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Infusion of Iloprost, a Prostacyclin Analogue, for Treatment of Raynaud's Phenomenon in Systemic Sclerosis

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Infusion of Iloprost, a Prostacyclin Analogue, for Treatment of Raynaud's Phenomenon in Systemic Sclerosis Ann Rheum Dis: first published as 10.1136/ard.47.1.43 on 1 January 1988. Downloaded from Annals of the Rheumatic Diseases, 1988; 47, 43-47 Infusion of Iloprost, a prostacyclin analogue, for treatment of Raynaud's phenomenon in systemic sclerosis N J McHUGH,' M CSUKA,2 H WATSON,3 G BELCHER,3 A AMADI,' E F J RING,' C M BLACK,2 AND P J MADDISON' From the 'Royal National Hospital for Rheum?latic Diseases, Bath; the 2West Middlesex Hospital, Isleworth, Middlesex; and -Schering Health Care Ltd, West Sulssex, UK SUMMARY Iloprost, a stable prostacyclin analogue, was given by intravenous infusion to 29 patients with severe Raynaud's phenomenon, 26 of whom had systemic sclerosis (SS), and compared with placebo infusion in a double blind crossover trial. Iloprost significantly lessened the number and the severity of attacks compared with placebo. Nine patients expressed a preference for effectiveness of treatment, eight of these in favour of Iloprost. Thermography failed to show any long term effect of Iloprost. Side effects of headache, flushing, nausea, and vomiting were common, and the inconvenience of intravenous administration may limit its routine use. copyright. Severe Raynaud's phenomenon is often the most double blind crossover trial. As symptomatic im- troublesome manifestation of SS and is difficult to provement of Raynaud's phenomenon has been treat successfully. Increased platelet activation may shown to correlate well with thermographic im- be a factor in its causation. ' The use of prostanoids, provement,8 measurement of digital temperature prostaglandin E,2 and prostacyclin,3 which are gradients by thermography was included in the potent vasodilators and inhibit platelet aggregation, study. http://ard.bmj.com/ has been shown to alleviate symptoms in many patients. Rapid metabolism in vivo, however, may Patients and methods limit their therapeutic potential. Iloprost is a chemi- cally stable carbacyclin derivative of prostacyclin Twenty nine patients (25 female, four male) with severe all at least with a half life exceeding that of prostacyclin by a Raynaud's phenomenon, suffering 12 attacks per week, were recruited for the study factor of 10.) It has been shown to be more potent conducted the winter to than prostacyclin as an antiplatelet agent but in- during months, January May 1986. Twenty six patients had PSS and three on September 24, 2021 by guest. Protected duces less vasodilatation.6 It inhibits platelet aggre- 'idiopathic' Raynaud's phenomenon (Table 1). gation in patients with progressive systemic sclerosis Patients were allocated to receive either (PSS) when given by a five hour intravenous randomly infusion.7 Iloprost or placebo infusion in a double blind crossover trial. Each treatment consisted of three A pilot study using Iloprost infusion in 12 patients six-hour infusions of Iloprost or placebo on three with secondary Raynaud's phenomenon showed successive days with six weeks between treatment improvement in symptoms and an increase in digital periods. The medication consisted of Iloprost blood flow for up to five weeks after therapy (ZK 36374) or placebo administered through a (unpublished data). We chose to assess the effec- peripheral venous cannula via a syringe pump tiveness of Iloprost compared with placebo in a controller. The dose of Iloprost was 2-0 ng/kg/min larger number of patients with severe Raynaud's and could be reduced by increments of 0-5 nglkglmin phenomenon secondary to PSS in a randomised dependent upon the tolerance of the patients to the side effects associated with the infusions. Accepted for publication 22 June 1987. Correspondence to Dr N J McHugh. Royal National Hospital for ASSESSMENTS Rheumatic Diseases. Upper Borough Walls. Bath BAI IRL. Assessments were made one day before treatment 43 Ann Rheum Dis: first published as 10.1136/ard.47.1.43 on 1 January 1988. Downloaded from 44 McHugh, Csuka, Watson, Belcher, Amadi, Ring, Black, Maddison and one day, two weeks, and six weeks after each received placebo first (Table 1). Twenty six patients treatment. Patients kept diary cards the week before fulfilled American Rheumatism Association criteria the first treatment and over the 12 week study for SS." Of these, 14 had at least four features of period. Patients recorded the date, the duration, the 'CREST' variant of SS, with anticentromere and the severity on a scale of 1-3 for each Raynaud's antibodies detected in the serum of six, and two attack they suffered as well as whether the attack patients had overlap features of mixed connective was painful or painless. For the purposes of analysis tissue disease (MCTD) with serum containing anti- a painless attack was given a score of 1 and a painful UlRNP. Three additional patients had severe attack a score of 2. At each assessment the patient Raynaud's phenomenon without evidence of under- reported any change in his or her condition and at lying connective tissue disease, though the serum the end of the study the effectiveness of both from one of these patients contained anti-Scl-70. treatments. Active lesions present on hands and feet Twenty five out of 29 patients completed the full were recorded at each assessment. treatment. Four patients withdrew for coincidental medical or social problems, three not being associ- THERMOGRAPHY ated with therapy. Thermography was performed at each assessment as previously described.9 For each scan the mean DIARY CARD DATA temperature of the dorsal hand and fingers was Twenty out of 25 patients who completed the study recorded with a Heimann KT41 infrared radiometer maintained their diaries regularly and accurately positioned 2 cm from the skin, or by infrared enough for them to be analysed. There were no thermography (AGA 782) and the values calculated significant differences in the baseline diary card data by image processing using a computer and video between the two treatment groups (Table 2). display. These measurements were repeated 10 minutes after cold stress. By subtracting the values Table 1 Details ofpatients randomly assigned to treatment of the temperature of the distal phalanges from the groups copyright. dorsum of the hand a thermal gradient was obtained. Thermal gradients for resting conditions (pre-cold All Iloprost Placebo stress) and for after cold stress (post-cold stress) patients first first were obtained. A combined thermal gradient was Mean age (years) 56-6 54-7 58.6 also derived by adding the pre- and post-cold stress Women 25 13 12 measurements. Men 4 2 2 PSS 26 13 13 CREST* 14 6 8 http://ard.bmj.com/ STATISTICAL METHODS non-CREST 10 6 4 The study was analysed by the method of Hills and MCTD* 2 1 1 Armitage " using the Van der Waerden test, the sign Primary Raynaud's disease 3 2 1 ANA positive* 24 12 12 test, and the x2 test. ACA positive* 7 3 4 Years since onset of Results Raynaud's disease 11-1 9-6 12-6 DEMOGRAPHIC DATA *CREST=calcinosis, Raynaud's phenomenon, oesophageal dys- on September 24, 2021 by guest. Protected motility, sclerodactyly, telangiectasia; MCTD=mixed connectivc There were no significant differences between the tissue disease; ANA=antinuclear antibody; ACA=anticentromere group who received Iloprost first and the group who antibody. Table 2 Comparison of the effects of Iloprost and placebo on the mean percentage change from baseline for number, duration, severity, and proportion of painful attacks of Raynaud's disease for weeks 2-6 of the study Treatment order Probabilities l,P* P.l Treatmentxperiod Treatment Period (n=11) (n =9J No of attacks a week -40-9 (17-7)t -13-5 (14-7) 0-31 0-035 0-40 Duration (min) -48-7 (83-1) -29-0 (30-2) 0-94 0-19 0-85 Severity (1-3) -17-0 (1-89) -24-9 (1-86) 0-08 0-013 056 Pain (1-2) -2-7 (1-48) -13-6 (1-47) 0-26 0-29 0-36 *I=Ik)prost; P=placebo. tValues are means (I-P) with absolute baseline values given in parentheses. Ann Rheum Dis: first published as 10.1136/ard.47.1.43 on 1 January 1988. Downloaded from Iloprost for treatment of Raynaud's phenomenon in systemic sclerosis 45 Table 2 shows the percentage change from base- 20 line for number, duration, severity, and proportion of painful attacks, comparing placebo and Iloprost for the two groups receiving either Iloprost or placebo first. A negative sign indicates greater 0) benefit from Iloprost than from placebo. Probabili- co O ties are given for a treatment period interaction (e.g., hangover effect of the drug beyond six weeks of the single drug effect), a treatment effect (i.e., a.008 -10 one treatment more effective than another), and period effects (i.e., the first or second period more -20 effective than the other, independent of the drug treatment). Week 1 after treatment was excluded from the analysis as there was a significant period -30 effect. 1 2 3 4 5 6 Iloprost was significantly more effective than weeks placebo in reducing the number of attacks Fig. 2 Percentage change in the severity ofattacks of (p=0035) and the severity of attacks (p=0-013) of Raynaud's disease for six weeks after three infusions of Raynaud's phenomenon for weeks 2-6 after treat- Iloprost or placebo (values were calculated combining ment, and this trend was shown throughout the results from the two periods ofthe crossover study). study period. The duration of attacks in general was reduced more by Iloprost than placebo, though this The proportion of painful attacks was reduced by only reached statistical significance at week 5 after 16% with Iloprost compared with 11% with treatment. No difference between Iloprost and placebo. placebo was shown in the proportion of painful copyright.
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