Nifedipine vs Plcebo for Tretment of Chronic Chilblins: A Rndomized Controlled Tril Ibo H. Souwer, MD 1 Jcobus H. J. Bor, BSc (Mth) 2 Pul Smits, MD, PhD 3 Antoine L. M. Lgro-Jnssen, MD, PhD 1 1 Deprtment of Primry nd Community Cre, Unit Gender nd Women s Helth, Rdboud University Medicl Center, Nijmegen, The Netherlnds 2 Deprtment of Primry nd Community Cre, Rdboud University Medicl Center, Nijmegen, The Netherlnds 3 Deprtment of Phrmcology nd Toxicology, Rdboud University Medicl Center, Nijmegen, The Netherlnds ABSTRACT PURPOSE Nifedipine is commonly prescribed for the tretment of chilblins (pernio, perniosis) on the bsis of observtionl studies nd single smll, older clinicl tril. We imed to confirm the proposed superiority of orl nifedipine 60 mg per dy over plcebo for tretment of chronic chilblins in primry cre. METHODS We performed rndomized, plcebo-controlled, double-blind, crossover tril, closely following the design of the older tril. A totl of 32 ptients with chronic chilblins were rndomly ssigned to nifedipine (30 mg controlled relese twice dy) or plcebo. The primry outcome ws ptient-reported complints; the secondry outcome ws ptient-reported disbility. Both were ssessed from dily rtings on 100-mm visul nlogue scles recorded in diry. We took mbient tempertures into ccount nd checked for crry-over effect, nd monitored for dverse effects. RESULTS After 6 weeks of tretment, men scores on the visul nlogue scle on complints showed nonsignificnt difference of 1.84 mm (95% CI, 6.67 to 2.99 mm) in fvor of nifedipine (P =.44). Men scores on the visul nlogue scle on disbility showed nonsignificnt difference of 0.56 mm (95% CI, 2.97 to 4.09 mm) in fvor of plcebo (P =.75). There ws no crry-over effect of prior study tretment. Nifedipine ws ssocited with significntly lower systolic blood pressure nd significntly higher incidence of edem. CONCLUSIONS In our study, nifedipine ws not superior to plcebo for treting chronic chilblins. These findings contrst with those of the older study nd do not support routine use of nifedipine for this condition. Ann Fm Med 2016;14:453-459. doi: 10.1370/fm.1966. Conflicts of interest: uthors report none. CORRESPONDING AUTHOR Ibo H. Souwer, MD Rdboud University Medicl Center Unit Gender nd Women s Helth Deprtment of Primry nd Community Cre Internl Post Code 118 PO Box 9101 6500 HB Nijmegen The Netherlnds i.souwer@wxs.nl INTRODUCTION Chilblins (pernio, perniosis) re cold-induced, pinful or itching lesions on the fingers, feet, ers, or thighs. The condition occurs throughout the world during the winter months when dily men tempertures drop below the rnge of 12 o C to 15 o C. 1 The prevlence in the Netherlnds s reported by the Netherlnds Institute for Helth Services Reserch (NIVEL) vries between 0.9 per 1,000 nd 1.7 per 1,000 depending on yer-to-yer vrition nd coding issues. The condition is more common mong women thn men, with respective prevlences of 0.9 to 2.1 per 1,000 vs 0.6 to 1.2 per 1,000 (written informtion provided by NIVEL). Ptients with chilblins report serious restrictions in dily life nd feel n urgent need for effective tretment. 2 A review of the literture through Mrch 15, 2016 reveled evidence tht vitmin D 3, corticosteroidcontining crem, nifedipine, nd pentoxyfylline, mong wide rnge of other therpies, re used to tret symptoms of chronic chilblins. 3,4 In n erlier study, we found tht vitmin D 3 ws not superior to plcebo, however. 5 Five studies evluting the effectiveness of nifedipine in ptients with chilblins hve been published nd hve concluded tht the drug is n effective tretment. These studies included only 1 rndomized controlled tril, hving 10 ptients nd conducted in 1989, compred 453
nifedipine with plcebo. 6 The others pilot cse study with 10 ptients, cse series with 34 ptients, rndomized tril compring diltizem with nifedipine in 34 ptients, nd study compring nifedipine with topicl minoxidil in 62 ptients were not plcebo controlled. 6-8 Physicins nd ptients re commonly dvised to consider the prescription of nifedipine for the tretment of chronic chilblins. 9-13 This dvice finds support in proposed disese mechnism for chilblins (ie, cold-induced vsospsm 9,14,15 ) nd in the results of the 5 studies previously described. 6-8 Current discussion in the field regrding the relibility nd reproducibility of these studies hs clled into question the soundness of the bsis for the dvice, however. 16 We undertook tril to confirm the proposed superiority of orl dministrtion of nifedipine 60 mg per dy compred with plcebo for the tretment of chronic chilblins in primry cre setting. METHODS Tril Design Following the methodology of the originl study by Rustin et l, 6 we conducted 13-week rndomized, double-blind, plcebo-controlled, cross-over tril. 6 A wshout period ws not incorported in the design for 3 resons. First, the originl tril did not include wshout period. Second, for obvious resons, the study hd to be completed during the winter months; wshout period would hve resulted in too long reserch period per ptient nd problems with higher mbient tempertures in spring. Third, the exct mechnism of the proposed effect of nifedipine is uncler, so the necessry durtion of wshout period is uncertin. Insted of using wshout period, we smpled the lst week of every 6-week tretment phse nd checked for possible crry-over effect. Prticipnts The study popultion consisted of consecutively enrolled ptients with chronic chilblins during the winters of 2010 to 2012. Ptients volunteered fter being informed of the tril by their primry cre physicin during consulttion. Ptients were eligible for the tril if they were ged 18 yers or older nd reported symptoms of chronic chilblins tht hd lsted t lest 3 weeks. The dignosis ws confirmed by n uthor (I.H.S.) bsed on commonly used dignostic criteri: symptoms emerging in the winter months with itching nd/or pinful purpleblue discolored lesions in ny of severl loctions (fingers, toes, feet, or lterl thigh) without history of persistence into the summer months. 1,9 Swelling nd ulcertion, nd reporting of erlier episodes in previous winters could lso be present but were not mndtory for dignosis. The vlidity of dignosis by this uthor hs previously been demonstrted. 5 We excluded ptients who hd known rheumtologic disorder, were lredy using nifedipine or nother clcium chnnel blocker, were pregnnt or lctting, or hd contrindictions to use of nifedipine. Our smple size clcultion ws bsed on the following premises relted to the visul nlogue scle (VAS) used for the tril s primry outcome. Specificlly, in n erlier study, 5 we observed bseline visul nlogue scle on complints (VOC) score of 27.97 mm (SD 18.82) in similr popultion. We used n estimte of 0.5 for the correltion between 2 scores from the sme ptient on 2 occsions. 5 We considered the tretment effect to be cliniclly relevnt if ptients experienced decrese in the VOC score of t lest 10 mm. On the bsis of use of t test for the difference between 2 dependent mens, 1-til testing, n α of 0.05, nd β of 0.10 (power of 90%), we clculted tht we would need minimum of 32 prticipnts for the tril. Procedures The intervention consisted of orl dministrtion of 30 mg nifedipine controlled relese once dy for 2 weeks followed by 30 mg nifedipine twice dy for nother 4 weeks. The reserch mediction ws produced nd certified under project number AKF 1720 by the Deprtment of Phrmcy nd Clinicl Phrmcology, Rdboud University Medicl Center, Nijmegen, The Netherlnds. The phrmcy tht produced the reserch mediction used block rndomiztion with block size of 10 to ssign ptients to 2 rms tht differed with respect to the order of tretments: plcebo first or nifedipine first. Both reserch personnel nd ptients were blinded to rm ssignment. Blinding ws ensured by use of indistinguishble cpsules for ctive mediction nd inctive plcebo. Consecutively enrolled ptients received mediction sets with consecutive therpy numbers. The phrmcy relesed the rndomiztion key only fter the lst ptient hd left the study. In the plcebo-first rm, ptients received no mediction for 1 week to collect bseline dt (phse 0), followed by use of plcebo once dy for 2 weeks, followed by use of plcebo twice dy for 4 weeks (phse 1), followed by nifedipine 30 mg controlled relese once dy for 2 weeks, followed by nifedipine 30 mg controlled relese twice dy for 4 weeks (phse 2). In the nifedipine-first rm, ptients received no mediction for 1 week to collect bseline dt (phse 0), followed by nifedipine 30 mg controlled relese once dy for 2 weeks, followed by nifedipine 30 mg controlled relese 454
twice dy for 4 weeks (phse 1), followed by use of plcebo once dy for 2 weeks, followed by use of plcebo twice dy for 4 weeks (phse 2). Ech dy, we documented the men mbient temperture provided by the Royl Netherlnds Meteorologicl Institute. Ptients used diry to score the presence nd severity of itch, pin, nd disbility using the VAS dily throughout the full reserch period, s described below. Investigtors hd 6 fce-to-fce contcts with ptients: t intke nd t the end of weeks 1, 3, 7, 9, nd 13. During these contcts, the investigtors checked diries for completeness, ssessed therpy complince by counting cpsules, nd documented remining lesions. The Dutch Competent Authority (NL31484.091.10 BI) nd the Medicl Reserch Ethics Committee CMO Arnhem-Nijmegen (CMO dossier number 2010/240) grnted permission for this study. nd ulcertion on 100-mm VAS. We lso monitored for dverse effects unfvorble chnges in blood pressure reding nd in scores for hedche, dizziness, nd peripherl edem on 100-mm VAS t ech of these contcts. Sttisticl Anlysis We used modified intention-to-tret nlysis, including dt only of ptients who begn the study. We performed nlysis of the primry nd secondry ptientreported outcomes using the 2-stge model originlly proposed by Grizzle 17 nd more recently reviewed, 18 correcting for temperture chnges during the reserch period for ech ptient with mixed effects model (Grizzle model using the mixed procedure with rndom effect, SAS PROC MIXED, SAS version 9.2; SAS Institute Inc). Investigtor-ssessed outcomes nd dverse effects were nlyzed using 2-smple pired t tests. Outcomes The tril s primry nd secondry outcomes were ptient-reported complints (symptoms) nd disbility, respectively, ssessed with VAS hving 100- mm rnges. Ptients rted these outcomes dily nd recorded their rtings in diries. The primry outcome ws the difference in score on the VOC between nifedipine nd plcebo fter 6 weeks of tretment. Ptients rted pin nd itch seprtely; we used the higher of these 2 scores t the time of reporting. The VOC score ws clculted s the men vlue for the lst 7 dys of the 6-week tretment period. Higher scores indicted greter pin or itch. The secondry outcome Enrollment ws the difference in score on the visul nlogue scle on disbility (VOD) between nifedipine nd plcebo fter 6 weeks of tretment. For this outcome, ptients rted their bility to function normlly in dily life. The VOD score ws lso clculted s the men vlue of Rndomiztion the lst 7 dys of the tretment period. Higher scores indicted greter disbility. To follow the design of the originl study 6 Follow-up s closely s possible, investigtors ssessed the chilblin lesions during fce-to-fce contcts nd rted Anlysis redness, purpleness, edem, RESULTS Ptient Chrcteristics The procedure used to ssess nd enroll ptients is shown in Figure 1. Dt for 32 ptients (18 women nd 14 men) were vilble for nlysis, nd their bseline chrcteristics re shown in Tble 1. The ptients hd men ge of 53 yers (SD 16.1). The men durtion of symptoms t intke ws 6.5 weeks (SD 3.6). At bseline, the men score on the VOC scle ws 24.92 mm (95% Figure 1. Flowchrt of ptients in the tril. 18 ptients ssigned to plcebo-first rm 17 ptients received ssigned intervention 42 ptients ssessed for eligibility 37 ptients rndomized 5 ptients met exclusion criteri 19 ptients ssigned to nifedipine-first rm 15 ptients received ssigned intervention 0 ptients lost to follow-up 0 ptients lost to follow-up 17 ptients nlyzed 15 ptients nlyzed 455
CI, 21.70-28.13) nd the men score on the VOD scle ws 16.11 mm (95% CI, 13.09-19.13). Eleven ptients hd possibly relevnt comorbidities, 6 smoked, nd 9 used potentilly relevnt drugs. Our cpsule counts indicted tht ptients did not tke 502 cpsules (11%) of the 4,480 they hd been ssigned to tke. Diries were conscientiously completed. No fce-to-fce contcts were missed. We did not find ny missing dt for the ptientreported primry nd secondry outcomes or for dverse effects. One ssessment for our investigtorssessed outcomes ws missing, representing 4 VAS scores out of 384 to be nlyzed; we did not replce these missing dt. Primry nd Secondry Outcomes Figure 2 shows the plots of men VOC nd VOD scores per week, not corrected for temperture, in ech rm nd study phse. The men VOC score t 6 weeks of tretment ws 11.44 mm (95% CI, 6.12-16.75 mm) with nifedipine tretment nd 13.28 mm (95% CI, 7.96-18.59 mm) with Tble 1. Ptient Chrcteristics t Bseline Chrcteristic Plcebo-First (n = 17) CHRONIC CHILBLAINS Nifedipine-First (n = 15) Age, men, y 50 59 Sex Women, No. 8 10 Men, No. 9 5 Chilblin symptoms Men durtion t intke, wk 7 6 Experiencing first episode, No. 2 2 Experienced >1 episode, No. 4 4 Experiences episode every yer, No. 12 10 Men VOC score, mm,b 25 24 Men VOD score, mm b 17 15 Smoking, No. 3 3 Comorbidity Dibetes, No. 0 1 Peripherl rteril disese, No. 1 0 Rynud phenomenon, No. 6 3 Relevnt mediction use β-blocker, No. 0 0 Nicotine replcement drug, No. 0 0 Acetylslicylic cid, No. 0 1 ACE or ngiotensin II receptor blocker, No. 3 2 ACE = ngiotensin-converting enzyme; VOC = visul nlogue scle on complints; VOD = visul nlogue scle on disbility. The higher of either the visul nlogue scle itch score or the visul nlogue scle pin score. b Scores mesured on 100-mm scles where higher vlues indicte more complints (symptoms) or greter disbility. plcebo tretment (Tble 2). This resulted in difference between rms of 1.84 mm (95% CI, 6.67 to 2.99 mm) in fvor of nifedipine (P =.44). The men VOD score t 6 weeks of tretment ws 4.65 mm (95% CI, 1.65-7.65 mm) with nifedipine tretment nd 4.09 mm (95% CI, 10.9-7.09 mm) with plcebo tretment. This resulted in difference between rms of 0.56 mm (95% CI, 2.97 to 4.09 mm) in fvor of plcebo (P =.75). Crry-Over Effect Results of nlyses ssessing ny crry-over effect on the primry outcome re shown in Tble 2. The men VOC score t 6 weeks of tretment ws 14.07 mm (95% CI, 7.16-20.98 mm) in the rm given plcebo first nd 10.46 mm (95% CI, 4.16-17.14 mm) in the rm given nifedipine first. This resulted in nonsignificnt difference between rms of 3.43 mm (95% CI, 6.08 to 12.93 mm) in fvor of the nifedipine-first rm (P =.47), indicting no crry-over effect. Results of nlyses ssessing ny crry-over effect on the secondry outcome re shown in Tble 3. The men VOD score t 6 weeks of tretment ws 4.95 mm (95% CI, 1.40-8.50 mm) in the plcebo-first rm nd 3.97 mm (95% CI, 0.46-7.12 mm) in the nifedipine-first rm. This resulted in nonsignificnt difference between rms of 1.17 mm (95% CI, 3.72 to 6.05 mm) in fvor of the nifedipine-first rm (P =.63), lso indicting no crry-over effect. Investigtor-Assessed Outcomes We found no sttisticlly significnt differences between nifedipine nd plcebo for investigtor-ssessed redness or purpleness, edem, or ulcertion fter 6 weeks of tretment (Tble 3). Adverse Effects Men systolic blood pressure ws 134.5 mm Hg fter 6 weeks of nifedipine use nd 147.1 mm Hg fter 6 weeks of plcebo use (Tble 4). The men difference ws 13.1 mm Hg (95% CI, 24.1 to 2.0 mm Hg), which ws sttisticlly significnt (P =.02). The men ssessed peripherl edem score on the VAS ws 12.1 mm fter 6 weeks of nifedipine use nd 2.5 mm fter 6 weeks of plcebo use. The men difference ws 9.6 mm (95% CI, 1.1-18.1 mm), which ws lso sttisticlly significnt (P =.03). Hedche nd dizziness did not differ significntly between nifedipine nd plcebo fter 6 weeks of tretment (Tble 4). 456
Figure 2. Ptient-reported scores for complints (VOC) nd disbility VOD (not corrected for temperture) for ech rm nd study phse. VAS Score, mm 30 25 20 15 10 5 0 Tble 2. Primry nd Secondry Outcomes Corrected for Differences in Ambient Temperture Outcome VOC Plcebo-first rm VOD Plcebo-first rm VOC Nifedipine-first rm VOD Nifedipine-first rm Phse 0 1 2 1 2 3 4 5 6 VAS = visul nlogue scle; VOC = visul nlogue scle on complints; VOD = visul nlogue scle on disbility. Notes: Scores mesured on 100-mm scles where higher vlues indicte more complints (symptoms) or greter disbility. Phse 0: no-tretment bseline; phse 1: first ssigned tretment; phse 2: second ssigned tretment. Test of Fixed Score, mm Effects Men (95% CI) Difference (95% CI) F Vlue P Vlue (r>f) Primry: VOC score Tretment Nifedipine 11.44 (6.12 to 16.75) Plcebo 13.28 (7.96 to 18.59) 1.84 ( 6.67 to 2.99) 0.61.44 Plcebo first 14.07 (7.16 to 20.98) Nifedipine first 10.65 (4.16 to 17.14) 3.43 ( 6.08 to 12.93) 0.54.47 Temperture 3.62.07 Secondry: VOD score Tretment Nifedipine 4.65 (1.65 to 7.65) Plcebo 4.09 (1.09 to 7.09) 0.56 ( 2.97 to 4.09) 0.10.75 Plcebo first 4.95 (1.40 to 8.50) Nifedipine first 3.79 (0.46 to 7.12) 1.17 ( 3.72 to 6.05) 0.24.63 Temperture 1.63.21 VAS = visul nlog scle; VOC = visul nlogue scle on complints; VOD = visul nlogue scle on disbility. On visul nlogue scle in week 6 of tretment. Scores mesured on 100-mm scles where higher vlues indicte more complints (symptoms) or greter disbility. 7 8 Week Number 9 10 11 12 13 DISCUSSION We did not find ny cliniclly or sttisticlly significnt differences in fvor of nifedipine over plcebo for the tretment of chronic chilblins. The difference in ptient-reported complints (symptoms) tended to fvor nifedipine, while the difference in ptient-reported disbility tended to fvor plcebo. Nifedipine ws ssocited with lower systolic blood pressure nd higher incidence of edem. We did not find ny significnt crry-over effect of prior tretment on the primry or secondry outcome. Differences between the nifedipinefirst nd plcebo-first rms tended to fvor the former. Strengths nd Limittions The min strength of this study is our effort to confirm the findings of the originl rndomized controlled tril tht led to the current generl dvice to consider nifedipine for the tretment of chronic chilblins. No such confirmtion study hd previously been performed. We followed the design of the originl study s closely s possible but tripled the number of ptients bsed on our smple size clcultion. Improving on the originl design, we further took into ccount mbient temperture s mjor confounder. 3,19,20 We ssessed primry nd secondry outcomes with VAS scores for pin, itch, nd disbility using ptient diries. These scles re generlly used nd vlidted for this purpose. 21-23 Ptient complince ws good. Although 11% of ssigned cpsules were not tken, known dverse effects of nifedipine (lower systolic blood pressure nd more edem) were still seen during nifedipine tretment. 457
Ptients conscientiously completed their diries nd did not miss ny fce-to-fce contcts. Becuse of the recruitment method used for our tril, we cn generlize our findings to ptients with idiopthic chronic chilblins in generl prctice. Almost one-hlf of our prticipnts reported hving Rynud phenomenon s comorbidity (Tble 1). This high figure my suggest some sort of reltionship between chronic chilblins nd Rynud phenomenon. We did not exclude prticipnts who hd this condition becuse it cn be esily distinguished from chronic chilblins. 24-26 It is unlikely tht the high prevlence of Rynud phenomenon ffected our results s plcebo-controlled trils indicte tht nifedipine nd other clcium chnnel blockers re effective for treting tht condition. 27 We found remrkble reduction of chilblins symptoms during plcebo tretment tht my hve severl explntions. First, the plcebo effect my hve been responsible. 28 Second, lmost ll studies on chilblins report tht 60% to 70% of the ptients experience n improvement. 3 None of these studies thoroughly corrected for the influence of exposure to cold nd other confounders, however. Third, we did not collect informtion bout therpy received for previous episodes, but in our opinion, prior therpy is unlikely to hve influenced our results. Lst, we did not sk our ptients not to chnge their hbits during the study, which rises the possibility of Hwthorne effect. 29 We re unble to exclude such n effect cused by ptients own efforts to llevite their symptoms by CHRONIC CHILBLAINS Tble 3. Investigtor-Assessed Outcomes After 6 Weeks of Tretment Outcome Plcebo Nifedipine Men Difference (95%CI) P Vlue Redness score, men, mm 17.0 18.3 1.9 ( 3.8 to 7.6).50 Purpleness score, men, mm 6.6 4.9 1.5 ( 5.6 to 2.6).47 Edem score, men, mm 4.9 7.8 3.2 ( 0.5 to 6.9).09 Ulcertion score, men, mm 0.0 0.2 0.2 ( 0.2 to 0.6).33 Assessed using 100-mm visul nlogue scles where higher vlues indicte greter severity. Tble 4. Adverse Effects After 6 Weeks of Tretment Outcome Plcebo Nifedipine Men Difference (95% CI) P Vlue Systolic blood pressure, 147.1 134.5 13.1 ( 24.1 to 2.01).02 men, mm Hg Hedche score, men, mm 2.2 6.9 4.7 ( 0.8 to 10.3).09 Dizziness score, men, mm 1.6 4.7 3.1 ( 1.0 to 7.2).13 Peripherl edem score, men, mm 2.5 12.1 9.6 (1.1 to 18.1).03 Assessed using 100-mm visul nlogue scles where higher vlues indicte greter severity. chnging hbits during the study. Nevertheless, we consider it to be unlikely becuse nerly ll ptients with chilblins hve lredy tried lmost everything to relieve their symptoms. 2 In our opinion, the reduction of symptoms during plcebo tretment likely reflects both plcebo effect nd the nturl course of the disese. Comprison With Existing Literture Our findings contrst with those of the originl rndomized controlled tril by Rustin et l. 6 We did not reproduce their cler positive effect of nifedipine compred with plcebo either in ptient diry dt or in our investigtor ssessment of the chilblins. Our findings re lso t odds with the results of the other, non plcebocontrolled studies on the use of nifedipine to tret chronic chilblins. 6-8 Implictions for Prctice Our rndomized controlled tril filed to confirm effectiveness of nifedipine for the tretment of chronic chilblins in generl prctice nd showed evidence tht its use in this context my cuse hrm. These findings underscore the importnce of rigorous evlution of tretments, with dequte numbers of ptients nd control for potentil confounders, before widespred doption. Current dvice to prescribe nifedipine for chilblins should be revisited, nd clinicins should weigh nd discuss with ptients evidence on the potentil benefits nd hrms of vrious tretment options before mking tretment decisions. To red or post commentries in response to this rticle, see it online t http://www.nnfmmed.org/content/14/5/453. Key words: chilblins; therpeutics; nifedipine; rndomized controlled tril; prctice-bsed reserch; primry cre Submitted Jnury 14, 2016; submitted, revised, April 8, 2016; ccepted April 25, 2016. Funding support: This work ws supported by the Netherlnds Orgniztion for Helth Reserch nd Development Progrm Common Diseses grnt number 42011006. Registrtion detils: EudrCT: registrtion number 2009-016397-33; Netherlnds Tril Register: registrtion number NTR 2591. Acknowledgments: The uthors re grteful for the ssistnce of Mrs C.M. (Rin) Siemons, reserch ssistnt. 458
References 1. Souwer IH, Lgro-Jnssen ALM. Chronic chilblins. BMJ. 2011;342: d2708. 2. Souwer IH, Robins LJH, Lgro-Jnssen ALM. Chilblins from the ptient s perspective. Eur J Gen Prct. 2007;13(3):159-160. 3. Souwer IH, Lgro-Jnssen ALM. De behndeling vn perniones [The tretment of perniosis. A literture study]. Huisrts Wet. 2004; 47(12):561-562. 4. Al-sudny NK. Tretment of primry perniosis with orl pentoxifylline ( double-blind plcebo-controlled rndomized therpeutic tril). Dermtol Ther. 2016;(2):1-6. 5. Souwer IH, Lgro-Jnssen ALM. Vitmin D3 is not effective in the tretment of chronic chilblins. Int J Clin Prct. 2009;63(2):282-286. 6. Rustin MHA, Newton JA, Smith NP, Dowd PM. The tretment of chilblins with nifedipine: the results of pilot study, double-blind plcebo-controlled rndomized study nd long-term open tril. Br J Dermtol. 1989;120(2):267-275. 7. Kubis TAI, Hsn AS, Awd KM, Twfiq EM. Tretment of perniosis with orl nifedipine in comprison with topicl 5% minoxidil solution in Irqi ptients. Single blind comprtive study. AL-Anbr Med J. 2010;8(1):40-46. 8. Ptr AK, Ds AL, Rmdsn P. Diltizem vs. nifedipine in chilblins: clinicl tril. Indin J Dermtol Venereol Leprol. 2003;69(3):209-211. 9. Goette DK. Chilblins (perniosis). J Am Acd Dermtol. 1990;23 (2 Pt 1):257-262. 10. Almhmeed A, Pinto DS. Pernio (chilblins). Curr Tret Options Crdiovsc Med. 2008;10(2):128-135. 11. Pul M, Shrm M, Littlewood S, Lech I. Minerv. BMJ. 2011;342: d3170. 12. Ntionl Orgniztion for Rre Disorders (NORD). For Ptients nd Fmilies. Perniosis. http://www.rrediseses.org/rre-diseseinformtion/rre-diseses/byid/736/printfullreport. Accessed Jn 30, 2015. 13. Myo Clinic. Ptient Cre nd Helth Informtion. Diseses nd Conditions. Chilblins. Tretment. http://www.myoclinic.org/ diseses-conditions/chilblins/bsics/tretment/con-20033727. Accessed Jn 30, 2015. 14. Lewis T. Observtions on some norml nd injurious effects of cold upon the skin nd underlying tissues: II. Chilblins nd llied conditions. Br Med J. 1941;2(4223):837-839. 15. Shhi V, Wetter DA, Cppel JA, Dvis MDP, Spittell PC. Vsospsm is consistent finding in pernio (chilblins) nd possible clue to pthogenesis. Dermtology. 2015;231(3):274-279. 16. Ionnidis JPA. Why most published reserch findings re flse. PLoS Med. 2005;2(8):e124. 17. Grizzle JE. The two-period chnge-over design nd its use in clinicl trils. Biometrics. 1965;21:467-480. 18. Wng SJ, Hung HM. Use of two-stge test sttistic in the twoperiod crossover trils. Biometrics. 1997;53(3):1081-1091. 19. Jcob JR, Weismn MH, Rosenbltt SI, Bookstein JJ. Chronic pernio. A historicl perspective of cold-induced vsculr disese. Arch Intern Med. 1986;146(8):1589-1592. 20. Rz N, Sjid Mu, Suhil M, Hroon-ur-Rshid. Onset of chilblins in reltion with wether conditions. J Ayub Med Coll Abbottbd. 2008;20(2):17-20. 21. Ferreir-Vlente MA, Pis-Ribeiro JL, Jensen MP. Vlidity of four pin intensity rting scles. Pin. 2011;152(10):2399-2404. 22. Reich A, Heisig M, Phn NQ, et l. Visul nlogue scle: evlution of the instrument for the ssessment of pruritus. Act Derm Venereol. 2012;92(5):497-501. 23. Boonstr AM, Schiphorst Preuper HR, Renemn MF, Posthumus JB, Stewrt RE. Relibility nd vlidity of the visul nlogue scle for disbility in ptients with chronic musculoskeletl pin. Int J Rehbil Res. 2008;31(2):165-169. 24. Mverkis E, Ptel F, Kronenberg DG, et l. Interntionl consensus criteri for the dignosis of Rynud s phenomenon. J Autoimmun. 2014;48-49:60-65. 25. Block JA, Sequeir W. Rynud s phenomenon. Lncet. 2001;357 (9273):2042-2048. 26. Wigley FM. Clinicl prctice. Rynud s phenomenon. N Engl J Med. 2002;347(13):1001-1008. 27. Ennis H, Anderson ME, Wilkinson J, Herrick AL. Clcium chnnel blockers for primry Rynud s phenomenon. [Review]. Cochrne Dtbse Syst Rev. 2014;(1):CD002069. 28. Brody H. The lie tht hels: the ethics of giving plcebos. Ann Intern Med. 1982;97(1):112-118. 29. Sedgwick P, Greenwood N. Understnding the Hwthorne effect. BMJ. 2015;351:h4672. 459