P. Carpentier

Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: systematic review and meta-analysis of randomised trials

Introduction Recent controlled trials have assessed the efficacy of phospodiesterase-5 (PDE-5) inhibitors in secondary Raynauds phenomenon (RP). However, the conclusions are conflicting, and whether these drugs are effective remains unclear. The objective of this meta-analysis was to determine the efficacy of PDE-5 inhibitors on Raynauds Condition Score (RCS) and frequency and duration of attacks. Methods A systematic review of articles was performed (sources included Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials). Only double-blind, randomised controlled trials (RCTs) were included. Studies were selected independently by two authors using predefined data fields, including study quality indicators. Results Six RCTs were included (one with sildenafil, one with modified-release sildenafil, three with tadalafil and one with vardenafil). PDE-5 inhibitors significantly decreased mean RCS by −0.46 (−0.74 to −0.17) (p=0.002), the daily frequency of ischaemic attacks by −0.49 (−0.71 to −0.28) (p<0.0001), and daily duration of RP attacks by −14.62 (−20.25 to −9.00) min (p<0.0001). Conclusions PDE-5 inhibitors appear to have significant but moderate efficacy in secondary RP. A further large RCT is needed.

Local hyperhemia to heating is impaired in secondary Raynaud's phenomenon

Accurate and sensitive measurement techniques are a key issue in the quantification of the microvascular and endothelial dysfunction in systemic sclerosis (SSc). Thermal hyperhemia comprises two separate mechanisms: an initial peak that is axon reflex mediated; and a sustained plateau phase that is nitric oxide dependent. The main objective of our study was to test whether thermal hyperhemia in patients with SSc differed from that in patients with primary Raynauds phenomenon (RP) and healthy controls. In a first study, we enrolled 20 patients suffering from SSc, 20 patients with primary RP and 20 healthy volunteers. All subjects were in a fasting state. Post-occlusive hyperhemia, 0.4 mg sublingual nitroglycerin challenge and thermal hyperhemia were performed using laser Doppler flowmetry on the distal pad of the third left finger. In a second study, thermal hyperhemia was performed in 10 patients with rheumatoid arthritis and 10 patients with primary RP. The thermal hyperhemia was dramatically altered in terms of amplitude and kinetics in patients with SSc. Whereas 19 healthy volunteers and 18 patients with primary RP exhibited the classic response, including an initial peak within the first 10 minutes followed by a nadir and a second peak, this occurred only in four of the SSc patients (p < 0.0001). The 10 minutes thermal peak was 43.4 (23.2 to 63), 42.6 (31 to 80.7) and 27 (14.7 to 51.4) mV/mm Hg in the healthy volunteers, primary RP and SSc groups, respectively (p = 0.01), while the 44°C thermal peak was 43.1 (21.3 to 62.1), 42.6 (31.6 to 74.3) and 25.4 (15 to 52.4) mV/mm Hg, respectively (p = 0.01). Thermal hyperhemia was more sensitive and specific than post-occlusive hyperhemia for differentiating SSc from primary RP. In patients with rheumatoid arthritis, thermal hyperhemia was also altered in terms of amplitude. Thermal hyperhemia is dramatically altered in patients with secondary RP in comparison with subjects with primary RP. Further studies are required to determine the mechanisms of this altered response, and whether it may provide additional information in a clinical setting.

Echographic and Doppler screening of the forearm arteries in professional volleyball players

We evaluated nine professional volleyball players by clinical, echographic, and Doppler technique examina tion of the forearm and digital arteries to determine vascular damage caused by repeated trauma. The re sults of these tests showed that one-third of the sub jects had vascular lesions in the right hand; only one of these was symptomatic. This suggests that noninva sive screening should be recommended and included in the regular medical check-ups of professional ath letes in whom repeated trauma to the hand is likely, such as volleyball players.

Cutaneous Iontophoresis of Treprostinil in Systemic Sclerosis: A Proof‐of‐Concept Study

Ischemic digital ulcer (DU) is a serious complication of systemic sclerosis (SSc). Intravenous prostanoids are the only approved treatment for active DUs, but they induce dose‐limiting side effects and require hospitalization. Our objective was to evaluate the effect of iontophoresis (a noninvasive drug delivery method) of treprostinil in SSc patients. Three studies were conducted: a pharmacokinetic study in 12 healthy volunteers showed that peak dermal concentration was reached at 2 hours, whereas plasma treprostinil was undetected. Then, a placebo‐controlled, double‐blind incremental dose study assessed the effect of treprostinil on digital skin blood flow in 22 healthy subjects. The effect of the highest dose was then compared with that of placebo in 12 SSc patients. Treprostinil significantly increased skin blood flow in healthy subjects (P = 0.006) and in SSc patients (P = 0.023). In conclusion, digital iontophoresis of treprostinil is feasible, is well tolerated, and increases digital skin perfusion. It could be tested as a treatment for SSc‐related DUs.

Use of bosentan for digital ulcers related to systemic sclerosis: a real-life retrospective French study of 89 patients treated since specific approval

Objectives: Ischaemic digital ulcers (DUs) are a common complication of systemic sclerosis (SSc). This study aimed to characterize patients with SSc and ongoing DUs treated with the endothelin receptor antagonist bosentan in clinical practice in France. Method: An observational, retrospective, longitudinal study was conducted in 10 French expert centres. Medical records from randomly selected adult SSc patients who received treatment with bosentan for DU prevention from March 2007 to December 2010 were analysed. The primary objective was to determine the profile of patients at treatment initiation. Secondary objectives were to monitor bosentan dosing, treatment schedule, and reasons for treatment termination. Results: The study included 89 patients (mean age 52 years, 69% female, 44% diffuse cutaneous SSc). At bosentan treatment initiation, the mean duration of Raynaud’s phenomenon was 15 ± 12 years, and the mean time since first episode with DU was 6.5 ± 7 years. Most patients had a history of at least two episodes with DUs, separated by < 12 months (61%), and had received intravenous iloprost (63%). Previous DU complications included auto-amputation (8%), surgical amputation (6%), osteitis (6%), and gangrene (4.5%). Active smokers (25%) had a history of significantly more surgical amputation (p = 0.004) and osteitis (p = 0.004) than non-smokers. At least one active DU at bosentan initiation was detected in 82% of patients. Bosentan was used according to prescription guidelines and was well tolerated; six patients (7%) withdrew from treatment because of raised liver enzymes. Conclusions: Patients treated with bosentan for DU prevention in France have severe, refractory, ongoing ulcerative disease. Active smoking was correlated to a history of DU complications. Tolerance of bosentan was comparable to previous studies.

The digital thermal hyperemia pattern is associated with the onset of digital ulcerations in systemic sclerosis during 3 years of follow-up

OBJECTIVES One of the most important skin complications in systemic sclerosis (SSc) is digital ulceration. Local thermal hyperemia (LTH) in the skin is a biphasic response to local heating involving both neurovascular and endothelial responses. Since LTH is abnormal in SSc patients, we aimed at testing whether LTH could be a prognostic tool for the onset of digital ulcers. METHODS We prospectively enrolled 51 patients with SSc. Nailfold capillaroscopy and LTH were recorded at baseline, and patients were followed for 3 years. RESULTS No patient with a LTH peak/plateau ratio ≥1 (n=19) developed digital ulcerations during the 3 year follow-up (100% negative predictive value), while 6 out of 32 patients with a LTH peak/plateau ratio <1 at enrolment presented with finger pad ulcerations within 3 years (p=0.05). In contrast, when lidocaine/prilocaine was applied to the finger pad, no relationship between thermal hyperemia and digital ulcerations was observed. CONCLUSIONS A LTH peak/plateau ratio on the finger pad greater than 1, which can easily be determined in routine clinical practice, could be used to reassure patients, whatever the subtype of SSc, about the low probability of future digital ulceration. However, the prognostic value of this parameter should be confirmed in a larger cohort.

Abnormal amplitude and kinetics of digital postocclusive reactive hyperemia in systemic sclerosis

OBJECTIVES Postocclusive reactive hyperemia is mediated by two major mediators: sensory nerves and endothelium-derived hyperpolarizing factors. We hypothesized that the skin microvascular response to 5 min ischemia would differ depending upon the hand location in patients with systemic sclerosis (SSc), primary Raynauds phenomenon (PRP) and healthy controls. METHODS Fifteen patients with SSc, 15 sex- and age-matched patients with PRP and healthy controls were enrolled. Their right hands were subjected to 5 min ischemia followed by a postocclusive hyperemia test, with local microcirculation monitoring by laser speckle contrast imaging on the dorsal face of the hand. RESULTS Postocclusive reactive hyperemia was abnormal in terms of peak and area under the curve (AUC) on all fingers except the thumb in patients with SSc and PRP compared with controls. In contrast, the kinetics of the response was longer only in SSc patients, with mean (SD) time to peak on the index, middle and ring finger were respectively 72 (58), 73 (51) and 67 (47) s for SSc; 40 (20), 40 (20) and 36 (19) s for PRP; and 34 (30), 34 (30) and 29 (24) s for controls (P=0.009 for interaction). CONCLUSIONS We observed decreased distal digital microvascular perfusion following 5 min of ischemia in patients presenting with PRP or SSc, while the kinetics was prolonged only in SSc. A dynamic assessment of digital skin blood flow using laser speckle contrast imaging following 5 min ischemia could be used as a tool to assess microvascular abnormalities in patients with Raynauds phenomenon secondary to SSc.

Is contrast enhanced ultrasonography a useful tool for the evaluation of muscular microcirculation in patients with critical limb ischaemia

BACKGROUND Evaluation of skin microcirculation in patients with critical limb ischemia (CLI) may be achieved by the measurement of transcutaneous oxygen pressure or skin perfusion pressure, but there is no practical method available for the evaluation of muscle microcirculation. Contrast enhanced ultrasonography (CEUS) has been used to assess muscle perfusion in patients with peripheral arterial disease. We conducted a monocentric pilot study evaluating the ability of CEUS to assess the impact of arterial revascularization on the perfusion of the calf muscle in patients with CLI. PATIENTS AND METHODS Patients with CLI (TASC II criteria) and a possibility of proximal or medial revascularization were included. In addition to TcPO2 and toe systolic blood pressure measurements, CEUS of the calf muscle was performed just before and one month after the therapeutic procedure. Parameters derived from muscular perfusion curves were evaluated in a blinded fashion and compared with the clinical outcome. RESULTS Thirty eight patients were included (74 % men, median age 71 years, 53 % diabetics). Thirty benefited from revascularization with a clinical success rate of 70 %. Twenty three patients could benefit from analysis before and after revascularization. No significant difference was shown in time to peak (22.3 s vs 24.0 s, P = 0.61) nor in peak intensity (2.30 dB vs 1.27 db, P = 0,26), contrasting with significant improvements of TcPO2 (43 mm Hg vs 20 mm Hg, P = 0.007) and toe systolic blood pressure (54 mm Hg vs 32 mm Hg, P = 0.002). CONCLUSIONS The evaluation of muscular microvascular perfusion by CEUS as performed in this study is not enough sensitive to change to allow a clinically relevant evaluation of the improvement in muscle microvascular perfusion in patients with CLI benefiting from revascularization procedures.

Treprostinil Iontophoresis Improves Digital Blood Flow during Local Cooling in Systemic Sclerosis.

Severe Raynauds syndrome and DUs are the most prevalent manifestations of SSc peripheral microvascular disease. We tested whether treprostinil iontophoresis on the finger pad of patients with SSc would improve digital blood flow during hand cooling.

THU0237 Impact of recurrent ischemic digital ulcers on hand disability in systemic sclerosis

Background Ischemic digital ulcers (DU) are a common complication of systemic sclerosis (SSc). Objectives To evaluate the impact of recurrent DU on hand disability in a prospective, longitudinal, observational study of 24 months. Methods Patients fulfilled ACR or Leroy-Medsger criteria for SSc, experienced at least one DU during the previous year with or without active DU at inclusion, and were eligible for bosentan therapy. Data were collected on SSc, characteristics of past and present DU, modified Rodnan skin score, factors influencing hand function and mobility, disability scores (Cochin hand function scale - CHFS, health assessment questionnaire disability index - HAQ-DI), and quality of life (SF36). Results 217 patients were included between October 2009 and March 2011 in 50 centers. The interim analysis includes 184 patients (128 women). Mean age was 43±15 years at diagnosis of SSc and 53±15 years at inclusion. SSc was diffuse in 44% of patients and Raynaud’s phenomenon (RP) started 14±12 years before inclusion. 11% of patients had pulmonary arterial hypertension. Mean Rodnan score was 14.3±8.8. Time elapsed since the first DU was 6±7 years. In 47% of patients, DU was an early complication (first non-RP sign) and 59% had recurrent DU. Sequelae of DU included loss of substance (62%), autoamputation (8%), and surgical amputation (10%). Complications were infection (8%), gangrene (5%), and osteitis (2%). 54% of patients had at least one active DU at inclusion. In these patients, the mean number of DU was 2.3±1.9; 54% had more than one DU, 37% had both hands involved, and on average 2.2±1.7 fingers were affected. 21% of cases had at least one extended DU (>1cm). Concomitant mechanical ulcers were localized at the dorsal face of fingers (19%), bony reliefs (13%), or calcinosis (1%). DU were painful (visual analogue scale, 6.18±2.56 vs. 2.49±2.56 without DU) and disabling, involving the dominant hand in 72% of patients. DU worsened hand disability (median CHFS, 42 with active DU vs. 26 without DU, p<0.0001), HAQ-DI, and affected SF36. Other factors contributing independently to hand disability were reduced proximal or distal interphalangeal joint mobility of at least one finger (56% and 66% of patients, respectively) and retraction of flexor tendons (45%). Conclusions DU represent an early complication of SSc. They are painful, affecting often multiple fingers and both hands. In patients with SSc, DU are significantly associated with hand disability. Prospective follow-up at two years will allow to further elucidate the specific role that DU episodes play in the disability of these patients. Disclosure of Interest L. Mouthon Consultant for: Lilly, Actelion France, GSK, Pfizer, P. Carpentier Consultant for: Actelion, A. Khau Van Kien: None Declared, P. Clerson: None Declared, H. Maillard: None Declared, E. Hachulla Consultant for: Actelion, GSK, Pfizer, C. Frances: None Declared, E. Diot: None Declared, C. Lok Consultant for: Actelion, E. Puzenat Consultant for: Actelion, A. Sparsa Consultant for: Actelion, A. Bérezné: None Declared, V. Gressin Employee of: Actelion France, M.-A. Richard Consultant for: Actelion