peripheral small and large fibers involvement by QST in patients with systemic sclerosis and to evaluate its relationship with digital ulcer formation. Methods: Patients with systemic sclerosis who applied to the rheumatology unit between April and September 2013 were included in the study. All patients were evaluated with a detailed medical history and physical examination. Imaging and laboratory results and information on organ involvements were obtained from hospital files. Patients were evaluated with QST to determine large and small fibers involvement. Results: The study was conducted with 50 (92% female) systemic sclerosis patients. The mean age was 47±12 years, the mean disease duration was 11.3±7.2 years. Sixty-six percent (n=33) of the patients had a history of digital ulcer and/or pitting scar. In QST evaluation, 84% (n=42) of patients had abnormality in vibration and/or cold detection thresholds. The number of patients with upper extremity vibration detection threshold abnormality was higher than that of the patients with lower extremity abnormality (74% vs 40%). There was no statistically significant difference between the groups with and without QST abnormalities regarding the clinical features including digital ulcer/pitting scar history (p>0.05 for all). Conclusion: In this study, significant number of patients with systemic sclerosis had QST abnormality, which is evident in the vibration detection thresholds. Longitudinal studies in early systemic sclerosis patients are needed to determine the clinical importance of QST. [ABSTRACT FROM AUTHOR]

Aim: To assess serum levels of vascular endothelial growth factor (VEGF) and its clinical correlates in patients with systemic sclerosis (SSc). Materials and methods: Forty six (46) patients with SSc aged from 19 to 77 years (median, 50 years), with duration of the disease from 0.5 to 24 years (median, 7 years) were recruited into the study. There were equal numbers of the patients with limited (LSSc) and diffuse (DSSc) types of the disease (23 patients in each group, or 50%). All patients underwent clinical examination, including measurement of the forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO) and pulmonary artery systolic pressure (PASP). Serum VEGF-A levels were determined by immunoenzyme assay in the patients and in 20 healthy controls. Results: VEGF levels in the healthy individuals were in the range from 0.2 to 264 pg/mL (median, 90.2). In SSc patients they varied from 0.02 to 1034.2 pg/mL (median, 147.2), with mean VEGF levels being over 2-fold higher than that in the control group (212.35 ± 253.93 and 97.74 ± 71.46 pg/mL, respectively; p = 0.032). DSSc patients had VEGF levels of 0.02 to 599.8 pg/mL (median, 93.6), whereas in LSSc they were from 0.02 to 1034.2 pg/mL (median, 162.4). Mean VEGF level in LSSc was higher than in DSSc (267.11 ± 268.74 vs 120.4 ± 141.09 pg/mL, respectively; p = 0.012). Current or past digital ulcers were found in 19 (41%) of all patients. Mean VEGF level in the patients with digital ulcers was higher than in those without ulcers; however, the difference was not statistically significant. PASP exceeded 30 mm Hg in 19 (43%) of the patients. VEGF levels in the patients with PASP of less than 30 mm Hg and ≥ 31 mm Hg were in the range of 0.02 to 363.6 pg/mL (median, 79.6) and 0.2–1034.2 pg/mL (median, 222.3), respectively. Mean VEGF level in the patients with high PASP was significantly higher than that in the patients with normal PASP (р = 0.0042). In the patients with DLCO ≥ 50% and

The treatment of digital ulcer (DU) in systemic sclerosis (SSc) has not been established. A 77-year-old female with a refractory DU in SSc on the right foot was transferred to our hospital. Wound healing had not been achieved despite several endovascular treatments (EVT) and minor amputations. We started Waon therapy 5 days per week as an adjunct therapy. She was placed in a far-infrared-ray dry sauna maintained at 45 °C for 15 min, and was subsequently kept to rest with soothing warmth using a blanket for additional 30 min outside the room. Gradually, the wound had become smaller and the skin perfusion pressure (SPP) had increased. The increase of the blood flow to the wound could be observed in the angiogram on day 109. An additional EVT on day 109 also accelerated wound healing. Finally, wound healing was completely achieved without additional amputations on day 173. In this presented case, Waon therapy contributed to increase of the blood flow to the wound, evidenced by SPP value. Waon therapy may serve as an effective adjunct therapy of DU in SSc. < Learning objective: Digital ulcer (DU) frequently occurs in patients with systemic sclerosis (SSc). However, the treatment of them has not been established. We experienced a case of complete wound healing of DU in SSc following Waon therapy. Waon therapy has a potential to increase the microcirculation, as evidenced by increased SPP and angiogram. Waon therapy can be considered one option of adjunct therapy for the patient with refractory DU in SSc.> [ABSTRACT FROM AUTHOR]

Introduction: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1. Method: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. Results: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. Conclusions: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone. [ABSTRACT FROM AUTHOR]

Objective. To date, "healed/non-healed" and clinical judgment are the only available assessment tools for digital ulcers (DU) in patients with systemic sclerosis (SSc). The aim of our study is to examine a preliminary composite DU clinical assessment score (DUCAS) for SSc for face, content, and construct validity. Methods. Patients with SSc presenting at least 1 finger DU were enrolled and assessed with the Health Assessment Questionnaire--Disability Index, Cochin scale, visual analog scale (VAS) for DU-related pain, patient global DU status, and global assessment as patient-reported outcomes (PRO), and physician VAS for DU status (phyGDU) as an SSc-DU expert physician/nurse measure. The DUCAS included 7 DU-related variables selected by a committee of SSc DU experts and weighted on a clinical basis. Face validity was examined by consensus and partial construct validity was tested through convergent correlation with other measures of hand function, using Spearman's correlations. A range of patients with SSc was examined. A linear regression model with backward stepwise analysis was used to determine the relationship of individual variables with the primary clinical parameter, phyGDU. Results. Forty-four patients with SSc (9 males, mean age 55 ± 15 yrs, mean disease duration 9.9 ± 5.8 yrs) were enrolled in the study. Overall DUCAS showed significant positive correlations with all abovementioned PRO (r > 0.4, p < 0.01). When all scores and scales were modeled, only DUCAS significantly predicted phyGDU (r = 0.59, R² = 0.354, Akaike information criterion = 385.4). Conclusion. Preliminarily, we suggest that the DUCAS may be a new clinical score for SSc-related DU, having face and content validity and convergent/divergent correlations (construct validity). These early data suggest that this score deserves further evaluation. [ABSTRACT FROM AUTHOR]

Nicola Ughi, Chiara Crotti, Francesca Ingegnoli Division of Rheumatology, Department of Clinical Sciences and Community Health, Gaetano Pini Institute, The University of Milan, Milan, Italy Abstract: Digital ulcers (DUs) are a severe and frequent clinical feature of patients with systemic sclerosis (SSc). The presence of DUs may cause severe pain and often lead to impairment of patient’s functional activities and health-related quality of life. Moreover, poor patient cooperation during the wound care procedure due to pain may be associated with a negative outcome of DU healing. Therefore, pain management has a key role in patients with SSc. These two case reports describe the effectiveness and safety of oxycodone/naloxone in patients with SSc complicated by painful chronic DUs. Such a therapy has provided pain relief and consequently an increased compliance during redressing wounds. Keywords: oxycodone, naloxone, systemic sclerosis, pain, digital ulcer, scleroderma, analgaesia, wound healing, opioids, calcinosis, UCLA-SCTC GIT 2.0

Introduction Digital ischemia is alike any other visceral ischemic event leading to severe tissue damage ultimately causing necrosis of the involved extremity. It's like a preview of the upcoming systemic disorder and can present itself in any specialty and hence everyone, be it a physician or a surgeon must be primed toward how to proceed with a case of digital ischemia. In this case series, we present six such cases that presented with digital ischemic events either as a sole presentation or were followed by other systemic manifestations that led to their evaluation and ultimately the etiology behind it. Material and method Patients visiting Rheumatology OPD with complaints suggestive of digital ischemia were included in this study. All patients underwent thorough history taking and clinical examination to establish the cause of digital ischemia. Patients with probable infective, trauma, cardiac, and drug-induced causes and malignancies were excluded. As per probable autoimmune causes, patients underwent evaluation via antinuclear antibodies by immunofluorescence (ANA by IF), antiphospholipid antibodies like lupus anticoagulant (LAC), anticardiolipin antibodies (AcL) and anti Beta2GP1 antibodies, extractable nuclear antigens (ENA) and in cases of suspected vasculitis doppler ultrasound and angiography.  Results Six patients were identified as cases primarily presenting with digital ischemia or with a prior history of digital ischemia. Two patients were of the pediatric age group, one 16-year-old male presenting with acute arthritis and a history of digital ischemia one year back, and the other was a 12-year-old female with blackening of the second toe in her left foot with a history of similar complaints in the left great toe for which she underwent amputation of that toe. Other four cases were of the adult age group, with two cases of scleroderma, one with systemic lupus erythematosus, and one with Takayasu arteritis. All of these patients primarily presented to departments other than rheumatology. Conclusion Digital ischemia is a pan-specialty problem with the etiologies spreading across a vast spectrum of rheumatological disorders, many of which may present to different specialties initially, later discovered to be part of the systemic manifestation of autoimmune diseases. Hence, it becomes imperative to have a rheumatological perspective in these cases of digital ischemia which all specialities should be aware of, and timely referral may prevent permanent loss of the digits and in some cases the entire limb., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Agrawal et al.)

Phosphodiesterase inhibitors (such as sildenafil) and endothelin receptor antagonist, bosentan, are effective for digital ulcer disease in systemic sclerosis (SSc-DU) and are endorsed in international treatment recommendations. Commissioning of high-cost drugs, such as bosentan, however, differs across devolved nations of the UK. We report a multicentre service evaluation project to examine 'real world' management of SSc-DU before and following the 2015 UK Scleroderma Study Group (UKSSG) guidance, across southwest (SW) England and Wales. Results showed that iloprost and sildenafil use for SSc-DU was higher in patients in Wales prior to 2015. Between 2015-2017, sildenafil use for SSc-DU increased in SW England while remaining stable in Wales. Bosentan use for SSc-DU after 2015 in SW England increased, while remaining stable and proportionately lower in Wales. These findings demonstrate that differing commissioning guidance across devolved nations of the UK seems to contribute to geographic variation in patient care. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic sclerosis (SSc) is an autoimmune chronic disease characterized by vascular impairment, immune dysfunction and collagen deposition. Raynaud's phenomenon (RP) and digital ulcers (DU) are prominent features of SSc. Intravenous (IV) iloprost (ILO), according to the recently updated EULAR recommendations, is indicated for RP after failure of oral therapy. Moreover, IV ILO could be useful in DU healing. IV ILO is currently available mainly on the European market approved for RP secondary to SSc with 3–5 days infusion cycle. Unfortunately, data published varies regarding regimen (dosage, duration and frequency). Up to now, ILO has been studied in small cohorts of patients and in few randomized controlled trials. Methods A systematic review of studies on IV ILO in patients with SSc complicated by DU and RP was performed. Insufficient data were available to perform a meta-analysis according to the GRADE system. We performed a three-stage internet-based Delphi consensus exercise. Results Three major indications were identified for IV ILO usage in SSc: RP non-responsive to oral therapy, DU healing, and DU prevention. IV ILO should be administered between 0.5 and 2.0 ng/kg/min according to patient tolerability with a frequency depending on the indication. Conclusions Although these suggestions are supported by this expert group to be used in clinical setting, it will be necessary to formally validate the present suggestions in future clinical trials. [ABSTRACT FROM AUTHOR]

Distal hallux gangrene and neuropathic ulceration associated with digit deformity frequently result in osteomyelitis of the distal phalanx. Ideal treatment would involve limited resection to preserve function. We describe our surgical technique and retrospective results for distal Syme hallux amputation with plantar flap closure. An institutional review board-approved review was conducted on cases performed over 8 years. A total of 15 consecutive patients (16 digits) with hallux soft tissue loss who had undergone distal Syme hallux amputation were included. In each case, initial resection removed the distal hallux wound, nail bed, and distal phalanx. The proximal phalanx tip was remodeled, allowing margin biopsy and reduction of prominence. Of the 16 digits, 5 (31.3%) had hammertoe deformity and 1 (6.3%) was excessively long. Positive probe-to-bone status was identified in 8 of the 16 digits (50.0%). All 8 ulcers (100.0%) that probed to bone had histologic or culture results consistent with distal phalanx osteomyelitis. A proximal margin biopsy was taken in 12 of 16 digits (75.0%), and proximal phalanx osteomyelitis was observed in 4 of 12 proximal margin biopsies (33.3%). Two digits (12.5%) failed to heal. Three digits (18.8%) required a more proximal amputation, and the remaining 13 (81.3%) were found to be well-healed and functional at the final follow-up examination. The mean follow-up period was 27.6 (range 8 to 97) months. We have found distal Syme hallux amputation to be an effective treatment when used judiciously for distal hallux gangrene and osteomyelitis associated with neuropathic ulceration. This procedure permits bone biopsy for early diagnosis, confirmation of clean margins, removal of nonviable tissue and the abnormal toenail, and some deformity correction. [ABSTRACT FROM AUTHOR]