Ischemic Digital Ulcers Research Articles

Iguratimod as an alternative therapy for systemic sclerosis and prevention of the occurrence of ischemic digital ulcer.

This 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). We 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. From 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). Our 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.

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review

Systemic sclerosis (SSc, scleroderma) is a multifaceted rare connective tissue disease whose pathogenesis is dominated by immune dysregulation, small vessel vasculopathy, impaired angiogenesis, and both cutaneous and visceral fibrosis. Microvascular impairment represents the initial event of the disease, preceding fibrosis by months or years and accounting for the main disabling and/or life-threatening clinical manifestations, including telangiectasias, pitting scars, periungual microvascular abnormalities (e.g., giant capillaries, hemorrhages, avascular areas, ramified/bushy capillaries) clinically detectable by nailfold videocapillaroscopy, ischemic digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. Despite a variety of available treatment options, treatment of SSc-related vascular disease remains problematic, even considering SSc etherogenity and the quite narrow therapeutic window. In this context, plenty of studies have highlighted the great usefulness in clinical practice of vascular biomarkers allowing clinicians to assess the evolution of the pathological process affecting the vessels, as well as to predict the prognosis and the response to therapy. The current narrative review provides an up-to-date overview of the main candidate vascular biomarkers that have been proposed for SSc, focusing on their main reported associations with characteristic clinical vascular features of the disease.

Increased Circulating Soluble Junctional Adhesion Molecules in Systemic Sclerosis: Association with Peripheral Microvascular Impairment

Systemic sclerosis (SSc, scleroderma) is a severe disease characterized by peripheral microcirculation abnormalities manifesting with Raynaud's phenomenon, nailfold videocapillaroscopic (NVC) changes, and even ischemic digital ulcers (DUs) that are often refractory to treatments. In the wake of previously described associations between the circulating levels of soluble junctional adhesion molecules (sJAMs) and SSc clinical features, here, we measured sJAM-A and sJAM-C levels by enzyme-linked immunosorbent assay in serum samples from a large case series of 110 SSc patients and 85 healthy controls, focusing on their possible association with peripheral vascular clinical features and their potential as biomarkers that are either diagnostic or mirror SSc-related microvasculopathy severity. Our data demonstrated that serum sJAM-A and sJAM-C are significantly increased in patients with SSc vs. healthy controls, especially in those featuring early/active NVC patterns and the presence of ischemic DUs. Moreover, circulating sJAM-C levels showed good diagnostic accuracy in discriminating between patients and controls, as assessed by receiver operator characteristics curve analysis. Finally, logistic regression revealed that, when comparing sJAM-A to sJAM-C, the latter might be better suited as a biomarker for SSc-related DUs. Our promising findings provide the necessary groundwork for longitudinal follow-up analyses of SSc patients aiming to assess whether circulating sJAM-C levels might be predictive for the development of new DUs, as well as DU recurrence and/or refractoriness to targeted therapies.

Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis.

Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease whose earliest clinical manifestations are microvascular tone dysregulation and peripheral microcirculatory abnormalities. Following previous evidence of an association between circulating neurovascular guidance molecules and SSc disturbed angiogenesis, here, we measured the levels of soluble neuropilin 1 (sNRP1), semaphorin 3E (Sema3E), and Slit2 by enzyme-linked immunosorbent assay in serum samples from a large case series of 166 SSc patients vs. 110 healthy controls. We focused on their possible correlation with vascular disease clinical features and applied logistic regression analysis to determine which of them could better reflect disease activity and severity. Our results demonstrate that, in SSc: (i) sNRP1 is significantly decreased, with lower sNRP1 serum levels correlating with the severity of nailfold videocapillaroscopy (NVC) abnormalities and the presence of ischemic digital ulcers (DUs); (ii) both Sema3E and Slit2 are increased, with Sema3E better reflecting early NVC abnormalities; and (iii) higher Sema3E correlates with the absence of DUs, while augmented Slit2 associates with the presence of DUs. Receiver operator characteristics curve analysis revealed that both circulating sNRP1 and Sema3E show a moderate diagnostic accuracy. Moreover, logistic regression analysis allowed to identify sNRP1 and Sema3E as more suitable independent biomarkers reflecting the activity and severity of SSc-related peripheral microvasculopathy.

Rehabilitative interventions for ischaemic digital ulcers, pain, and hand functioning in systemic sclerosis: a prospective before-after study

BackgroundSystemic sclerosis (SSc) is a rare connective tissue disease characterised by immune dysfunction, vasculopathy, cellular inflammation, fibrosis of the skin associated with multiple internal organs involvement. Ischaemic digital ulcers (IDU) of the hands commonly occur in patients with SSc adversely affecting functional independence.PurposeAim of the study is to investigate the effectiveness of a rehabilitation protocol based on the combined use of ultrasound (US) therapy and therapeutic exercise in terms of ulcers healing, pain relief, and hand functioning in patients affected by SSc with IDUs. Moreover, we also investigated the safety of the proposed intervention.Study designProspective before-after study.MethodsWe included 20 patients with IDUs secondary to SSc. All patients were treated with US combined with manual therapy, including McMennel joint manipulation, pompage mobilization technique and connective tissue massage, for 10 sessions. We evaluated softness, dyschromia, pain, and hand mobility using the Pressure Sore Status Tool (PSST), the Numerical Rating Scale (NRS), and the Duruoz Hand Index (DHI) at T0 and at the end of the treatment (T1).ResultsTreatment with US combined with manual therapy significantly reduced ulcers depth, improved ulcers margins, and reduced periwound skin damage (median PSST score 16 at T1, p<0.0001). Moreover, significant benefits were reported in terms of pain relief (NRS 3 at T1; p<0.0005), and hand function (DHI score 19 at T1; p<0.0005). Finally, this approach seems to be safe, without side effects reported at the end of treatment, along with an optimal compliance.ConclusionTherapeutic US combined with manual therapy should be used as additional intervention to manage IDUs in SSc patients.

High NEMO score values in nailfold videocapillaroscopy are associated with the subsequent development of ischaemic digital ulcers in patients with systemic sclerosis

BackgroundNailfold videocapillaroscopy (NVC) is a feasible method that allows the observation of the microvascular changes that mark the course of systemic sclerosis (SSc). In previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages and microthromboses, is a good indicator of the steady-state level and overtime changes of disease activity (DA) in SSc.ObjectivesTo verify whether high NEMO scores, which mirror a very active microvascular derangement in the fingers, may be associated with the subsequent development of ischaemic digital ulcers (IDUs).MethodsThe NEMO score was assessed at baseline (T0) in 98 patients with SSc, all classified according to the ACR-EULAR criteria. Of them, 90 were females, 48 had the limited and 50 had the diffuse cutaneous variant of SSc. Afterwards, the patients were closely followed up for 2 years, and the appearance of new IDUs recorded at any time of the follow-up. The T0-NEMO score values of patients who developed IDUs were compared to those of patients who did not. A receiver operating curve (ROC) was constructed, and the area under the curve (AUC) calculated by plotting the sensitivity and 1-specificity of the different NEMO score values in predicting the subsequent development of IDUs.ResultsDuring the follow-up, 38 out of 98 patients developed one or more IDUs. The NEMO score at T0 was significantly higher in those who developed IDUs with respect to those who did not [median 14.5 (95% CI 11.0–21.5) and 4.5 (95% CI 4.0–6.0), respectively, p < 0.0001]. The ROC curve derived from different T0-NEMO score values had an AUC of 0.79 (95% CI 0.69–0.86, p < 0.0001). A NEMO score of ≥ 12 had a sensitivity of 83.3% (95% CI 71.5–91.7) and a specificity of 63.2% (95% CI 46.0–78.2), with positive (P) and negative (N) predictive (PV) values of 58.9% (95% CI 44.7–72.2) and 85.6% (71.8–94.4), respectively. A NEMO score of ≥ 16 had a sensitivity of 95.0% (95% CI 86.1–99.0) and a NPV of 93.4% (77.5–99.2).ConclusionsBeing a valid tool to measure DA levels in SSc, the NEMO score also appears to be closely related to the subsequent development of IDUs in this disease.

Serum level of endostatin and digital ulcers in systemic sclerosis patients.

Patients with systemic sclerosis (SSc) are at a high risk of the development of ischaemic digital ulcers (DUs) that can be complicated with infections, gangrene, and osteomyelitis. The aim of this study is to evaluate the role of endostatin in scleroderma DUs.In total, 90 SSc patients were enrolled in this study. Serum endostatin levels and DU assessment were determined in all SSc patients. The serum levels of endostatin significantly increased with progression of capillaroscopic damage (P < .01). The serum levels of endostatin are significantly (P < .05) higher in SSc patients with new DUs than in SSc patients without new DUs (127 ± 31.1 ng/mL vs 116.3 ± 39.7 ng/mL). The Receiver Operating Characteristic (ROC) curves demonstrated good accuracy of new DU prediction for the serum level of endostatin (0.70, P < .01 [95% confidence interval (CI) 0.59-0.81]). Using a cut-off value of 116 ng/mL, the odds ratio was 2.609 (CI 1.075-6.330, P < .05). The serum levels of endostatin are significantly (P < .01) higher in SSc patients with infected DUs than in SSc patients without infected DUs (139.2 [114.6-340.91] ng/mL vs 117.5 [64.3-163.9] ng/mL). Serum levels of endostatin are higher in patients with DUs, especially in those with infected DUs.

Endothelial dysfunction, microvascular damage and ischemic peripheral vasculopathy in systemic sclerosis.

To evaluate endothelial dysfunction and microvascular damage in secondary Raynaud Phenomenon (SRP) and Systemic sclerosis (SSc)-associated patients as possible predictors of ischemic fingertip digital ulcers (DU) in a 3-year clinical follow-up. Flow-mediated dilatation (FMD), nailfold videocapillaroscopy (NVC), endothelin-1 (ET-1) and asymmetric dimethylarginine (ADMA) were analysed in a 3-year observational cohort study of 77 SRP patients with systemic sclerosis. The primary outcome was the occurrence of a new DU. Risk factors for DU at baseline were low FMD% (p < 0.001), NVC pattern (p < 0.001), high microangiopathy evolution score (MES) (p < 0.001), increased ET-1 (p < 0.001) and increased ADMA serum levels (p = 0.001). Median time to the occurrence of a new DU was 4.50 (1.25-16.25) months. The risk factors for the occurrence of at least one new DU episode in follow-up included a history of at least one DU before enrolment (p < 0.001), autoantibody anti-scleroderma-70 (p = 0.012), NVC late pattern (p < 0.001), high MES score (p < 0.001), low FMD% (p < 0.001) and increased ET-1 serum levels (p < 0.001).We used univariate Cox regression analysis to show that FMD >9.41% (HR: 0.37 95% CI: 0.14-0.99) and ET-1 >11.85 pmol/L (HR: 3.81 95% CI: 1.41-10.26) and NVC (HR: 2.29 95% CI: 0.97-5.38) were predictors of DU recurrence. In terms of first DU event in naïve DU patients at baseline, late NVC pattern (HR: 12.66 95% CI: 2.06-77.89) and MES score (HR: 1.693 95% CI: 1.257-2.279) were independent predictors. This study identified endothelium dysfunction biomarkers (FMD and ET-1) and severe microvascular damage in NVC as strong predictors of new DU in SSc patients.

Risk of Digital Vascular Events in Scleroderma Patients Who Have Both Anticentromere and Anti-Interferon-Inducible Protein 16 Antibodies.

To evaluate whether scleroderma patients who are double-positive for anti-interferon-inducible protein 16 (anti-IFI-16) antibodies and anticentromere (anti-CENP) antibodies are at increased risk for significant digital vascular events relative to patients positive for anti-CENP antibodies alone. Sera from 165 scleroderma patients who tested positive for anti-CENP antibodies upon clinical evaluation were reassayed for both anti-CENP and anti-IFI-16 antibodies using enzyme-linked immunosorbent assay testing. Patients who were positive for anti-CENP antibodies alone were then compared to patients who were double-positive for both anti-IFI-16 and anti-CENP antibodies. The association between a history of significant digital vascular events (digital pits, ischemic digital ulcers, and/or gangrene) and double-positive antibody status was examined using chi-square tests. After completion of univariate analysis, multivariable analyses were done to adjust for clinically relevant covariates. Of the 165 anti-CENP antibody positive patients, 21 (12.7%) also had anti-IFI-16 antibodies. Patients who were double-positive for anti-CENP and anti-IFI-16 antibodies were more likely to have had digital pits, ischemic digital ulcers, and/or gangrene (P = 0.03). After adjustment for clinically relevant covariates (age, cutaneous subtype, disease duration, and smoking), double-positive patients remained at significantly higher odds of having severe Raynaud's phenomenon (odds ratio 3.5 [95% confidence interval 1.1-11.1]; P = 0.03). Scleroderma patients who are double-positive for antibodies recognizing CENP and IFI-16 are significantly more likely to have significant digital vascular events during the course of their disease. This study provides further evidence that anti-CENP and anti-IFI-16 antibodies are disease biomarkers that may be used for risk stratification of vascular events in scleroderma.

Vascular Evaluation of the Hand by Power Doppler Ultrasonography and New Predictive Markers of Ischemic Digital Ulcers in Systemic Sclerosis: Results of a Prospective Pilot Study.

To evaluate the relevance of power Doppler ultrasonography (PDUS) as a predictive tool of 1-year digital ulcer (DU) occurrence in systemic sclerosis (SSc). A total of 55 SSc patients and 19 controls underwent PDUS of both hands to evaluate the prevalence of ulnar artery occlusion (UAO) at baseline. Finger pulp blood flow (FPBF) of the third and fourth fingers was also assessed and considered as pathologic if a defect of the Doppler signal on a finger pulp was observed. All patients were clinically re-evaluated 6 and 12 months later and new ischemic DU occurrences in the meantime were retrospectively recorded. Patients were also asked to call if new DUs occurred between consultations. PDUS parameters were normal in all controls. The prevalence of UAO was 36.4% and was bilateral in 70% of the SSc cases. A total of 56.4% of SSc patients had a pathologic FPBF. UAO and pathologic FPBF were associated with a history of multiple DU episodes (odds ratio [OR] 8.98 [95% confidence interval (95% CI) 2.52-32.01], P < 0.001, and OR 4.69 [95% CI 1.30-16.93], P = 0.014, respectively) and the occurrence of new DUs during the followup in the univariable model (OR 8.73 [95% CI 2.00-38.16], P = 0.005, and OR 12.65 [95% CI 1.50-106.77], P = 0.005, respectively). The association of UAO and pathologic FPBF in the same patient was a predictive factor of new DUs in the multivariable analysis (P = 0.015). This study suggests that UAO and pathologic FPBF are associated with a history of multiple DUs and are predictors of new ischemic DUs. These parameters could be used as prognostic factors and considered in further studies evaluating DU treatment strategies.

Controlling the digital ulcerative disease in systemic sclerosis is associated with improved hand function

Ischemic digital ulcers (DU) represent a major complication of systemic sclerosis (SSc). We investigated the impact of controlling the ulcerative disease on disability, pain, and quality of life in SSc patients receiving bosentan. ECLIPSE (Study AC-052-517) is a 2-year prospective, multicenter, and observational study. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan were included between October 2009 and March 2011. Disability scores [Cochin Hand Function Scale (CHFS) and Health Assessment Questionnaire Disability Index (HAQ-DI)], pain scores (visual analog scale), and quality-of-life scores (SF-36) were collected at inclusion and 1 year later (primary endpoint). A controlled ulcerative disease was defined by the absence of ongoing/new DU episode between inclusion and 1-year follow-up. Data were available at 1 year for 120 patients out of 190 included. During follow-up, 46 (38.3%) patients experienced a new DU episode. The number of DU per patient decreased from 1.4 ± 1.8 at inclusion to 0.6 ± 1.6 (p < 0.0001) at 1 year. Disability scores decreased from 1.0 ± 0.7 to 0.9 ± 0.7 (p = 0.04) for the HAQ-DI and from 29 ± 20 to 25 ± 20 (p = 0.005) for the CHFS; the pain score decreased from 4.3 ± 3.1 to 2.9 ± 2.8 (p < 0.0001). This improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improved HAQ-DI (p = 0.04), CHFS (p = 0.04), and pain score (p = 0.046). In patients with SSc, control of the ulcerative disease for 1 year was associated with significant attenuation of hand disability.

Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate

ObjectivesIn patients with systemic sclerosis (SSc), fingertip digital ulcers (DUs) are believed to be ischaemic, and extensor surface DUs a result of mechanical factors/microtrauma. Our aim was to assess blood flow response to topical glyceryl trinitrate (GTN) compared to placebo in SSc DUs, looking for differences in pathophysiology between fingertip and extensor lesions. MethodThis was a double-blind, randomised, crossover, placebo-controlled study. Sixteen (6 fingertip, 10 extensor) DUs were each studied twice (one day apart): once with GTN and once with placebo ointment. Perfusion at the DU centre (‘DUCore’) and periphery (‘DUPeriphery’), as measured by laser Doppler imaging was performed before and immediately after ointment application, then every 10min, up to 90min post-application. We calculated the area under the response curve (AUC) and the ratio of peak perfusion to baseline, then compared these between GTN and placebo. ResultsPerfusion was lower in the DUCore compared to the DUPeriphery (ratio of 0.52). The microvessels of the DUCore were responsive to GTN, with an increase in perfusion, with a similar effect in both fingertip and extensor DUs. The AUC and peak/baseline perfusion difference in means (ratio, 95% confidence interval) between GTN and placebo at the DUCore were 1.2 (1.0–1.6) and 1.2 (1.0–1.5) respectively, and at the DUPeriphery were 1.1 (0.8–1.6) and 1.0 (0.9–1.2) respectively. ConclusionDUs (both fingertip and extensor) were responsive to topical GTN, with an increase in perfusion to the ischaemic DU centre. If both fingertip and extensor DUs have a (potentially reversible) ischaemic aetiology, this has important treatment implications.

In systemic sclerosis skin perfusion of hands is reduced and may predict the occurrence of new digital ulcers

Systemic sclerosis (SSc) patients are at high risk for the development of ischemic digital ulcers (DUs). The aim of this study was to assess in SSc patients a correlation between skin perfusion evaluated by LDPI and DUs and to evaluate the prognostic value of skin perfusion to predict the new DUs occurrence.Fifty eight (47 female, 11 male) SSc patients were enrolled. Skin perfusion of hands and region of interest (ROIs) was measured by Laser Doppler perfusion Imager (LDPI). The proximal-distal gradient (PDG) was present when the perfusion mean difference between ROI1 and ROI2 was >30 pU.The skin perfusion of hands is lower in SSc patients than in healthy controls. The skin perfusion decreased with severity of capillaroscopic damage. Both mean perfusion of hand and PDG are significantly (p<0.01 and p<0.0001, respectively) lower in SSc patients with new DUs than in SSc patients without DUs. Only 2 of 11 SSc patients (18.2%) with PDG developed new digital ulcers, conversely 36 of 47 (76.6%) SSc patients without PDG developed new digital ulcers (p<0.001). The ROC curves demonstrated a good accuracy of new DUs prediction for PDG (0.78, p<0.0001). Using this cut-off value of 30 pU, RR for new DUs development in SSc patients without PDG is 4,2 (p<0.001).LDPI indices could be used in association to the capillaroscopic and clinical findings or serological tests in the identification of patients at high risk of developing DUs.

Autoantibodies against Endothelin 1 Type A Receptor Are Strong Predictors of Digital Ulcers in Systemic Sclerosis

To determine the predictive value of functional autoantibodies against vascular receptors for the development of ischemic digital ulcers (DU) in patients with systemic sclerosis (SSc). Angiotensin II Type 1 receptor (AT1R) and endothelin 1 Type A receptor (ETAR) autoantibodies were measured at baseline in a prospective cohort of 90 patients with SSc together with 5 validated angiogenic markers. The primary outcome was the occurrence of at least 1 new ischemic DU during the 5-year followup. Twenty-four patients developed at least 1 new DU during the followup period. Univariate Cox analysis revealed that concentrations above the median value of anti-AT1R and anti-ETAR antibodies were predictive of the occurrence of ischemic DU (HR 2.85, 95% CI 1.19-6.84 and HR 3.39, 95% CI 1.35-8.50, respectively). A first multivariate Cox analysis including functional autoantibodies and clinical predictors of new DU confirmed anti-ETAR autoantibodies as independent predictors of the occurrence of new ischemic DU (HR 3.15, 95% CI 1.22-8.13) together with a history of DU at baseline. In a second model implemented with angiogenic markers, anti-ETAR autoantibodies remained an independent predictor of the occurrence of new ischemic DU (HR 9.59, 95% CI 1.75-52.64) together with the presence at baseline of active DU or history of DU. Anti-ETAR autoantibodies can be used together with the presence of current or past DU to identify patients with SSc who are at risk for the development of subsequent DU. These autoantibodies may allow for earlier management and therapeutic intervention.

Adherence to recommendations for cervical and breast cancer screening in systemic sclerosis

The aim of the study was to evaluate the adherence of systemic sclerosis (SSc) female patients to cervix and breast cancer screening procedures, as suggested by local guidelines. A cohort of 84 SSc women was asked if they had undergone mammography and Pap test during the previous 2- and 3-year intervals, as indicated according to the Italian recommendations. The results were compared with those collected in patients affected by other chronic rheumatic disorders and in the general population. More than 85% of SSc women declared to comply with an age-related cervix and breast cancer screening schedule. The data were similar to those collected in patients affected by other chronic rheumatic disorders, whereas the subjects belonging to the general population reported to undergo breast cancer screening more frequently. Among SSc women, neither the educational level, nor the lung and skin involvement influenced their cancer screening program compliance. Only a positive history of ischemic digital ulcers seemed to interfere with mammography. Our study reported a very high percentage of SSc female patients who adhered to programs for the early detection of cervical and breast cancer. The significant adherence to guidelines may be due to the schedule adopted by the local health public service, which regularly invites eligible subjects by mail to undergo cancer screening at no charge.

Is iloprost effective in secondary Raynaud's phenomenon?

Patients with systemic sclerosis frequently have Raynaud's phenomenon and digital ischemic ulcers. Iloprost, a synthetic prostacyclin analogue, may be effective in these cases. Searching in Epistemonikos database, which is maintained by screening 20 databases, we identified three systematic reviews including seven randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded iloprost may lead to little or no difference in the frequency or severity of secondary Raynaud, and it is associated to adverse effects and important costs.

Macitentan: An important addition to the treatment of pulmonary arterial hypertension.

Macitentan is an orphan drug for the treatment of pulmonary arterial hypertension (PAH). Endothelin-1 (ET-1) plays a critical role of pathophysiology of PAH. Macitentan, a new dual endothelin receptor antagonist, has reportedly improved prognosis of PAH patients by delaying the progression of disease. It prevents the binding of ET-1 to both endothelin A (ETA) and endothelin B (ETB) receptors. Macitentan displays higher efficacy, lesser adverse effects and drug interactions. It has completed phase III trials in 2012 for treatment of PAH and has been tried for ischemic digital ulcers in systemic sclerosis, recurrent glioblastoma and combination with chemotherapeutic agents against various cancers. Safety data for macitentan were obtained primarily from a placebo-controlled clinical study in 742 patients with PAH. The Food and Drug Administration (FDA) approved the drug on 13 October 2013. It is an important addition to long-term treatment of PAH.

Increased Intrarenal Arterial Stiffness May Predict the Occurrence of New Digital Ulcers in Systemic Sclerosis

Patients with systemic sclerosis (SSc; scleroderma) are at high risk for the development of ischemic digital ulcers (DUs), which occur in 35-60% of SSc patients. The aim of this study was to assess the correlation between intrarenal arterial stiffness and DUs in SSc patients and to evaluate the prognostic value of Doppler indices to predict new DU occurrence. Seventy unselected, consecutive patients with SSc (58 women and 12 men, mean ± SD age 49.5 ± 13.8 years) were enrolled. In all patients, Doppler ultrasound examination was performed. The following Doppler indices of intrarenal stiffness were measured: peak systolic velocity (PSV), end diastolic velocity (EDV), resistive index (RI), pulsatile index (PI), and systolic/diastolic ratio (S/D). In total, 30 (42%) of 70 patients experienced new DUs. RI, S/D, and PI were significantly higher in SSc patients with new DUs than in SSc patients without new DUs. The receiver operating characteristic (ROC) curves demonstrated a good accuracy of new DU prediction for RI (0.94, P < 0.0001), S/D (0.92, P < 0.0001), and PI (0.88, P < 0.0001). Conversely, the ROC curve showed no performance for PSV (0.58, P > 0.05) and EDV (0.28, P > 0.05). Using a cutoff value of 0.70 for RI and 3.25 for S/D, the positive predictive value was 90.6% and 92.9%, respectively. We can conclude that Doppler indices of intrarenal stiffness are reliable markers of new DU occurrence. Doppler indices could be used in association with the capillaroscopic and clinical findings or serologic tests for the identification of patients at high risk of developing DUs.

Ischemic digital ulcers affect hand disability and pain in systemic sclerosis.

Ischemic digital ulcers (DU) are frequent and severe complications of systemic sclerosis (SSc). The purpose of our study was to assess the effect of DU on hand disability and pain in patients with SSc. The Evaluation of the Impact of Recurrent Ischemic DU on Hand Disability in Patients with SSc (ECLIPSE) is a prospective, multicenter, noninterventional study with a 2-year followup. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan therapy were included between October 2009 and March 2011. This cohort is described at the time of inclusion. There were 190 patients (132 females) from 53 centers. Mean age ± SD was 43 ± 15 years at SSc diagnosis and 53 ± 15 years at inclusion. In 105 patients (56.2%), DU were the first non-Raynaud symptoms of SSc. The mean time interval between the occurrence of Raynaud phenomenon and the first DU episode was 6.6 ± 9.1 years. The mean numbers of active DU and fingers affected per patient for both hands were 2.3 ± 1.8 and 2.2 ± 1.6, respectively. Presence of active DU at inclusion was significantly associated with pain and impaired hand function: Visual Analog Scale for pain (0 to 10) was 6.2 ± 2.6 versus 2.5 ± 2.4 (p < 0.0001) and Cochin Hand Function Scale for hand disability (0 to 90) was 38 ± 20 versus 25 ± 19 (p < 0.0001), respectively. DU represent a major sign of SSc, often affecting multiple fingers and both hands. They are significantly associated with pain and hand disability.

FRI0507 Dual Energy Computed Tomography for the Evaluation of Calcinosis in Systemic Sclerosis

BackgroundCalcinosis, the deposition of calcified material in the skin and subcutaneous soft tissues, is frequently seen in up to 40% patients with SSc (1, 2). Calcium hydroxyapatite (3) is the...