Raynaud's phenomenon (RP) is an exaggerated vascular response characterized by at least biphasic change (pallor and cyanosis) in the skin color of the digits, induced by cold temperature or emotional stress, The prevalence varies from 3 to 5%. In primary RP, there is no evidence of a secondary cause and patients have a younger age at onset (between 15 and 30 years), whereas in secondary RP, patients are older and have a connective tissue diseases (CTD), such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), dermatomyositis (DM), Sjögren's syndrome and rheumatoid arthritis. In secondary RP there are endothelial dysfunction and intimal fibrosis that compromise capillary blood flow. The treatment includes maintaining warmth of the whole body, smoking cessation and avoiding cold exposure, sympathomimetic medications and emotional stress. When these measures fail, the first line drugs are calcium-channel blockers (CCBs), eg. nifedipine. If CCBs are ineffective or not tolerated, a phosphodiesterase type 5 inhibitor (PDE-5), eg. sildenafil, or a topical nitrate should be used alone or in combination with CCBs. Other drugs includes serotonin reuptake inhibitors, angiotensin receptor blockers and prostaglandins. Unfortunately, secondary RP in patients with CTD most often is refractory to standard therapies, becoming a therapeutic challenge for clinicians. Based on the pathophysiology, topical vasodilators may act as an adjuvant therapy. Several randomized trials have demonstrated the benefit of various forms of topical nitrates (eg. nitroglycerin). In relation to other topical agents, solid evidence is lacking. Color Doppler ultrasound is a noninvasive imaging method that allows observation with good definition of skin and deep planes, including vascularization in real time.

The aim of this study is to compare the efficacy of topical 10% nifedipine versus 5% sildenafil in patients with secondary RP using high-frequency color Doppler ultrasound Patients The inclusion criteria considered patients with secondary RP associated with a CTD diagnosed and under follow-up in the Department of Dermatology. Diagnosis of CTD was made according to the ACR classification criteria for SSc, the Mixed Connective Tissue Disease criteria proposed by Kasukawa et al, the Bohan and Peter DM criteria and the SLICC SLE criteria. The exclusion criteria were primary RP patients; concurrent infection of any digit; allergic reaction and current use of any CCB or PDE-5 inhibitor;, , pregnancy, hypo and hypertension, history of myocardial infarction, stroke, or life-threatening arrhythmia. All patients signed a written informed consent. The Ethics Committee of Pontificia Universidad Católica de Chile approved the study protocol.

Study design This prospective study was conducted in August 2016 (winter). After screening, patients who were being treated with a vasodilator were required to discontinue it for at least 24 hours before randomization. All patients were receiving immunosuppressive treatment for their underlying disease. Patient hands (right versus left) were randomized to treatment with topical sildenafil or nifedipine cream. The thumbs of both hands didn't receive any cream so that each subject served as her own control. Subjects were instructed to apply 5 grams of 10% nifedipine cream in one hand and 5 grams of 5% sildenafil cream to the opposite hand. Vinyl gloves were supplied to improve the absorption of the cream into the hand, leaving the thumb of both hands out of the glove without any cream.

Clinical assessments The temperature of the examination room was set at 19ºC (66ºF) for ≥ 30 min and all patients underwent a high-frequency color Doppler ultrasound examination before and 1 hour after the topical treatments. The same radiologist with extensive experience in dermatologic ultrasound, performed all sonographic examinations. The radiologist was blinded to the clinical data of the study and the senior dermatologist in charge of the supervision of the application of the topical treatments was blinded to the color Doppler ultrasound results. The ultrasound equipment was a Logic E9 XD Clear working with a high frequency (upper range 18 MHz) compact linear probe (General Electric Health Systems, Waukesha, WI). The ultrasound protocol included grey scale, color Doppler and spectral curve analysis of the arterial flow using the settings of the machine for studying skin and superficial structures. The ultrasound device automatically provided the values. The primary outcome was the improvement of blood flow in the digital arteries. For Doppler sonography, peak systolic velocity (PSV, cm/sec) and diameter (mm) were measured at the palmar proper digital (PPD) arteries (proximal phalanx level) of radial aspect of the index, middle and thumb fingers of both hands. Also, PSV and diameter were measured at the dorsal (PD) arterial arch of the proximal nail fold of the index, middle and thumb fingers of both hands. Immediate and late adverse effects were monitored in all patients until 3 months after the study.

Statistical analysis PSV of the PPD artery and PD arterial arch of the index and middle fingers were added for a total PSV. The diameter of the PPD artery and PD arterial arch of the index and middle fingers were added for a total diameter. Due to the low velocity ranges, the values of peak systolic velocities in cm/sec were transformed into mm/sec. Treatment efficacy was assessed by using the differences in digital artery blood flows (total PSV) and diameters (total diameter) at baseline (time \[t\] = 0) and after 60 minutes (t = 60). Difference in digital artery blood flow and the digital artery diameter was defined as (t = 0) minus (t = 60); thus, the efficacy of the treatment was reflected by a negative difference. In all cases, mean differences less than zero indicates that the study drug cream was effective; mean differences greater than or equal to zero indicates that the study drug cream was ineffective. The Wilcoxon signed-rank tests and paired t-tests were used to assess the changes in outcomes within the group before and after treatment as appropriate. All tests were performed using two-tailed probabilities and p ≤ 0.05 was considered statistically significant.