Acute and chronic effects of two different intravenous iloprost regimens in systemic sclerosis: a pragmatic non-randomized trial

Acute and chronic effects of two different intravenous iloprost regimens in systemic sclerosis: a... Abstract Objectives I.v. iloprost (ILO) may be used in the treatment of refractory RP and digital ulcers. We aim to evaluate the acute and chronic effects of two different ILO regimens by power Doppler US (PDUS) and nailfold videocapillaroscopy. Methods In this 3-month single-centre pragmatic non-randomized trial, 96 SSc patients were included and stratified according to ILO treatment as: no ILO (group A), ILO once monthly (group B) and ILO for five consecutive days (group C). Resistivity index (RI), finger pulp blood flow and periungual vascularization by PDUS, and sum of capillaries apex width in 1 mm by nailfold videocapillaroscopy were evaluated. Results were adjusted for the average outdoor temperature at the place of residence. Results An acute ILO effect was observed for only finger pulp blood flow in groups B and C (P < 0.001 and P < 0.005, respectively). An acute effect was observed for RI and periungual vascularization only in group B. A progressive increase was observed for other parameters without statistical difference. ILO effects were not observed any longer before the following infusion. Some parameters (finger pulp blood flow in group B and RI in group C) showed a statistically higher increase the lower the outdoor temperature was. Conclusion ILO had an acute effect as assessed by PDUS, especially in group B. By contrast, an ILO chronic effect was not detectable before the following infusion in both treatment groups. More studies are needed to define how often ILO should be administered. iloprost, prostacyclin, systemic sclerosis, Raynaud’s phenomenon, digital ulcers, ultrasound, nailfold capillaroscopy Rheumatology key messages Iloprost increases finger pulp blood flow after 6 h infusion (acute effect). Iloprost effects, assessed by power Doppler US and nailfold videocapillaroscopy, are not maintained after 1 month. Outdoor temperature seems to inversely influence response to iloprost therapy. Introduction SSc is a multi-organ disease characterized by immune dysregulation, tissue fibrosis and vascular impairment [1]. Intimal hyperplasia, endothelial cell dysfunction and occlusive vasculopathy are prominent features of the vascular involvement [2]. In particular, vascular disease-specific manifestations are quite frequent in SSc patients; RP is the most common manifestation, affecting ∼96%, and about 75% of patients experience digital ulcers (DUs) during the first 5 years of the disease [3]. According to recently revised EULAR recommendations for SSc treatment, dihydropyridine-type calcium antagonists (usually nifedipine) are suggested as first-line therapy for RP, and Phosphodiesterase type 5 (PDE-5) inhibitors can also be considered. I.v. prostanoids, in particularly iloprost (ILO), should be used, after oral therapy failure, for severe RP [4]. Furthermore, i.v. ILO is considered effective for DU healing and it should be considered in the treatment of DU [4]. Unfortunately, recommendations do not provide any indications about i.v. ILO dosage and regimen. Although there is some evidence from clinical trials [5–7], nowadays, in clinical practice, i.v. ILO is administered according to different non-validated regimens, often based on the physician’s experience. Several imaging modalities are available to monitor therapeutic effects. According to our knowledge, there are no recommendations for the use of a specific validated imaging technique [8–11]. Previous studies described the utility of some echographic [11–13] and capillaroscopic [14, 16] parameters in order to assess vascular involvement in patients with SSc. In our clinical practice SSc patients are treated with i.v. ILO for RP refractory to oral therapy or for DU. Two different regimens (1 day monthly and five consecutive days every 3 months) may be administered to patients according to their own preferences and needs. The aim of our study was to evaluate the acute and chronic effects of two different ILO regimens as assessed by imaging techniques such as power Doppler US (PDUS) and nailfold videocapillaroscopy (NVC). Methods Study design This was a 3-month observational, prospective, pragmatic, single-centre and no-profit study. The study complies with the Declaration of Helsinki. The local ethical committee (Comitato Etico Milano Area B) granted ethical approval (591_2016bis), and written consent forms were obtained from all subjects. We designed the study as a pragmatic trial because our intention was to estimate the impact of two different i.v. ILO regimen in SSc patients [17–19]. The study population consisted of all consecutive individuals aged ⩾18 years who met the 2013 ACR criteria for SSc [20] referring to our in- and out-patient rheumatology clinic (Azienda socio-sanitaria territoriale Pini-CTO, Università degli Studi di Milano, Milan, Italy). Patients were enrolled between autumn 2016 and winter 2017. Patients were excluded if they had an overlap syndrome, had the amputation of the third or fourth finger of the dominant hand, or declined to sign the informed consent or were not able to understand the study protocol. Each patient was treated according to current clinical practice and stratified into three main groups: SSc patients from the out-patient clinic not requiring therapy with i.v. ILO (group A), SSc patients treated with i.v. ILO once monthly (group B) and SSc patients treated with i.v. ILO for five consecutive days every 3 months (group C). Groups B and C were treated with i.v. ILO at the dosage of 0.5–2.0 ng/kg/min for six consecutive hours. Group A was then evaluated after 3 months. Group B was evaluated every month, before and after 6 h infusion, for three consecutive months (a total of four ILO infusions were administered). Group C was evaluated at baseline before and after 6 h and 5 days of therapy, and again after 3 months (supplementary Fig. S1, available at Rheumatology online). Acute and chronic ILO effects were evaluated for each treatment group. For the acute ILO effect a comparison between pre-treatment and 6 h post-treatment measurements was performed; in addition, for patients treated for five consecutive days every 3 months a comparison between 6 h post-treatment and 5 days post-treatment was performed. For the chronic ILO effect the comparison between measurements before therapy at baseline and measurements before therapy at 3 months of follow-up was considered. Physical examinations, demographic data, SSc-related parameters, comorbidities and pharmacological therapy were recorded at baseline, at each visit before the infusion and after 3 months (supplementary Table S1, available at Rheumatology online). Safety was assessed by adverse events, serious adverse events, discontinuations due to adverse events and laboratory observations. Outcomes The primary endpoint was to evaluate acute and chronic effects of ILO administered with two different regimens (groups B and C) as assessed by PDUS. Secondary endpoints included the assessment of acute and chronic ILO effects by NVC. PDUS All the exams were performed after 15 min of acclimation in a room with an ambient temperature ranging from 19 to 22°C by the same operator (T.S.). US measurements were performed using the same US apparel (MyLab 70 XVG by Esaote (Genova, Italy) equipped with a high-frequency, 10–22 MHz, linear-array probe). Greyscale frequency was set to 22 MHz; power Doppler settings were standardized for all evaluations (frequency 14.3 MHz, gain 55%, pulse repetition frequency 750 Hz). No pressure was applied on fingers to prevent mistakes due to leaving a layer of gel between the probe and patient’s skin. US was performed at the third and fourth finger of the dominant hand if ulnar artery occlusion (UAO) was not found. UAO was defined as an abolition of blood flow as assessed by US. UAO was confirmed by Allen test and, if found positive, the non-dominant hand was evaluated. If UAO was found at both hands, the dominant hand was considered. Resistivity index (RI) was calculated at radial and ulnar proper digital arteries at the level of the proximal phalanx of the third and fourth fingers. Each estimation has been performed twice for every anatomical site. The transducer was held transversal to the long axis of the artery examined. The RI was calculated using on-board software. Peripheral vascularization was evaluated at finger pulp and nailbed area for the same fingers considered for RI. As shown in Fig. 1, finger pulp blood flow (FPBF) and periungual vascularization were graduated according to Newman et al. [21] from 1 (no signal) to 4 (yellow). The transducer was held sagittal to the nailbed for periungual vascularization and FPBF. Fig. 1 View largeDownload slide PDUS grading system used at nailbed and finger pulp PDUS: power Doppler US. Fig. 1 View largeDownload slide PDUS grading system used at nailbed and finger pulp PDUS: power Doppler US. NVC NVC was performed using equipment with a 200× optical probe, with the images being captured, coded and stored using Videocap software (DS-Medica, Milan, Italy). All of the recordings were made with the subject in a sitting position, with temperature ranging from 22 to 25°C and with their hands at heart level. The procedure was explained and a drop of immersion oil was applied to the nailfold to maximize the translucency of the keratin layer. The exams were performed by two operators (T.S. and F.I.), and capillaroscopic images were evaluated by an experienced observer (F.I.). At baseline and after 3 months, all the fingers, excluded thumbs, were examined in order to establish the overall pattern classified as within the normal range [22] or scleroderma pattern [23]. Moreover, at the third and fourth finger of the same hand analysed by US, the sum of capillaries width apex in 1 mm was calculated [24]. Statistical analysis Distribution of PDUS and NVC measurements regarding the three groups (A–C) at the corresponding detection times are reported in terms of percentages for categorical variables (FPBF and periungual vascularization) and in terms of mean for continuous variables (RI and sum of capillaries width apex). As regards the acute or chronic effect of ILO on periungual vascularization (or FPBF), ordinal logistic models were fitted. The response variable was periungual vascularization or FPBF (using four ordinal categories). To evaluate the acute effect, the explanatory variables were time (pre- and post-therapy), follow-up time (baseline, 1, 2 or 3 months, as adjusting variable) and temperature (as adjusting variable); the interaction between time and follow-up time was also considered to evaluate whether the effect of the therapy was different depending on follow-up time. To evaluate the chronic effect, the explanatory variables were follow-up time (at baseline and at 3 months of follow-up) and temperature (as adjusting variable). In order to take into account the association between measures of periungual vascularization or FPBF on the same finger and on the same patient, finger and subject ID are included in the model as random effects. For each grade category j, the exponential of the regression coefficient of this regression model is interpreted as the ratio of the odds of being above category j after the therapy and the odds of being above category j before the therapy. This model assumes that the odds ratio is the same for each category j. An odds ratio >1 indicates that after the therapy, there is a greater percentage of patients with higher grade of periungual vascularization or FPBF. As regards an effect of ILO on RI (or sum of capillary width), linear regression models were fitted. The response variable was the RI (or sum of capillary width). To evaluate the acute effect, the explanatory variables were time (pre- and post- therapy), follow-up time (baseline, 1, 2 or 3 months, as adjusting variable) and temperature (as adjusting variable); the interaction between time and follow-up time was also considered to evaluate whether the effect of the therapy was different depending on follow-up time. To evaluate the chronic effect, the explanatory variables were follow-up time (at baseline and at 3 months of follow-up) and temperature (as adjusting variable). In order to take into account the association between measures of RI (or sum of capillary width) on the same finger and on the same patient, finger and subject ID are included in the model as random effects. The regression coefficient of this model is interpreted as the mean difference of RI (or sum of capillary width) before and after ILO treatment. To assess whether the variation in PDUS or NVC measurements is different according to average temperature in the patient’s place of residence during the week before the evaluation, an interaction term between time and temperature was considered. All analyses were performed using R software, version 3.4.3, with packages lmerTest and ordinal added. Results Study population Between autumn 2016 and winter 2017, a total of 109 SSc patients were enrolled in the study. Thirteen did not satisfy eligibility criteria and were excluded. Among the 96 SSc patients included, 52 were not on ILO therapy (group A), 24 were treated with i.v. ILO 1 monthly (group B) and 20 received i.v. ILO 5 days every 3 months (group C). Of these, for each group, respectively, 35, 21 and 16 completed the study. The proportion of patients who discontinued treatment was similar between the two treatment arms (Fig. 2). Since this was a pragmatic trial, patients were stratified according to former therapy. Therapeutic regimen was not modified with trial enrolment. Fig. 2 View largeDownload slide Trial profile ILO: iloprost. Fig. 2 View largeDownload slide Trial profile ILO: iloprost. Baseline demographics, disease characteristics, internal organs involvement, physical examination and autoantibody profile were similar between groups of patients included in the final analysis (Table 1). The three groups were similar in terms of vascular involvement (i.e. visual analogue scale severity for RP, presence of DUs, gangrene and pitting scars). Detailed information on treatment and comorbidities is available in supplementary Tables S2–S6, available at Rheumatology online. Table 1 Baseline demographics and disease characteristics of patients included in the final analysis Demographics and disease characteristics No i.v. ILO (group A, n = 35) I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Age, median (range), years 64.78 (20.49–82.55) 59.11 (35.1–76.27) 57.75 (22.46–79.18) Female 30 (85.71) 19 (90.48) 13 (81.25) Caucasian 35 (100) 21 (100) 15 (93.75) Disease subset: lcSSc 34 (97.14) 18 (85.71) 11 (68.75) RP duration, median (range), years 13.5 (2–38) 16 (3–58) 13 (1–25) Disease duration, median (range) 7 (1–31) 8 (2–24) 7.5 (0–18) VAS RP, median (range) 5 (0–9) 5 (0–8) 4.5 (0–9) Active smokers 5 (14.29) 1 (4.76) 5 (31.25) ANA 35 (100) 21 (100) 14 (93.33) Centromere pattern 23 (65.71) 8 (38.1) 5 (35.71) Anti-Scl70 11 (31.43) 9 (42.86) 8 (50) Clinical features     Heart involvement 3 (8.57) 4 (19.05) 2 (12.5)     Oesophageal involvement 14 (40) 16 (76.19) 12 (75)     Gastric involvement 0 (0) 1 (4.76) 0 (0)     Intestinal involvement 0 (0) 1 (4.76) 0 (0)     Interstitial lung disease 9 (25.71) 12 (57.14) 8 (50)     Pulmonary arterial hypertension 2 (5.71) 2 (9.52) 0 (0)     Scleroderma renal crisis 0 (0) 0 (0) 0 (0)     Myositis 0 (0) 0 (0) 1 (6.25)     History of arthritis 2 (5.71) 4 (19.05) 1 (6.25)     Calcinosis 6 (17.14) 9 (42.86) 6 (37.5)     Telangiectasia 25 (71.43) 16 (76.19) 11 (68.75)     Sclerodactitys 20 (57.14) 18 (85.71) 15 (93.75)     History of 1 DU 2 (5.71) 3 (14.29) 1 (6.25)     History of >1 DU 6 (17.14) 6 (28.57) 6 (37.5) Physical examination     DU 0 (0) 0 (0) 0 (0)     Gangrene 0 (0) 0 (0) 0 (0)     Pitting scars 8 (22.86) 10 (47.62) 8 (50)     Finger acral reabsorption 2 (5.71) 6 (28.57) 3 (18.75)     Skin score (median, min–max) 2 (0–13) 2 (0–8) 2 (0–21) Demographics and disease characteristics No i.v. ILO (group A, n = 35) I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Age, median (range), years 64.78 (20.49–82.55) 59.11 (35.1–76.27) 57.75 (22.46–79.18) Female 30 (85.71) 19 (90.48) 13 (81.25) Caucasian 35 (100) 21 (100) 15 (93.75) Disease subset: lcSSc 34 (97.14) 18 (85.71) 11 (68.75) RP duration, median (range), years 13.5 (2–38) 16 (3–58) 13 (1–25) Disease duration, median (range) 7 (1–31) 8 (2–24) 7.5 (0–18) VAS RP, median (range) 5 (0–9) 5 (0–8) 4.5 (0–9) Active smokers 5 (14.29) 1 (4.76) 5 (31.25) ANA 35 (100) 21 (100) 14 (93.33) Centromere pattern 23 (65.71) 8 (38.1) 5 (35.71) Anti-Scl70 11 (31.43) 9 (42.86) 8 (50) Clinical features     Heart involvement 3 (8.57) 4 (19.05) 2 (12.5)     Oesophageal involvement 14 (40) 16 (76.19) 12 (75)     Gastric involvement 0 (0) 1 (4.76) 0 (0)     Intestinal involvement 0 (0) 1 (4.76) 0 (0)     Interstitial lung disease 9 (25.71) 12 (57.14) 8 (50)     Pulmonary arterial hypertension 2 (5.71) 2 (9.52) 0 (0)     Scleroderma renal crisis 0 (0) 0 (0) 0 (0)     Myositis 0 (0) 0 (0) 1 (6.25)     History of arthritis 2 (5.71) 4 (19.05) 1 (6.25)     Calcinosis 6 (17.14) 9 (42.86) 6 (37.5)     Telangiectasia 25 (71.43) 16 (76.19) 11 (68.75)     Sclerodactitys 20 (57.14) 18 (85.71) 15 (93.75)     History of 1 DU 2 (5.71) 3 (14.29) 1 (6.25)     History of >1 DU 6 (17.14) 6 (28.57) 6 (37.5) Physical examination     DU 0 (0) 0 (0) 0 (0)     Gangrene 0 (0) 0 (0) 0 (0)     Pitting scars 8 (22.86) 10 (47.62) 8 (50)     Finger acral reabsorption 2 (5.71) 6 (28.57) 3 (18.75)     Skin score (median, min–max) 2 (0–13) 2 (0–8) 2 (0–21) Values are given as n (%) unless otherwise stated. ILO: iloprost; VAS: visual analogue scale; DU: digital ulcer. Table 1 Baseline demographics and disease characteristics of patients included in the final analysis Demographics and disease characteristics No i.v. ILO (group A, n = 35) I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Age, median (range), years 64.78 (20.49–82.55) 59.11 (35.1–76.27) 57.75 (22.46–79.18) Female 30 (85.71) 19 (90.48) 13 (81.25) Caucasian 35 (100) 21 (100) 15 (93.75) Disease subset: lcSSc 34 (97.14) 18 (85.71) 11 (68.75) RP duration, median (range), years 13.5 (2–38) 16 (3–58) 13 (1–25) Disease duration, median (range) 7 (1–31) 8 (2–24) 7.5 (0–18) VAS RP, median (range) 5 (0–9) 5 (0–8) 4.5 (0–9) Active smokers 5 (14.29) 1 (4.76) 5 (31.25) ANA 35 (100) 21 (100) 14 (93.33) Centromere pattern 23 (65.71) 8 (38.1) 5 (35.71) Anti-Scl70 11 (31.43) 9 (42.86) 8 (50) Clinical features     Heart involvement 3 (8.57) 4 (19.05) 2 (12.5)     Oesophageal involvement 14 (40) 16 (76.19) 12 (75)     Gastric involvement 0 (0) 1 (4.76) 0 (0)     Intestinal involvement 0 (0) 1 (4.76) 0 (0)     Interstitial lung disease 9 (25.71) 12 (57.14) 8 (50)     Pulmonary arterial hypertension 2 (5.71) 2 (9.52) 0 (0)     Scleroderma renal crisis 0 (0) 0 (0) 0 (0)     Myositis 0 (0) 0 (0) 1 (6.25)     History of arthritis 2 (5.71) 4 (19.05) 1 (6.25)     Calcinosis 6 (17.14) 9 (42.86) 6 (37.5)     Telangiectasia 25 (71.43) 16 (76.19) 11 (68.75)     Sclerodactitys 20 (57.14) 18 (85.71) 15 (93.75)     History of 1 DU 2 (5.71) 3 (14.29) 1 (6.25)     History of >1 DU 6 (17.14) 6 (28.57) 6 (37.5) Physical examination     DU 0 (0) 0 (0) 0 (0)     Gangrene 0 (0) 0 (0) 0 (0)     Pitting scars 8 (22.86) 10 (47.62) 8 (50)     Finger acral reabsorption 2 (5.71) 6 (28.57) 3 (18.75)     Skin score (median, min–max) 2 (0–13) 2 (0–8) 2 (0–21) Demographics and disease characteristics No i.v. ILO (group A, n = 35) I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Age, median (range), years 64.78 (20.49–82.55) 59.11 (35.1–76.27) 57.75 (22.46–79.18) Female 30 (85.71) 19 (90.48) 13 (81.25) Caucasian 35 (100) 21 (100) 15 (93.75) Disease subset: lcSSc 34 (97.14) 18 (85.71) 11 (68.75) RP duration, median (range), years 13.5 (2–38) 16 (3–58) 13 (1–25) Disease duration, median (range) 7 (1–31) 8 (2–24) 7.5 (0–18) VAS RP, median (range) 5 (0–9) 5 (0–8) 4.5 (0–9) Active smokers 5 (14.29) 1 (4.76) 5 (31.25) ANA 35 (100) 21 (100) 14 (93.33) Centromere pattern 23 (65.71) 8 (38.1) 5 (35.71) Anti-Scl70 11 (31.43) 9 (42.86) 8 (50) Clinical features     Heart involvement 3 (8.57) 4 (19.05) 2 (12.5)     Oesophageal involvement 14 (40) 16 (76.19) 12 (75)     Gastric involvement 0 (0) 1 (4.76) 0 (0)     Intestinal involvement 0 (0) 1 (4.76) 0 (0)     Interstitial lung disease 9 (25.71) 12 (57.14) 8 (50)     Pulmonary arterial hypertension 2 (5.71) 2 (9.52) 0 (0)     Scleroderma renal crisis 0 (0) 0 (0) 0 (0)     Myositis 0 (0) 0 (0) 1 (6.25)     History of arthritis 2 (5.71) 4 (19.05) 1 (6.25)     Calcinosis 6 (17.14) 9 (42.86) 6 (37.5)     Telangiectasia 25 (71.43) 16 (76.19) 11 (68.75)     Sclerodactitys 20 (57.14) 18 (85.71) 15 (93.75)     History of 1 DU 2 (5.71) 3 (14.29) 1 (6.25)     History of >1 DU 6 (17.14) 6 (28.57) 6 (37.5) Physical examination     DU 0 (0) 0 (0) 0 (0)     Gangrene 0 (0) 0 (0) 0 (0)     Pitting scars 8 (22.86) 10 (47.62) 8 (50)     Finger acral reabsorption 2 (5.71) 6 (28.57) 3 (18.75)     Skin score (median, min–max) 2 (0–13) 2 (0–8) 2 (0–21) Values are given as n (%) unless otherwise stated. ILO: iloprost; VAS: visual analogue scale; DU: digital ulcer. Acute effect of ILO infusion The results of the ordinal logistic regression and the linear regression models are reported in Table 2. In group B, a significant increase was observed in periungual vascularization (P < 0.001), FPBF (P < 0.001) and RI (P < 0.001). The acute effect of ILO was observed at every infusion from baseline throughout the whole follow-up period (Fig. 3). Table 2 Acute effect of i.v. ILO: pre- and post-first day and fifth day of infusion Power Doppler US and nailfold videocapillaroscopy parameters I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Pre- vs post-therapy first day Post-therapy first day vs post-therapy fifth day Power Doppler US     Finger pulp blood flow, OR (95% CI) 3.52 (2.18, 5.67) 2.63 (1.33, 5.19) 2.41 (1.17, 5.00)         P-value <0.001 0.005 0.017     Periungual vascularization OR (95% CI) 4.35 (2.66, 7.12) 1.56 (0.76, 3.18) 1.39 (0.65, 2.95)         P-value <0.001 0.225 0.396     Resistivity index mean difference (95% CI) 0.034 (0.021, 0.046) −0.009 (−0.029, 0.011) 0.032 (0.011, 0.052)         P-value <0.001 0.368 0.002 Nailfold videocapillaroscopy     Sum of capillaries width apex mean difference (95% CI) 9.803 (−7.117, 26.723) 11.267 (−12.986, 35.521) 16.381 (−8.117, 40.879)         P-value 0.257 0.364 0.192 Power Doppler US and nailfold videocapillaroscopy parameters I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Pre- vs post-therapy first day Post-therapy first day vs post-therapy fifth day Power Doppler US     Finger pulp blood flow, OR (95% CI) 3.52 (2.18, 5.67) 2.63 (1.33, 5.19) 2.41 (1.17, 5.00)         P-value <0.001 0.005 0.017     Periungual vascularization OR (95% CI) 4.35 (2.66, 7.12) 1.56 (0.76, 3.18) 1.39 (0.65, 2.95)         P-value <0.001 0.225 0.396     Resistivity index mean difference (95% CI) 0.034 (0.021, 0.046) −0.009 (−0.029, 0.011) 0.032 (0.011, 0.052)         P-value <0.001 0.368 0.002 Nailfold videocapillaroscopy     Sum of capillaries width apex mean difference (95% CI) 9.803 (−7.117, 26.723) 11.267 (−12.986, 35.521) 16.381 (−8.117, 40.879)         P-value 0.257 0.364 0.192 ILO: iloprost; OR: odds ratio. Table 2 Acute effect of i.v. ILO: pre- and post-first day and fifth day of infusion Power Doppler US and nailfold videocapillaroscopy parameters I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Pre- vs post-therapy first day Post-therapy first day vs post-therapy fifth day Power Doppler US     Finger pulp blood flow, OR (95% CI) 3.52 (2.18, 5.67) 2.63 (1.33, 5.19) 2.41 (1.17, 5.00)         P-value <0.001 0.005 0.017     Periungual vascularization OR (95% CI) 4.35 (2.66, 7.12) 1.56 (0.76, 3.18) 1.39 (0.65, 2.95)         P-value <0.001 0.225 0.396     Resistivity index mean difference (95% CI) 0.034 (0.021, 0.046) −0.009 (−0.029, 0.011) 0.032 (0.011, 0.052)         P-value <0.001 0.368 0.002 Nailfold videocapillaroscopy     Sum of capillaries width apex mean difference (95% CI) 9.803 (−7.117, 26.723) 11.267 (−12.986, 35.521) 16.381 (−8.117, 40.879)         P-value 0.257 0.364 0.192 Power Doppler US and nailfold videocapillaroscopy parameters I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Pre- vs post-therapy first day Post-therapy first day vs post-therapy fifth day Power Doppler US     Finger pulp blood flow, OR (95% CI) 3.52 (2.18, 5.67) 2.63 (1.33, 5.19) 2.41 (1.17, 5.00)         P-value <0.001 0.005 0.017     Periungual vascularization OR (95% CI) 4.35 (2.66, 7.12) 1.56 (0.76, 3.18) 1.39 (0.65, 2.95)         P-value <0.001 0.225 0.396     Resistivity index mean difference (95% CI) 0.034 (0.021, 0.046) −0.009 (−0.029, 0.011) 0.032 (0.011, 0.052)         P-value <0.001 0.368 0.002 Nailfold videocapillaroscopy     Sum of capillaries width apex mean difference (95% CI) 9.803 (−7.117, 26.723) 11.267 (−12.986, 35.521) 16.381 (−8.117, 40.879)         P-value 0.257 0.364 0.192 ILO: iloprost; OR: odds ratio. Fig. 3 View largeDownload slide Acute effect of i.v. iloprost demonstrated by PDUS and NVC PDUS: Power Doppler US; NVC: nailfold videocapillaroscopy. Fig. 3 View largeDownload slide Acute effect of i.v. iloprost demonstrated by PDUS and NVC PDUS: Power Doppler US; NVC: nailfold videocapillaroscopy. Similarly in group C, FPBF increased significantly 6 h after the therapy (P = 0.005) and a further increase was observed thereafter (P = 0.017). The same trend was observed for periungual vascularization, even though its increase was not statistically significant. RI increased significantly only after 5 days of therapy with respect to the end of the first day of therapy (P = 0.002). In both groups the sum of capillaries width apex was not different before and after infusion, although it is possible to observe a progressive trend (group B: P = 0.257 and group C: P = 0.364 after the first day of therapy and 0.192 after the fifth day of therapy). Distribution of PDUS parameters (FPBF, periungual vascularization and RI) and NVC (sum of capillaries width apex) measurements regarding the three groups before and after 6-h infusion are reported in supplementary Table S7, available at Rheumatology online. Chronic effect of ILO infusion No differences in imaging parameters (i.e. PDUS and NVC) were observed between baseline and before the last round of therapy in both groups of patients, suggesting that i.v. ILO effects cannot be maintained overtime (supplementary Table S8, available at Rheumatology online). Since allocation to groups was not performed randomly, a direct comparison between them cannot be conducted. However, two considerations can be drawn: at baseline patients not requiring i.v. ILO therapy tended to have a better grade of vascularization (FPBF and periungual vascularization); and patients requiring therapy, once treated with i.v. ILO, tended to be similar to those not treated and to show a better grade of vascularization compared with baseline, especially after 5 days of therapy. Percentages of patients, classified according to grade of FPBF and periungual vascularization, are shown in Fig. 4. Fig. 4 View largeDownload slide Changes of PDUS parameters over time Finger pulp blood flow (A) and periungual vascularization (B) at T0: baseline; T1: 1 month follow-up; T2: 2 months follow-up; T3: 3 months follow-up. PDUS: Power Doppler US. Fig. 4 View largeDownload slide Changes of PDUS parameters over time Finger pulp blood flow (A) and periungual vascularization (B) at T0: baseline; T1: 1 month follow-up; T2: 2 months follow-up; T3: 3 months follow-up. PDUS: Power Doppler US. Temperature effect Finally, we studied whether outdoor temperature was able to affect treatment response assessed by PDUS. In particular, in group A the difference in RI between baseline and after 3 months tended towards increasing concurrently with the reduction of temperature; moreover, taking into account the acute effect of ILO, FPBF increased in group B and RI increased in group C concurrently with the decrease of outdoor temperature. By contrast, outdoor temperature did not have an impact on chronic effect in the two treatment groups. Discussion I.v. ILO is currently used to treat RP and DU secondary to SSc, even though no precise indications about the regimen have been suggested. Moreover, according to some authors, i.v. ILO, based on its biological properties, might play a role as a DMARD [25]. In our clinical practice we propose i.v. ILO to SSc patients with RP not adequately controlled by oral therapy (i.e. calcium channel blockers) or with DU. Patients can choose between two different regimens (once monthly or 5 consecutive days every 3 months) according to their own preferences and needs. I.v. ILO therapy was able to cause an acute effect with respect to the PDUS parameters considered. The acute effect was statistically significant in group B, while in group C statistical significance was not reached for all the parameters. On the contrary, the i.v. ILO effect observed immediately after the infusion was no longer detectable before the following infusion. This means that the acute effect, as assessed by PDUS, is not maintained over time until the next infusion. These data support the need for further studies to understand the optimal timing of the retreatment strategy. Since this study was a non-interventional pragmatic study, a direct comparison between treatment groups was not feasible. Despite this consideration, patients receiving i.v. ILO showed at baseline worse levels of peripheral vascularization (PDUS and periungual vascularization) compared with patients not requiring i.v. ILO. The opportunity for discontinuing i.v. ILO therapy during summer is a subject of ongoing debate. In our study the outdoor temperature was able to inversely influence the acute response to ILO therapy for some of the PDUS parameters considered. These results might support a rationale for i.v. ILO summertime suspension even though we performed the study during the autumn–winter period, and some studies have suggested the opposite [26]. Future studies are needed to assess how long i.v. ILO effects last and to assess the best i.v. ILO regimens. Moreover, it is of fundamental importance to validate the imaging parameters to monitor the therapeutic effects. Acknowledgements We thank Meteo Operations Italia SrL—Centro Epson Meteo, Cinisello Balsamo, Italy for kindly providing temperature data. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 Denton CP , Khanna D. Systemic sclerosis . Lancet 2017 ; 390 : 1685 – 99 . Google Scholar CrossRef Search ADS PubMed 2 Matucci-Cerinic M , Kahaleh B , Wigley FM. Review: evidence that systemic sclerosis is a vascular disease . Arthritis Rheum 2013 ; 65 : 1953 – 62 . Google Scholar CrossRef Search ADS PubMed 3 Hachulla E , Clerson P , Launay D et al. Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study . J Rheumatol 2007 ; 34 : 2423 – 30 . Google Scholar PubMed 4 Kowal-Bielecka O , Fransen J , Avouac J et al. Update of EULAR recommendations for the treatment of systemic sclerosis . Ann Rheum Dis 2017 ; 76 : 1327 – 39 . Google Scholar CrossRef Search ADS PubMed 5 Wigley FM , Wise RA , Seibold JR et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study . Ann Int Med 1994 ; 120 : 199 – 206 . Google Scholar CrossRef Search ADS PubMed 6 Bellando-Randone S , Bruni C , Lepri G et al. The safety of iloprost in systemic sclerosis in a real-life experience . Clin Rheumatol 2018 ; 37 : 1249 – 1255 . Google Scholar CrossRef Search ADS PubMed 7 Fraticelli P , Martino GP , Murri M , Mattioli M , Gabrielli A. A novel iloprost administration method with portable syringe pump for the treatment of acral ulcers and Raynaud's phenomenon in systemic sclerosis patients. A pilot study (ILOPORTA) . Clin Exp Rheumatol 2017 ; 35(Suppl 106) : 173 – 8 . Google Scholar PubMed 8 Rotondo C , Nivuori M , Chialà A et al. Evidence for increase in finger blood flow, evaluated by laser Doppler flowmetry, following iloprost infusion in patients with systemic sclerosis: a week-long observational longitudinal study . Scand J Rheumatol 2018 ; 7 : 1 – 8 . 9 Trombetta AC , Pizzorni C , Ruaro B et al. Effects of longterm treatment with Bosentan and iloprost on nailfold absolute capillary number, fingertip blood perfusion, and clinical status in systemic sclerosis . J Rheumatol 2016 ; 43 : 2033 – 41 . Google Scholar CrossRef Search ADS PubMed 10 Lescoat A , Coiffier G , de Carlan M et al. Combination of capillaroscopic and ultrasonographic evaluations in systemic sclerosis: results of a cross-sectional study . Arthritis Care Res 2017 ; doi: 10.1002/acr.23413. 11 Lescoat A , Coiffier G , Rouil A et al. 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 . Arthritis Care Res 2017 ; 69 : 543 – 51 . Google Scholar CrossRef Search ADS 12 Bregenzer N , Distler O , Meyringer R et al. Doppler ultrasound identifies increased resistive indices in SSc . Ann Rheum Dis 2004 ; 63 : 109 – 10 . Google Scholar CrossRef Search ADS PubMed 13 Keberle M , Tony HP , Hau M et al. Colour Doppler ultrasound of the nailbed: an objective tool for monitoring responses to vasodilatory treatment of connective tissue disorders? Rheumatology (Oxford) 2001 ; 40 : 954 – 5 . Google Scholar CrossRef Search ADS PubMed 14 Cutolo M , Ferrone C , Pizzorni C et al. Peripheral blood perfusion correlates with microvascular abnormalities in systemic sclerosis: a laser-Doppler and nailfold videocapillaroscopy study . J Rheumatol 2010 ; 37 : 1174 – 80 . Google Scholar CrossRef Search ADS PubMed 15 Cutolo M , Ruaro B , Pizzorni C et al. Longterm treatment with endothelin receptor antagonist bosentan and iloprost improves fingertip blood perfusion in systemic sclerosis . J Rheumatol 2014 ; 41 : 881 – 6 . Google Scholar CrossRef Search ADS PubMed 16 Ingegnoli F , Ughi N , Dinsdale G et al. An international SUrvey on non-iNvaSive tecHniques to assess the mIcrocirculation in patients with RayNaud's phEnomenon (SUNSHINE survey) . Rheumatol Int 2017 ; 37 : 1879 – 90 . Google Scholar CrossRef Search ADS PubMed 17 Ford I , Norrie J. Pragmatic trials . N Engl J Med 2016 ; 375 : 454 – 63 . Google Scholar CrossRef Search ADS PubMed 18 Biasi D , Carletto A , Caramaschi P et al. Iloprost as cyclic five-day infusions in the treatment of scleroderma. An open pilot study in 20 patients treated for one year . Rev Rhum Engl Ed 1998 ; 65 : 745 – 50 . Google Scholar PubMed 19 Caramaschi P , Martinelli N , Volpe A et al. A score of risk factors associated with ischemic digital ulcers in patients affected by systemic sclerosis treated with iloprost . Clin Rheumatol 2009 ; 28 : 807 – 13 . Google Scholar CrossRef Search ADS PubMed 20 van den Hoogen F , Khanna D , Fransen J et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative . Arthritis Rheum 2013 ; 65 : 2737 – 47 . Google Scholar CrossRef Search ADS PubMed 21 Newman JS , Laing TJ , McCarthy CJ , Adler RS. Power Doppler sonography of synovitis: assessment of therapeutic response–preliminary observations . Radiology 1996 ; 198 : 582 – 4 . Google Scholar CrossRef Search ADS PubMed 22 Ingegnoli F , Gualtierotti R , Lubatti C et al. Nailfold capillary patterns in healthy subjects: a real issue in capillaroscopy . Microvasc Res 2013 ; 90 : 90 – 5 . Google Scholar CrossRef Search ADS PubMed 23 Cutolo M , Pizzorni C , Tuccio M et al. Nailfold videocapillaroscopic patterns and serum autoantibodies in systemic sclerosis . Rheumatology (Oxford) 2004 ; 43 : 719 – 26 . Google Scholar CrossRef Search ADS PubMed 24 Etehad Tavakol M , Fatemi A , Karbalaie A , Emrani Z , Erlandsson BE. Nailfold capillaroscopy in rheumatic diseases: which parameters should be evaluated? Biomed Res Int 2015 ; 2015 : 974530 . Google Scholar CrossRef Search ADS PubMed 25 Airo P , Rossi M , Scarsi M et al. Disease-modifying effects of long-term cyclic iloprost therapy in systemic sclerosis. A retrospective analysis and comparison with a control group . Clin Exp Rheumatol 2007 ; 25 : 722 – 7 . Google Scholar PubMed 26 Auriemma M , Vianale G , Reale M et al. Iloprost treatment summer-suspension: effects on skin thermal properties and cytokine profile in systemic sclerosis patients. G Ital Dermatol Venereol 2013 ; 148 : 209 – 16 . © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Acute and chronic effects of two different intravenous iloprost regimens in systemic sclerosis: a pragmatic non-randomized trial

Rheumatology , Volume Advance Article (8) – May 3, 2018

Loading next page...
 
/lp/ou_press/acute-and-chronic-effects-of-two-different-intravenous-iloprost-0POYUErJY7
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
ISSN
1462-0324
eISSN
1462-0332
D.O.I.
10.1093/rheumatology/key113
Publisher site
See Article on Publisher Site

Abstract

Abstract Objectives I.v. iloprost (ILO) may be used in the treatment of refractory RP and digital ulcers. We aim to evaluate the acute and chronic effects of two different ILO regimens by power Doppler US (PDUS) and nailfold videocapillaroscopy. Methods In this 3-month single-centre pragmatic non-randomized trial, 96 SSc patients were included and stratified according to ILO treatment as: no ILO (group A), ILO once monthly (group B) and ILO for five consecutive days (group C). Resistivity index (RI), finger pulp blood flow and periungual vascularization by PDUS, and sum of capillaries apex width in 1 mm by nailfold videocapillaroscopy were evaluated. Results were adjusted for the average outdoor temperature at the place of residence. Results An acute ILO effect was observed for only finger pulp blood flow in groups B and C (P < 0.001 and P < 0.005, respectively). An acute effect was observed for RI and periungual vascularization only in group B. A progressive increase was observed for other parameters without statistical difference. ILO effects were not observed any longer before the following infusion. Some parameters (finger pulp blood flow in group B and RI in group C) showed a statistically higher increase the lower the outdoor temperature was. Conclusion ILO had an acute effect as assessed by PDUS, especially in group B. By contrast, an ILO chronic effect was not detectable before the following infusion in both treatment groups. More studies are needed to define how often ILO should be administered. iloprost, prostacyclin, systemic sclerosis, Raynaud’s phenomenon, digital ulcers, ultrasound, nailfold capillaroscopy Rheumatology key messages Iloprost increases finger pulp blood flow after 6 h infusion (acute effect). Iloprost effects, assessed by power Doppler US and nailfold videocapillaroscopy, are not maintained after 1 month. Outdoor temperature seems to inversely influence response to iloprost therapy. Introduction SSc is a multi-organ disease characterized by immune dysregulation, tissue fibrosis and vascular impairment [1]. Intimal hyperplasia, endothelial cell dysfunction and occlusive vasculopathy are prominent features of the vascular involvement [2]. In particular, vascular disease-specific manifestations are quite frequent in SSc patients; RP is the most common manifestation, affecting ∼96%, and about 75% of patients experience digital ulcers (DUs) during the first 5 years of the disease [3]. According to recently revised EULAR recommendations for SSc treatment, dihydropyridine-type calcium antagonists (usually nifedipine) are suggested as first-line therapy for RP, and Phosphodiesterase type 5 (PDE-5) inhibitors can also be considered. I.v. prostanoids, in particularly iloprost (ILO), should be used, after oral therapy failure, for severe RP [4]. Furthermore, i.v. ILO is considered effective for DU healing and it should be considered in the treatment of DU [4]. Unfortunately, recommendations do not provide any indications about i.v. ILO dosage and regimen. Although there is some evidence from clinical trials [5–7], nowadays, in clinical practice, i.v. ILO is administered according to different non-validated regimens, often based on the physician’s experience. Several imaging modalities are available to monitor therapeutic effects. According to our knowledge, there are no recommendations for the use of a specific validated imaging technique [8–11]. Previous studies described the utility of some echographic [11–13] and capillaroscopic [14, 16] parameters in order to assess vascular involvement in patients with SSc. In our clinical practice SSc patients are treated with i.v. ILO for RP refractory to oral therapy or for DU. Two different regimens (1 day monthly and five consecutive days every 3 months) may be administered to patients according to their own preferences and needs. The aim of our study was to evaluate the acute and chronic effects of two different ILO regimens as assessed by imaging techniques such as power Doppler US (PDUS) and nailfold videocapillaroscopy (NVC). Methods Study design This was a 3-month observational, prospective, pragmatic, single-centre and no-profit study. The study complies with the Declaration of Helsinki. The local ethical committee (Comitato Etico Milano Area B) granted ethical approval (591_2016bis), and written consent forms were obtained from all subjects. We designed the study as a pragmatic trial because our intention was to estimate the impact of two different i.v. ILO regimen in SSc patients [17–19]. The study population consisted of all consecutive individuals aged ⩾18 years who met the 2013 ACR criteria for SSc [20] referring to our in- and out-patient rheumatology clinic (Azienda socio-sanitaria territoriale Pini-CTO, Università degli Studi di Milano, Milan, Italy). Patients were enrolled between autumn 2016 and winter 2017. Patients were excluded if they had an overlap syndrome, had the amputation of the third or fourth finger of the dominant hand, or declined to sign the informed consent or were not able to understand the study protocol. Each patient was treated according to current clinical practice and stratified into three main groups: SSc patients from the out-patient clinic not requiring therapy with i.v. ILO (group A), SSc patients treated with i.v. ILO once monthly (group B) and SSc patients treated with i.v. ILO for five consecutive days every 3 months (group C). Groups B and C were treated with i.v. ILO at the dosage of 0.5–2.0 ng/kg/min for six consecutive hours. Group A was then evaluated after 3 months. Group B was evaluated every month, before and after 6 h infusion, for three consecutive months (a total of four ILO infusions were administered). Group C was evaluated at baseline before and after 6 h and 5 days of therapy, and again after 3 months (supplementary Fig. S1, available at Rheumatology online). Acute and chronic ILO effects were evaluated for each treatment group. For the acute ILO effect a comparison between pre-treatment and 6 h post-treatment measurements was performed; in addition, for patients treated for five consecutive days every 3 months a comparison between 6 h post-treatment and 5 days post-treatment was performed. For the chronic ILO effect the comparison between measurements before therapy at baseline and measurements before therapy at 3 months of follow-up was considered. Physical examinations, demographic data, SSc-related parameters, comorbidities and pharmacological therapy were recorded at baseline, at each visit before the infusion and after 3 months (supplementary Table S1, available at Rheumatology online). Safety was assessed by adverse events, serious adverse events, discontinuations due to adverse events and laboratory observations. Outcomes The primary endpoint was to evaluate acute and chronic effects of ILO administered with two different regimens (groups B and C) as assessed by PDUS. Secondary endpoints included the assessment of acute and chronic ILO effects by NVC. PDUS All the exams were performed after 15 min of acclimation in a room with an ambient temperature ranging from 19 to 22°C by the same operator (T.S.). US measurements were performed using the same US apparel (MyLab 70 XVG by Esaote (Genova, Italy) equipped with a high-frequency, 10–22 MHz, linear-array probe). Greyscale frequency was set to 22 MHz; power Doppler settings were standardized for all evaluations (frequency 14.3 MHz, gain 55%, pulse repetition frequency 750 Hz). No pressure was applied on fingers to prevent mistakes due to leaving a layer of gel between the probe and patient’s skin. US was performed at the third and fourth finger of the dominant hand if ulnar artery occlusion (UAO) was not found. UAO was defined as an abolition of blood flow as assessed by US. UAO was confirmed by Allen test and, if found positive, the non-dominant hand was evaluated. If UAO was found at both hands, the dominant hand was considered. Resistivity index (RI) was calculated at radial and ulnar proper digital arteries at the level of the proximal phalanx of the third and fourth fingers. Each estimation has been performed twice for every anatomical site. The transducer was held transversal to the long axis of the artery examined. The RI was calculated using on-board software. Peripheral vascularization was evaluated at finger pulp and nailbed area for the same fingers considered for RI. As shown in Fig. 1, finger pulp blood flow (FPBF) and periungual vascularization were graduated according to Newman et al. [21] from 1 (no signal) to 4 (yellow). The transducer was held sagittal to the nailbed for periungual vascularization and FPBF. Fig. 1 View largeDownload slide PDUS grading system used at nailbed and finger pulp PDUS: power Doppler US. Fig. 1 View largeDownload slide PDUS grading system used at nailbed and finger pulp PDUS: power Doppler US. NVC NVC was performed using equipment with a 200× optical probe, with the images being captured, coded and stored using Videocap software (DS-Medica, Milan, Italy). All of the recordings were made with the subject in a sitting position, with temperature ranging from 22 to 25°C and with their hands at heart level. The procedure was explained and a drop of immersion oil was applied to the nailfold to maximize the translucency of the keratin layer. The exams were performed by two operators (T.S. and F.I.), and capillaroscopic images were evaluated by an experienced observer (F.I.). At baseline and after 3 months, all the fingers, excluded thumbs, were examined in order to establish the overall pattern classified as within the normal range [22] or scleroderma pattern [23]. Moreover, at the third and fourth finger of the same hand analysed by US, the sum of capillaries width apex in 1 mm was calculated [24]. Statistical analysis Distribution of PDUS and NVC measurements regarding the three groups (A–C) at the corresponding detection times are reported in terms of percentages for categorical variables (FPBF and periungual vascularization) and in terms of mean for continuous variables (RI and sum of capillaries width apex). As regards the acute or chronic effect of ILO on periungual vascularization (or FPBF), ordinal logistic models were fitted. The response variable was periungual vascularization or FPBF (using four ordinal categories). To evaluate the acute effect, the explanatory variables were time (pre- and post-therapy), follow-up time (baseline, 1, 2 or 3 months, as adjusting variable) and temperature (as adjusting variable); the interaction between time and follow-up time was also considered to evaluate whether the effect of the therapy was different depending on follow-up time. To evaluate the chronic effect, the explanatory variables were follow-up time (at baseline and at 3 months of follow-up) and temperature (as adjusting variable). In order to take into account the association between measures of periungual vascularization or FPBF on the same finger and on the same patient, finger and subject ID are included in the model as random effects. For each grade category j, the exponential of the regression coefficient of this regression model is interpreted as the ratio of the odds of being above category j after the therapy and the odds of being above category j before the therapy. This model assumes that the odds ratio is the same for each category j. An odds ratio >1 indicates that after the therapy, there is a greater percentage of patients with higher grade of periungual vascularization or FPBF. As regards an effect of ILO on RI (or sum of capillary width), linear regression models were fitted. The response variable was the RI (or sum of capillary width). To evaluate the acute effect, the explanatory variables were time (pre- and post- therapy), follow-up time (baseline, 1, 2 or 3 months, as adjusting variable) and temperature (as adjusting variable); the interaction between time and follow-up time was also considered to evaluate whether the effect of the therapy was different depending on follow-up time. To evaluate the chronic effect, the explanatory variables were follow-up time (at baseline and at 3 months of follow-up) and temperature (as adjusting variable). In order to take into account the association between measures of RI (or sum of capillary width) on the same finger and on the same patient, finger and subject ID are included in the model as random effects. The regression coefficient of this model is interpreted as the mean difference of RI (or sum of capillary width) before and after ILO treatment. To assess whether the variation in PDUS or NVC measurements is different according to average temperature in the patient’s place of residence during the week before the evaluation, an interaction term between time and temperature was considered. All analyses were performed using R software, version 3.4.3, with packages lmerTest and ordinal added. Results Study population Between autumn 2016 and winter 2017, a total of 109 SSc patients were enrolled in the study. Thirteen did not satisfy eligibility criteria and were excluded. Among the 96 SSc patients included, 52 were not on ILO therapy (group A), 24 were treated with i.v. ILO 1 monthly (group B) and 20 received i.v. ILO 5 days every 3 months (group C). Of these, for each group, respectively, 35, 21 and 16 completed the study. The proportion of patients who discontinued treatment was similar between the two treatment arms (Fig. 2). Since this was a pragmatic trial, patients were stratified according to former therapy. Therapeutic regimen was not modified with trial enrolment. Fig. 2 View largeDownload slide Trial profile ILO: iloprost. Fig. 2 View largeDownload slide Trial profile ILO: iloprost. Baseline demographics, disease characteristics, internal organs involvement, physical examination and autoantibody profile were similar between groups of patients included in the final analysis (Table 1). The three groups were similar in terms of vascular involvement (i.e. visual analogue scale severity for RP, presence of DUs, gangrene and pitting scars). Detailed information on treatment and comorbidities is available in supplementary Tables S2–S6, available at Rheumatology online. Table 1 Baseline demographics and disease characteristics of patients included in the final analysis Demographics and disease characteristics No i.v. ILO (group A, n = 35) I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Age, median (range), years 64.78 (20.49–82.55) 59.11 (35.1–76.27) 57.75 (22.46–79.18) Female 30 (85.71) 19 (90.48) 13 (81.25) Caucasian 35 (100) 21 (100) 15 (93.75) Disease subset: lcSSc 34 (97.14) 18 (85.71) 11 (68.75) RP duration, median (range), years 13.5 (2–38) 16 (3–58) 13 (1–25) Disease duration, median (range) 7 (1–31) 8 (2–24) 7.5 (0–18) VAS RP, median (range) 5 (0–9) 5 (0–8) 4.5 (0–9) Active smokers 5 (14.29) 1 (4.76) 5 (31.25) ANA 35 (100) 21 (100) 14 (93.33) Centromere pattern 23 (65.71) 8 (38.1) 5 (35.71) Anti-Scl70 11 (31.43) 9 (42.86) 8 (50) Clinical features     Heart involvement 3 (8.57) 4 (19.05) 2 (12.5)     Oesophageal involvement 14 (40) 16 (76.19) 12 (75)     Gastric involvement 0 (0) 1 (4.76) 0 (0)     Intestinal involvement 0 (0) 1 (4.76) 0 (0)     Interstitial lung disease 9 (25.71) 12 (57.14) 8 (50)     Pulmonary arterial hypertension 2 (5.71) 2 (9.52) 0 (0)     Scleroderma renal crisis 0 (0) 0 (0) 0 (0)     Myositis 0 (0) 0 (0) 1 (6.25)     History of arthritis 2 (5.71) 4 (19.05) 1 (6.25)     Calcinosis 6 (17.14) 9 (42.86) 6 (37.5)     Telangiectasia 25 (71.43) 16 (76.19) 11 (68.75)     Sclerodactitys 20 (57.14) 18 (85.71) 15 (93.75)     History of 1 DU 2 (5.71) 3 (14.29) 1 (6.25)     History of >1 DU 6 (17.14) 6 (28.57) 6 (37.5) Physical examination     DU 0 (0) 0 (0) 0 (0)     Gangrene 0 (0) 0 (0) 0 (0)     Pitting scars 8 (22.86) 10 (47.62) 8 (50)     Finger acral reabsorption 2 (5.71) 6 (28.57) 3 (18.75)     Skin score (median, min–max) 2 (0–13) 2 (0–8) 2 (0–21) Demographics and disease characteristics No i.v. ILO (group A, n = 35) I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Age, median (range), years 64.78 (20.49–82.55) 59.11 (35.1–76.27) 57.75 (22.46–79.18) Female 30 (85.71) 19 (90.48) 13 (81.25) Caucasian 35 (100) 21 (100) 15 (93.75) Disease subset: lcSSc 34 (97.14) 18 (85.71) 11 (68.75) RP duration, median (range), years 13.5 (2–38) 16 (3–58) 13 (1–25) Disease duration, median (range) 7 (1–31) 8 (2–24) 7.5 (0–18) VAS RP, median (range) 5 (0–9) 5 (0–8) 4.5 (0–9) Active smokers 5 (14.29) 1 (4.76) 5 (31.25) ANA 35 (100) 21 (100) 14 (93.33) Centromere pattern 23 (65.71) 8 (38.1) 5 (35.71) Anti-Scl70 11 (31.43) 9 (42.86) 8 (50) Clinical features     Heart involvement 3 (8.57) 4 (19.05) 2 (12.5)     Oesophageal involvement 14 (40) 16 (76.19) 12 (75)     Gastric involvement 0 (0) 1 (4.76) 0 (0)     Intestinal involvement 0 (0) 1 (4.76) 0 (0)     Interstitial lung disease 9 (25.71) 12 (57.14) 8 (50)     Pulmonary arterial hypertension 2 (5.71) 2 (9.52) 0 (0)     Scleroderma renal crisis 0 (0) 0 (0) 0 (0)     Myositis 0 (0) 0 (0) 1 (6.25)     History of arthritis 2 (5.71) 4 (19.05) 1 (6.25)     Calcinosis 6 (17.14) 9 (42.86) 6 (37.5)     Telangiectasia 25 (71.43) 16 (76.19) 11 (68.75)     Sclerodactitys 20 (57.14) 18 (85.71) 15 (93.75)     History of 1 DU 2 (5.71) 3 (14.29) 1 (6.25)     History of >1 DU 6 (17.14) 6 (28.57) 6 (37.5) Physical examination     DU 0 (0) 0 (0) 0 (0)     Gangrene 0 (0) 0 (0) 0 (0)     Pitting scars 8 (22.86) 10 (47.62) 8 (50)     Finger acral reabsorption 2 (5.71) 6 (28.57) 3 (18.75)     Skin score (median, min–max) 2 (0–13) 2 (0–8) 2 (0–21) Values are given as n (%) unless otherwise stated. ILO: iloprost; VAS: visual analogue scale; DU: digital ulcer. Table 1 Baseline demographics and disease characteristics of patients included in the final analysis Demographics and disease characteristics No i.v. ILO (group A, n = 35) I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Age, median (range), years 64.78 (20.49–82.55) 59.11 (35.1–76.27) 57.75 (22.46–79.18) Female 30 (85.71) 19 (90.48) 13 (81.25) Caucasian 35 (100) 21 (100) 15 (93.75) Disease subset: lcSSc 34 (97.14) 18 (85.71) 11 (68.75) RP duration, median (range), years 13.5 (2–38) 16 (3–58) 13 (1–25) Disease duration, median (range) 7 (1–31) 8 (2–24) 7.5 (0–18) VAS RP, median (range) 5 (0–9) 5 (0–8) 4.5 (0–9) Active smokers 5 (14.29) 1 (4.76) 5 (31.25) ANA 35 (100) 21 (100) 14 (93.33) Centromere pattern 23 (65.71) 8 (38.1) 5 (35.71) Anti-Scl70 11 (31.43) 9 (42.86) 8 (50) Clinical features     Heart involvement 3 (8.57) 4 (19.05) 2 (12.5)     Oesophageal involvement 14 (40) 16 (76.19) 12 (75)     Gastric involvement 0 (0) 1 (4.76) 0 (0)     Intestinal involvement 0 (0) 1 (4.76) 0 (0)     Interstitial lung disease 9 (25.71) 12 (57.14) 8 (50)     Pulmonary arterial hypertension 2 (5.71) 2 (9.52) 0 (0)     Scleroderma renal crisis 0 (0) 0 (0) 0 (0)     Myositis 0 (0) 0 (0) 1 (6.25)     History of arthritis 2 (5.71) 4 (19.05) 1 (6.25)     Calcinosis 6 (17.14) 9 (42.86) 6 (37.5)     Telangiectasia 25 (71.43) 16 (76.19) 11 (68.75)     Sclerodactitys 20 (57.14) 18 (85.71) 15 (93.75)     History of 1 DU 2 (5.71) 3 (14.29) 1 (6.25)     History of >1 DU 6 (17.14) 6 (28.57) 6 (37.5) Physical examination     DU 0 (0) 0 (0) 0 (0)     Gangrene 0 (0) 0 (0) 0 (0)     Pitting scars 8 (22.86) 10 (47.62) 8 (50)     Finger acral reabsorption 2 (5.71) 6 (28.57) 3 (18.75)     Skin score (median, min–max) 2 (0–13) 2 (0–8) 2 (0–21) Demographics and disease characteristics No i.v. ILO (group A, n = 35) I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Age, median (range), years 64.78 (20.49–82.55) 59.11 (35.1–76.27) 57.75 (22.46–79.18) Female 30 (85.71) 19 (90.48) 13 (81.25) Caucasian 35 (100) 21 (100) 15 (93.75) Disease subset: lcSSc 34 (97.14) 18 (85.71) 11 (68.75) RP duration, median (range), years 13.5 (2–38) 16 (3–58) 13 (1–25) Disease duration, median (range) 7 (1–31) 8 (2–24) 7.5 (0–18) VAS RP, median (range) 5 (0–9) 5 (0–8) 4.5 (0–9) Active smokers 5 (14.29) 1 (4.76) 5 (31.25) ANA 35 (100) 21 (100) 14 (93.33) Centromere pattern 23 (65.71) 8 (38.1) 5 (35.71) Anti-Scl70 11 (31.43) 9 (42.86) 8 (50) Clinical features     Heart involvement 3 (8.57) 4 (19.05) 2 (12.5)     Oesophageal involvement 14 (40) 16 (76.19) 12 (75)     Gastric involvement 0 (0) 1 (4.76) 0 (0)     Intestinal involvement 0 (0) 1 (4.76) 0 (0)     Interstitial lung disease 9 (25.71) 12 (57.14) 8 (50)     Pulmonary arterial hypertension 2 (5.71) 2 (9.52) 0 (0)     Scleroderma renal crisis 0 (0) 0 (0) 0 (0)     Myositis 0 (0) 0 (0) 1 (6.25)     History of arthritis 2 (5.71) 4 (19.05) 1 (6.25)     Calcinosis 6 (17.14) 9 (42.86) 6 (37.5)     Telangiectasia 25 (71.43) 16 (76.19) 11 (68.75)     Sclerodactitys 20 (57.14) 18 (85.71) 15 (93.75)     History of 1 DU 2 (5.71) 3 (14.29) 1 (6.25)     History of >1 DU 6 (17.14) 6 (28.57) 6 (37.5) Physical examination     DU 0 (0) 0 (0) 0 (0)     Gangrene 0 (0) 0 (0) 0 (0)     Pitting scars 8 (22.86) 10 (47.62) 8 (50)     Finger acral reabsorption 2 (5.71) 6 (28.57) 3 (18.75)     Skin score (median, min–max) 2 (0–13) 2 (0–8) 2 (0–21) Values are given as n (%) unless otherwise stated. ILO: iloprost; VAS: visual analogue scale; DU: digital ulcer. Acute effect of ILO infusion The results of the ordinal logistic regression and the linear regression models are reported in Table 2. In group B, a significant increase was observed in periungual vascularization (P < 0.001), FPBF (P < 0.001) and RI (P < 0.001). The acute effect of ILO was observed at every infusion from baseline throughout the whole follow-up period (Fig. 3). Table 2 Acute effect of i.v. ILO: pre- and post-first day and fifth day of infusion Power Doppler US and nailfold videocapillaroscopy parameters I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Pre- vs post-therapy first day Post-therapy first day vs post-therapy fifth day Power Doppler US     Finger pulp blood flow, OR (95% CI) 3.52 (2.18, 5.67) 2.63 (1.33, 5.19) 2.41 (1.17, 5.00)         P-value <0.001 0.005 0.017     Periungual vascularization OR (95% CI) 4.35 (2.66, 7.12) 1.56 (0.76, 3.18) 1.39 (0.65, 2.95)         P-value <0.001 0.225 0.396     Resistivity index mean difference (95% CI) 0.034 (0.021, 0.046) −0.009 (−0.029, 0.011) 0.032 (0.011, 0.052)         P-value <0.001 0.368 0.002 Nailfold videocapillaroscopy     Sum of capillaries width apex mean difference (95% CI) 9.803 (−7.117, 26.723) 11.267 (−12.986, 35.521) 16.381 (−8.117, 40.879)         P-value 0.257 0.364 0.192 Power Doppler US and nailfold videocapillaroscopy parameters I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Pre- vs post-therapy first day Post-therapy first day vs post-therapy fifth day Power Doppler US     Finger pulp blood flow, OR (95% CI) 3.52 (2.18, 5.67) 2.63 (1.33, 5.19) 2.41 (1.17, 5.00)         P-value <0.001 0.005 0.017     Periungual vascularization OR (95% CI) 4.35 (2.66, 7.12) 1.56 (0.76, 3.18) 1.39 (0.65, 2.95)         P-value <0.001 0.225 0.396     Resistivity index mean difference (95% CI) 0.034 (0.021, 0.046) −0.009 (−0.029, 0.011) 0.032 (0.011, 0.052)         P-value <0.001 0.368 0.002 Nailfold videocapillaroscopy     Sum of capillaries width apex mean difference (95% CI) 9.803 (−7.117, 26.723) 11.267 (−12.986, 35.521) 16.381 (−8.117, 40.879)         P-value 0.257 0.364 0.192 ILO: iloprost; OR: odds ratio. Table 2 Acute effect of i.v. ILO: pre- and post-first day and fifth day of infusion Power Doppler US and nailfold videocapillaroscopy parameters I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Pre- vs post-therapy first day Post-therapy first day vs post-therapy fifth day Power Doppler US     Finger pulp blood flow, OR (95% CI) 3.52 (2.18, 5.67) 2.63 (1.33, 5.19) 2.41 (1.17, 5.00)         P-value <0.001 0.005 0.017     Periungual vascularization OR (95% CI) 4.35 (2.66, 7.12) 1.56 (0.76, 3.18) 1.39 (0.65, 2.95)         P-value <0.001 0.225 0.396     Resistivity index mean difference (95% CI) 0.034 (0.021, 0.046) −0.009 (−0.029, 0.011) 0.032 (0.011, 0.052)         P-value <0.001 0.368 0.002 Nailfold videocapillaroscopy     Sum of capillaries width apex mean difference (95% CI) 9.803 (−7.117, 26.723) 11.267 (−12.986, 35.521) 16.381 (−8.117, 40.879)         P-value 0.257 0.364 0.192 Power Doppler US and nailfold videocapillaroscopy parameters I.v. ILO 1 monthly (group B, n = 21) I.v. ILO for 5 days every 3 months (group C, n = 16) Pre- vs post-therapy first day Post-therapy first day vs post-therapy fifth day Power Doppler US     Finger pulp blood flow, OR (95% CI) 3.52 (2.18, 5.67) 2.63 (1.33, 5.19) 2.41 (1.17, 5.00)         P-value <0.001 0.005 0.017     Periungual vascularization OR (95% CI) 4.35 (2.66, 7.12) 1.56 (0.76, 3.18) 1.39 (0.65, 2.95)         P-value <0.001 0.225 0.396     Resistivity index mean difference (95% CI) 0.034 (0.021, 0.046) −0.009 (−0.029, 0.011) 0.032 (0.011, 0.052)         P-value <0.001 0.368 0.002 Nailfold videocapillaroscopy     Sum of capillaries width apex mean difference (95% CI) 9.803 (−7.117, 26.723) 11.267 (−12.986, 35.521) 16.381 (−8.117, 40.879)         P-value 0.257 0.364 0.192 ILO: iloprost; OR: odds ratio. Fig. 3 View largeDownload slide Acute effect of i.v. iloprost demonstrated by PDUS and NVC PDUS: Power Doppler US; NVC: nailfold videocapillaroscopy. Fig. 3 View largeDownload slide Acute effect of i.v. iloprost demonstrated by PDUS and NVC PDUS: Power Doppler US; NVC: nailfold videocapillaroscopy. Similarly in group C, FPBF increased significantly 6 h after the therapy (P = 0.005) and a further increase was observed thereafter (P = 0.017). The same trend was observed for periungual vascularization, even though its increase was not statistically significant. RI increased significantly only after 5 days of therapy with respect to the end of the first day of therapy (P = 0.002). In both groups the sum of capillaries width apex was not different before and after infusion, although it is possible to observe a progressive trend (group B: P = 0.257 and group C: P = 0.364 after the first day of therapy and 0.192 after the fifth day of therapy). Distribution of PDUS parameters (FPBF, periungual vascularization and RI) and NVC (sum of capillaries width apex) measurements regarding the three groups before and after 6-h infusion are reported in supplementary Table S7, available at Rheumatology online. Chronic effect of ILO infusion No differences in imaging parameters (i.e. PDUS and NVC) were observed between baseline and before the last round of therapy in both groups of patients, suggesting that i.v. ILO effects cannot be maintained overtime (supplementary Table S8, available at Rheumatology online). Since allocation to groups was not performed randomly, a direct comparison between them cannot be conducted. However, two considerations can be drawn: at baseline patients not requiring i.v. ILO therapy tended to have a better grade of vascularization (FPBF and periungual vascularization); and patients requiring therapy, once treated with i.v. ILO, tended to be similar to those not treated and to show a better grade of vascularization compared with baseline, especially after 5 days of therapy. Percentages of patients, classified according to grade of FPBF and periungual vascularization, are shown in Fig. 4. Fig. 4 View largeDownload slide Changes of PDUS parameters over time Finger pulp blood flow (A) and periungual vascularization (B) at T0: baseline; T1: 1 month follow-up; T2: 2 months follow-up; T3: 3 months follow-up. PDUS: Power Doppler US. Fig. 4 View largeDownload slide Changes of PDUS parameters over time Finger pulp blood flow (A) and periungual vascularization (B) at T0: baseline; T1: 1 month follow-up; T2: 2 months follow-up; T3: 3 months follow-up. PDUS: Power Doppler US. Temperature effect Finally, we studied whether outdoor temperature was able to affect treatment response assessed by PDUS. In particular, in group A the difference in RI between baseline and after 3 months tended towards increasing concurrently with the reduction of temperature; moreover, taking into account the acute effect of ILO, FPBF increased in group B and RI increased in group C concurrently with the decrease of outdoor temperature. By contrast, outdoor temperature did not have an impact on chronic effect in the two treatment groups. Discussion I.v. ILO is currently used to treat RP and DU secondary to SSc, even though no precise indications about the regimen have been suggested. Moreover, according to some authors, i.v. ILO, based on its biological properties, might play a role as a DMARD [25]. In our clinical practice we propose i.v. ILO to SSc patients with RP not adequately controlled by oral therapy (i.e. calcium channel blockers) or with DU. Patients can choose between two different regimens (once monthly or 5 consecutive days every 3 months) according to their own preferences and needs. I.v. ILO therapy was able to cause an acute effect with respect to the PDUS parameters considered. The acute effect was statistically significant in group B, while in group C statistical significance was not reached for all the parameters. On the contrary, the i.v. ILO effect observed immediately after the infusion was no longer detectable before the following infusion. This means that the acute effect, as assessed by PDUS, is not maintained over time until the next infusion. These data support the need for further studies to understand the optimal timing of the retreatment strategy. Since this study was a non-interventional pragmatic study, a direct comparison between treatment groups was not feasible. Despite this consideration, patients receiving i.v. ILO showed at baseline worse levels of peripheral vascularization (PDUS and periungual vascularization) compared with patients not requiring i.v. ILO. The opportunity for discontinuing i.v. ILO therapy during summer is a subject of ongoing debate. In our study the outdoor temperature was able to inversely influence the acute response to ILO therapy for some of the PDUS parameters considered. These results might support a rationale for i.v. ILO summertime suspension even though we performed the study during the autumn–winter period, and some studies have suggested the opposite [26]. Future studies are needed to assess how long i.v. ILO effects last and to assess the best i.v. ILO regimens. Moreover, it is of fundamental importance to validate the imaging parameters to monitor the therapeutic effects. Acknowledgements We thank Meteo Operations Italia SrL—Centro Epson Meteo, Cinisello Balsamo, Italy for kindly providing temperature data. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 Denton CP , Khanna D. Systemic sclerosis . Lancet 2017 ; 390 : 1685 – 99 . Google Scholar CrossRef Search ADS PubMed 2 Matucci-Cerinic M , Kahaleh B , Wigley FM. Review: evidence that systemic sclerosis is a vascular disease . Arthritis Rheum 2013 ; 65 : 1953 – 62 . Google Scholar CrossRef Search ADS PubMed 3 Hachulla E , Clerson P , Launay D et al. Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study . J Rheumatol 2007 ; 34 : 2423 – 30 . Google Scholar PubMed 4 Kowal-Bielecka O , Fransen J , Avouac J et al. Update of EULAR recommendations for the treatment of systemic sclerosis . Ann Rheum Dis 2017 ; 76 : 1327 – 39 . Google Scholar CrossRef Search ADS PubMed 5 Wigley FM , Wise RA , Seibold JR et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study . Ann Int Med 1994 ; 120 : 199 – 206 . Google Scholar CrossRef Search ADS PubMed 6 Bellando-Randone S , Bruni C , Lepri G et al. The safety of iloprost in systemic sclerosis in a real-life experience . Clin Rheumatol 2018 ; 37 : 1249 – 1255 . Google Scholar CrossRef Search ADS PubMed 7 Fraticelli P , Martino GP , Murri M , Mattioli M , Gabrielli A. A novel iloprost administration method with portable syringe pump for the treatment of acral ulcers and Raynaud's phenomenon in systemic sclerosis patients. A pilot study (ILOPORTA) . Clin Exp Rheumatol 2017 ; 35(Suppl 106) : 173 – 8 . Google Scholar PubMed 8 Rotondo C , Nivuori M , Chialà A et al. Evidence for increase in finger blood flow, evaluated by laser Doppler flowmetry, following iloprost infusion in patients with systemic sclerosis: a week-long observational longitudinal study . Scand J Rheumatol 2018 ; 7 : 1 – 8 . 9 Trombetta AC , Pizzorni C , Ruaro B et al. Effects of longterm treatment with Bosentan and iloprost on nailfold absolute capillary number, fingertip blood perfusion, and clinical status in systemic sclerosis . J Rheumatol 2016 ; 43 : 2033 – 41 . Google Scholar CrossRef Search ADS PubMed 10 Lescoat A , Coiffier G , de Carlan M et al. Combination of capillaroscopic and ultrasonographic evaluations in systemic sclerosis: results of a cross-sectional study . Arthritis Care Res 2017 ; doi: 10.1002/acr.23413. 11 Lescoat A , Coiffier G , Rouil A et al. 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 . Arthritis Care Res 2017 ; 69 : 543 – 51 . Google Scholar CrossRef Search ADS 12 Bregenzer N , Distler O , Meyringer R et al. Doppler ultrasound identifies increased resistive indices in SSc . Ann Rheum Dis 2004 ; 63 : 109 – 10 . Google Scholar CrossRef Search ADS PubMed 13 Keberle M , Tony HP , Hau M et al. Colour Doppler ultrasound of the nailbed: an objective tool for monitoring responses to vasodilatory treatment of connective tissue disorders? Rheumatology (Oxford) 2001 ; 40 : 954 – 5 . Google Scholar CrossRef Search ADS PubMed 14 Cutolo M , Ferrone C , Pizzorni C et al. Peripheral blood perfusion correlates with microvascular abnormalities in systemic sclerosis: a laser-Doppler and nailfold videocapillaroscopy study . J Rheumatol 2010 ; 37 : 1174 – 80 . Google Scholar CrossRef Search ADS PubMed 15 Cutolo M , Ruaro B , Pizzorni C et al. Longterm treatment with endothelin receptor antagonist bosentan and iloprost improves fingertip blood perfusion in systemic sclerosis . J Rheumatol 2014 ; 41 : 881 – 6 . Google Scholar CrossRef Search ADS PubMed 16 Ingegnoli F , Ughi N , Dinsdale G et al. An international SUrvey on non-iNvaSive tecHniques to assess the mIcrocirculation in patients with RayNaud's phEnomenon (SUNSHINE survey) . Rheumatol Int 2017 ; 37 : 1879 – 90 . Google Scholar CrossRef Search ADS PubMed 17 Ford I , Norrie J. Pragmatic trials . N Engl J Med 2016 ; 375 : 454 – 63 . Google Scholar CrossRef Search ADS PubMed 18 Biasi D , Carletto A , Caramaschi P et al. Iloprost as cyclic five-day infusions in the treatment of scleroderma. An open pilot study in 20 patients treated for one year . Rev Rhum Engl Ed 1998 ; 65 : 745 – 50 . Google Scholar PubMed 19 Caramaschi P , Martinelli N , Volpe A et al. A score of risk factors associated with ischemic digital ulcers in patients affected by systemic sclerosis treated with iloprost . Clin Rheumatol 2009 ; 28 : 807 – 13 . Google Scholar CrossRef Search ADS PubMed 20 van den Hoogen F , Khanna D , Fransen J et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative . Arthritis Rheum 2013 ; 65 : 2737 – 47 . Google Scholar CrossRef Search ADS PubMed 21 Newman JS , Laing TJ , McCarthy CJ , Adler RS. Power Doppler sonography of synovitis: assessment of therapeutic response–preliminary observations . Radiology 1996 ; 198 : 582 – 4 . Google Scholar CrossRef Search ADS PubMed 22 Ingegnoli F , Gualtierotti R , Lubatti C et al. Nailfold capillary patterns in healthy subjects: a real issue in capillaroscopy . Microvasc Res 2013 ; 90 : 90 – 5 . Google Scholar CrossRef Search ADS PubMed 23 Cutolo M , Pizzorni C , Tuccio M et al. Nailfold videocapillaroscopic patterns and serum autoantibodies in systemic sclerosis . Rheumatology (Oxford) 2004 ; 43 : 719 – 26 . Google Scholar CrossRef Search ADS PubMed 24 Etehad Tavakol M , Fatemi A , Karbalaie A , Emrani Z , Erlandsson BE. Nailfold capillaroscopy in rheumatic diseases: which parameters should be evaluated? Biomed Res Int 2015 ; 2015 : 974530 . Google Scholar CrossRef Search ADS PubMed 25 Airo P , Rossi M , Scarsi M et al. Disease-modifying effects of long-term cyclic iloprost therapy in systemic sclerosis. A retrospective analysis and comparison with a control group . Clin Exp Rheumatol 2007 ; 25 : 722 – 7 . Google Scholar PubMed 26 Auriemma M , Vianale G , Reale M et al. Iloprost treatment summer-suspension: effects on skin thermal properties and cytokine profile in systemic sclerosis patients. G Ital Dermatol Venereol 2013 ; 148 : 209 – 16 . © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

RheumatologyOxford University Press

Published: May 3, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off