efigure 2. measures for total cholesterol · 38.80 (32.68 - 44.92) hanstad4 norw ay rct 0.5 38...

© 2015 American Medical Association. All rights reserved. 1

Supplementary Online Content

Lee YH, Scharnitz TP, Muscat J, Chen A, Gupta-Elera G, Kirby JS. Laboratory monitoring during isotretinoin therapy for acne: a systematic review and meta-analysis. JAMA Dermatol. Published online December 2, 2105. doi:10.1001/jamadermatol.2015.3091.

eAppendix 1. PRISMA and AMSTAR Checklists Used to Guide the Project

eAppendix 2. Complete Description of the Search Methods

eTable 1. References Included in the Study and the Study Characteristics

eTable 2. Discontinuation Rates Related to Laboratory Abnormalities for the Studies Included in the Meta-analysis

eTable 3. Excluded Full-Text References

eFigure 1. Measures for Triglycerides

eFigure 2. Measures for Total Cholesterol

eFigure 3. Mean and 99% CI for LDL-C and HDL-C

eFigure 4. Measures for AST

eFigure 5. Measures for AP

eFigure 6. Mean and 99% CI for White Blood Cell Count

eReferences.

This supplementary material has been provided by the authors to give readers additional information about their work.

Downloaded From: https://jamanetwork.com/ by a Non-Human Traffic (NHT) User on 11/02/2020


eAppendix 1. PRISMA and AMSTAR Checklists Used to Guide the Project



eAppendix2.CompleteDescriptionoftheSearchMethodsThemostextensiveandcomprehensivesearchwasdonewithMedlineontheOVIDplatform.Eachrelevantconceptwassearchedwithallavailablesynonyms,bothfortreatmentofAcneaswellasdiagnosticproceduresformonitoringpatients.Eventhoughtheoriginalintentwastoincludeindividuals12‐30yearsold,itwasdecidedthattheMedlineagerangesforAdolescent(13–18years)andYoungAdult(19‐24years)beused.Theinitialsearchcovered1960–August2013.Thesearchstrategyislistedbelow.Atotalof186citationswereretrievedforscreening.AdditionalsearchingwasdonewithEmbasethroughProquest.MoregeneraltermswereusedinordertosearchEmbase,EmbaseAlertandMedlinetogetherandtheneliminatecitationsalreadyfoundinMedlinesoastoidentifyuniquelyEmbasecitations.Thesearchstrategyforthisprocessislistedbelow.Atotalof140citationswereretrievedforscreening.Todiscoverpotentiallyrelevantgreyliterature,asearchwasperformedonGoogleScholarusingthefollowingterms‐acneAND(retinORisotretinoinORtretinoinORaccutane)ANDadolescentAND(testingORmonitoring)AND(lipidsOR"liverfunction"OR"bloodcount");thedaterangewaslimitedto1960‐2013andcitationsandpatentswereremoved.Thesearchstrategyforthisprocessislistedbelow.WiththeunusuallylargenumberofcitationsthatGoogleScholargenerallyturnsoutwithitsundisclosedalgorithm,wewereabletoidentify16workstobeincludedfortheinitialreview.Ovid/Medline1.isotretinoin.mp.orIsotretinoin/2.13‐cis‐retinoicacid.mp.3.roaccutane.mp.4.ro43780.mp.5.ro43780.mp.6.13cisretinoicacid.mp.7.accutane.mp.8.ro4‐3780.mp.9.1or2or3or4or5or6or7or810.Tretinoin.mp.orTretinoin/11.alltransretinoicacid.mp.12.all‐trans‐retinoicacid.mp.13.retin‐a.mp.14.betaalltransretinoicacid.mp.15.trans‐retinoicacid.mp.16.acidbeta‐all‐trans‐retinoic.mp.17.vesanoid.mp.18.acidall‐trans‐retinoic.mp.19.beta‐all‐trans‐retinoicacid.mp.20.acidtrans‐retinoic.mp.21.retinoicacid.mp.22.acidvitamina.mp.23.transretinoicacid.mp.24.retina.mp.25.acidretinoic.mp.26.vitaminaacid.mp.



27.10or11or12or13or14or15or16or17or18or19or20or21or22or23or24or25or2628.Carotenoids.mp.orexpCarotenoids/29.carotene.mp.30.carotenes.mp.31.28or29or3032.vitamina.mp.orVitaminA/33.alltransretinol.mp.34.retinol.mp.35.aquasola.mp.36.11‐cis‐retinol.mp.37.all‐trans‐retinol.mp.38.vitamina1.mp.39.32or33or34or35or36or37or3840.9or27or31or3941.acne.mp.orAcneVulgaris/42.40and4143.completebloodcount.mp.orBloodCellCount/44.bloodcellcounts.mp.45.completebloodcounts.mp.46.bloodcellnumbers.mp.47.bloodcountcomplete.mp.48.countscompleteblood.mp.49.numberbloodcell.mp.50.numbersbloodcell.mp.51.countsbloodcell.mp.52.bloodcountscomplete.mp.53.countcompleteblood.mp.54.countbloodcell.mp.55.bloodcellnumber.mp.56.43or44or45or46or47or48or49or50or51or52or53or54or5557.liverfunctiontest.mp.orLiverFunctionTests/58.testsliverfunction.mp.59.functiontestsliver.mp.60.testliverfunction.mp.61.liverfunctiontests.mp.62.functiontestliver.mp.63.57or58or59or60or61or6264.diagnostictests.mp.orDiagnosticTests,Routine/65.testsroutinediagnostic.mp.66.diagnostictest.mp.67.testdiagnostic.mp.68.diagnostictestsroutine.mp.69.routinediagnostictests.mp.70.routinediagnostictest.mp.71.testroutinediagnostic.mp.72.testsdiagnostic.mp.73.64or65or66or67or68or69or70or71or7274.expLipids/orlipids.mp.75.lipidpanel.mp.



76.74or7577.drugmonitoring.mp.orDrugMonitoring/78.monitoringdrug.mp.79.monitoringtherapeuticdrug.mp.80.therapeuticdrugmonitoring.mp.81.drugmonitoringtherapeutic.mp.82.77or78or79or80or8183.56or63or73or76or8284.42and8385.limit84to("adolescent(13to18years)"or"youngadult(19to24years)")86.limit84toyr="1960‐Current"87.limit84to(clinicaltrial,allorcomparativestudyorcontrolledclinicaltrialormetaanalysisormulticenterstudyorrandomizedcontrolledtrialorsystematicreviews)88.Cholesterol/bl[Blood]89.76or8890.56or63or73or82or8991.84and90EmbasethroughProquestacne*retin**acutanevesanoid“vitamina”caroten*“aquasola”2or3or4or5or6or71and8“diagnostictest*”“routinetest*”“drugmonitor*”10or11or12“liverfunctiontest*”“bloodcount”cbclipid14or15or16or179and139and1819or20(19or20)andpd(19600101‐20131)



(19OR20)AND(fdb(100001341007817)NOTfdb(10000136)ANDpd(19600101‐20131231))GoogleScholar1.SearchStatement:acneAND(retinORisotretinoinORtretinoinORaccutane)ANDadolescentAND(testingORmonitoring)AND(lipidsOR"liverfunction"OR"bloodcount")2.DateRange:1960–20133.Remove(belowDateRange):Citations,Patents



eTable 1. References Included in the Study and the Study Characteristics

Citation Country Study Design

Isotretinoin dose

No. of patients

Follow-up Weeks

CHOL Mean (99% CI)

Ragos et al1 Canada Observation 1 140 2-8 28.00 (22.16 - 33.85)

Michaëlsson et al2 Sweden RCT 0.5 90 12 15.90 (7.98 - 23.82)

Bershad et al (Males)3 USA RCT 1 17 4-20 24.13 (9.25 - 39.00)

Bershad et al (Females)3 USA RCT 1 36 4-20 13.97 (3.42 - 24.53)

Hanstad4 Norway RCT 0.5 38 16-24 27.10 (15.39 - 38.81)

Pigatto et al5 Italy RCT 1 12 10-20 7.56 (-16.28 - 31.41) *

Laker et al6 UK RCT 1 13 2-16 36.6 (15.84 - 57.37)

Melnik et al7 Germany RCT 0.73 ± 0.26 36 14 7.4 (-4.10 - 18.90) *

Lyons et al 8 UK RCT 0.8 18 12 38.7 (18.77 - 58.63)

Strauss 1984 (low dose)9 USA RCT 0.5 46 4-20 13.04 (4.38 - 21.71)

Strauss 1984 (high dose)9 USA RCT 1 46 4-20 30.72 (20.42 - 41.02)

Ostlere et al10 UK RCT 1 12 16 34.80 (10.28 - 59.32)

Strauss 2001 et al11 USA RCT 1 290 20 23.20 (19.18 - 27.22)

Koistinen 2001 et al12 Finland RCT 0.5 11 20 17.40 (2.83 - 31.97)

Altman et al13 USA Observation 1 140 4-12 13.27 (7.61 - 18.92)

Ferahbas et al14 Turkey RCT 1 23 1-16 12.47 (0.92 - 24.02)

Koistinen 2006 et al15 Finland RCT 0.5 11 20 19.40 (5.42 - 33.38)

Polat et al 16 Turkey RCT 0.5 74 6 21.90 (14.90 - 28.90)

Roodsari et al17 Iran RCT 0.5 47 8 20.30 (11.46 - 29.14)

Ertugrul 2011 et al18 Turkey RCT 0.88 48 12 11.30 (3.70 - 18.90)



Dursun et al19 Turkey RCT 0.8 45 4-24 14.75 (6.40 - 23.10)

Karadag et al20 Turkey RCT 0.75 66 16 19.50 (12.02 - 26.98)

Erturan et al21 Turkey RCT 0.7 31 8 15.10 (4.76 - 25.44)

Buckley et al22 Ireland Observation 1 88 4-16 26.14 (18.57 - 33.74)



eTable 1. (continued)

Citation Country

Study Design

Isotretinoin dose

No. of patients

Follow-up Weeks

TAG Mean (99% CI)

LDL Mean (99% CI)

HDL Mean (99% CI)

Ragos et al1 Canada

Obs. 1 140 2-8 70.31 (60.47 - 80.15)

Michaëlsson et al2

Sweden

RCT 0.5 90 12 18.60 (6.50 - 30.70)

Bershad et al3 USA RCT 1 53 4-20 38.56 (22.63 - 54.50)

17.00 (6.74 - 27.26)

38.80 (32.68 - 44.92)

Hanstad4 Norway

RCT 0.5 38 16-24 22.87 (7.77 - 37.98)

Pigatto et al5 Italy RCT 1 12 10-20 28.81 (9.88 - 47.73)

9.36 (-10.44 - 29.16)*

32.44 (16.99 - 47.90)

Laker et al6 UK RCT 1 13 2-16 45.42 (7.17 - 83.67)

Melnik et al7 Germany

RCT 0.73 ± 0.26 36 14 30.60 (19.54 - 41.66)

10.60 (-0.70 - 21.90)

43.00 (39.09 - 46.91)

Lyons et al8 UK RCT 0.8 18 12 115.20 (93.84 - 136.56)

34.80 (26.60 - 43.00)

Jones et al23 UK RCT 0.75 50 4-16 19.56 (4.68 - 34.533)

Strauss 19849 USA RCT 0.75 92 4-20 56.20 (45.7 - 66.7)

39.29 (33.95 - 44.63)

Ostlere et al10 UK RCT 1 12 16 23.00 (5.54 - 40.46)

Strauss 2001 et al11

USA RCT 1 290 20 87.70 (82.33 - 93.07)



Koistinen 2001 et al12

Finland

RCT 0.5 11 20 20.30 (6.55 - 34.05)

Altman et al13 USA Obs. 1 140 4-12 46.18 (35.63 - 56.72)

Ferahbas et al14

Turkey

RCT 1 23 1-16 25.97 (5.90 - 46.05)

41.56 (35.09 - 48.02)

Koistinen 2006 et al15

Finland

RCT 0.5 11 20 23.10 (7.89 - 38.31)

19.30 (4.81 - 33.79)

51.00 (40.51 - 61.49)

Polat et al16 Turkey

RCT 0.5 74 6 27.70 (16.93 - 38.47)

18.20 (12.46 - 23.95)

40.80 (37.57 - 44.03)

Roodsari et al17

Iran RCT 0.5 47 8 35.00 (19.68 - 50.32)

15.80 (8.34 - 23.26)

42.60 (37.68 - 47.52)

Ertugrul 2011 et al18

Turkey

RCT 0.88 48 12 28.80 (10.31 - 47.29)

15.00 (6.92 - 23.08)

46.40 (42.21 - 50.59)

Dursun et al19 Turkey

RCT 0.8 45 4-24 26.02 (13.62 - 38.41)

16.69 (9.38 - 23.99)

42.62 (37.82 - 47.42)

Karadag et al20 Turkey

RCT 0.75 66 16 26.30 (12.48 - 40.12)

15.70 (7.78 - 23.63)

45.50 (41.44 - 49.56)

Erturan et al21 Turkey

RCT 0.7 31 8 15.10 (-4.49 - 34.69)

15.20 (6.67 - 23.73)

50.80 (46.13 - 55.47)

Vieira et al24 Brazil Obs. 41.4 ± 10.5 70 12 18.30 (7.73 - 28.90)

Buckley et al22 Ireland

Obs. 1 88 4-16 38.60 (30.26 - 46.94)



Table 1. (continued) Citation Count

ry Study Design

Isotretinoin dose

No. of patients

Follow-up Weeks

AST Mean (99% CI)

ALT Mean (99% CI)

AP Mean (99% CI)

WBC Mean (99%CI)

Michaëlsson et al2

Sweden

RCT 0.5 90 12 6.00 (3.81 - 8.19)

4.80 (1.71 - 7.89)

-1.30 (-1.66 --0.94)

Lyons et al8 UK RCT 0.8 18 12 3.70 (0.65 - 6.75)

4.00 (-12.29 - 20.29)*

Jones et al23 UK RCT 0.75 50 4-16 3.865 (1.97-5.76)

van der Meeren et al25

Netherlands

RCT 0.75 58 24 -2.55 (-4.017 - -1.08)

Strauss 19849

USA RCT 0.75 92 4-20 6.12 (4.52 - 7.71)

2.59 (-0.48 - 5.67)

5.48 (-5.92 - 16.88)*

Wagner et al26

Germany

RCT 1.4 18 2-12 -1.77 (-3.16 - -0.37)

Strauss 2001 et al11

USA RCT 1 290 20 2.00 (-2.81 - 6.81)*

Altman et al13

USA Obs. 1 140 4-12 2.15 (0.67 - 3.63)

-1.04 (-3.61 - 1.55)

9.72 (-0.39 - 19.83)

0.347 (-0.40 - 1.10) *

Ferahbas et al14

Turkey

RCT 1 23 1-16 2.34 (-0.24 - 4.92)

0.85 (-4.39 -6.09) *

Polat et al16 Turkey

RCT 0.5 74 6 3.50 (2.29 - 4.71)

7.00 (3.23 - 10.77)

10.10 (1.02 - 19.18)

Roodsari et al17

Iran RCT 0.5 47 8 6.50 (2.83 - 10.17)

12.60 (3.66 -21.54)

-5.90 (-22.40 - 10.60)

Ertugrul 2011 et al18

Turkey

RCT 0.88 48 12 2.50 (1.21 - 3.79)

0.30 (-1.66 - 2.26) *

Karadag et Turke RCT 0.75 66 16 0.70 (-1.27 - 1.90 (0.51 -



al20 y 2.67)* 3.29) Erturan et al21

Turkey

RCT 0.7 31 8 4.60 (1.38 - 7.82)

5.00 (1.13 - 8.87)

-0.84 (-1.50 - -0.18)

Vieira et al24 Brazil Obs. 41.4 ± 10.5

70 12 4.00 (1.45 - 6.55)

5.10 (0.54 - 9.67)



eTable2.DiscontinuationRatesRelatedtoLaboratoryAbnormalitiesfortheStudiesIncludedintheMeta‐analysisCitation Subjects

Discontinued

Comment/Description

Ragosetal

1/140(0.7%)

1subjectdiscontinuedforhypertriglyceridemia

Michaëlssonetal

1/90.0(1.1%)

1subjectwithunspecifiedelevation

Bershadetal

1/53.0(1.8%)

1subjectdiscontinuedforhypertriglyceridemia

Hanstad NR

Pigattoetal

NR

Lakeretal NRMelniketal

NR

Lyonsetal

NR

Jonesetal 3/76.0(3.9%)

drugschedulealteredin3subjectsduetounspecifiedsideeffectsandthesesubjectswere3excludedfromstudy

vanderMeerenetal

NR

vanderMeerenetal

NR

Strauss1984

NR

Strauss1984

NR

Wagneretal

NR



Ostlereetal

NR

Strauss2001etal

10/290(3.4%)

10subjectsdiscontinuedduetolababnormalitiesofunspecifiedamount 1withleukopenia,6withhypertriglyceridemia,3withtransaminites.Also,1subjectwithappendicitis,notfelttobecausedbyisotretinoin

Koistinen2001etal

NR

Altmanetal

1/140(0.7%)

1subjectwithtransaminitis

Ferahbasetal

2/45.0(4.4%)

2/45subjectswithunspecifiedadversedrugreaction

Koistinen2006etal

NR

Polatetal NRRoodsarietal

NR

Ertugrul2011etal

NR

Dursunetal

NR

Karadagetal

NR

Erturanetal

9/40.0(22.5%)

9/40subjectswithunspecifiedadversedrugreaction

Vieiraetal

NR

Buckleyetal

1/88.0(1.1%)

1subjectwithdrew1weekafterisotretinoinbeganduetobaselinehypercholesterolemia

NR:datanotreported



eTable3.ExcludedFull‐TextReferencesAuthor Country Design Reasonforomission

Kumaretal India RCT SubtherapeuticdoseManolache Romania RCT SubtherapeuticdoseRodondi Switzerland Obs. Patientsselectedfromothertrialsbypre‐selectedcriteria(normalvs.elevatedbaselinevalues)Walker Scotland Obs. VariabilityindurationoftreatmentandfollowupintervalsMarsden England RCT Populationdoesnotfitinclusioncriteria(N=8)Jones UnitedKingdom RCT SubtherapeuticdoseFex Sweden RCT Patientstakingerythromycinconcomitantly;populationdoesnotfitinclusioncriteria(N=5)Lin Taiwan RCT SubtherapeuticdoseLestringant UnitedArabEmirates RCT Nomeanormediandosagedataprovided(onlyrange)andstates"dose‐dependentresults"Schulpis Greece WrongpaperinPSUdatabase(duplicateof11277950)Plewig Germany/USA RCT SubtherapeuticdoseGeißler Germany RCT SubtherapeuticdoseHeliövaara Finland RCT NodosagedataprovidedBener UnitedArabEmirates Obs. TimecourseofthestudywasnotspecifiedSchmitt Brazil Obs. TimecourseofthestudywasnotspecifiedGeorgala Greece RCT Integrity*Georgala Greece RCT Integrity*Schulpis Greece RCT Integrity*Baxter UnitedKingdom Obs. Onlydataintervalprovidedwasat24.5monthsKaptanoglu Turkey RCT NodosagedataprovidedKrishna USA Obs. NodosagedataprovidedRademaker NewZealand Obs. Doesnotspecifywhichdosinggroup,oneofwhichissubtherapeutic,hadalteredvaluesCentinozman Turkey RCT Onlydataintervalprovidedwasat24monthsErtugrul(2010) Turkey RCT DatawasnearidenticaltoErtugrul2011Meigel Germany RCT Datawasonlyprovidedinranges(didnotprovidemeanorSD) 1



eFigure1.MeasuresforTriglycerides



eFigure2.MeasuresforTotalCholesterol



eFigure3.Meanand99%CIforLDL‐CandHDL‐C.Meannon‐baselinevaluesforLDL(a)andHDL(c)andmeandifferencefrombaselinetomeanfollow‐upforLDL(b)andHDL(d).Studiesareindicatedbyfirstauthor.CI=confidenceintervalNIHCCreferencefor“highrisk”forLDLandHDLareabove160mg/dLandbelow40mg/dL,respectively.EmedicinenormalrangesforLDLandHDLare85‐125mg/dLand40‐80mg/dL.



eFigure 4. Measures for ASTeFigure 5. Measures for ALT and AP



eFigure 5. MeasuresforALTandAP



eFigure 6. Mean and 99% CI for White Blood Cell Count (WBC). Mean non-baseline values for WBC (a) and mean difference from baseline to mean follow-up for WBC (b). Studies are indicated by first author. CI = confidence interval NIHCC reference for “high risk” for WBC is above 3,000 cells/uL. Merck Manual normal range for WBC is 3,9000-10,700 cells/uL.



eReferences

1. Ragos G, Houlden R, Danby FW. Effect of isotretinoin therapy on serum total cholesterol and triglycerides. The Canadian Journal of Clinical Pharmacology. 1998;5(1):43-47.

2. Michaëlsson G, Vahlquist A, Mobacken H, et al. Changes in laboratory variables induced by isotretinoin treatment of acne. Acta Derm Venereol. 1986;66(2):144-148.

3. Bershad S, Rubinstein A, Paterniti JR, et al. Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med. Oct 17 1985;313(16):981-985.

4. Hanstad IK, Thune P. Nodulocystisk akne. Behandling med isotretinoin (Roaccutan)--kvantitative malinger av hudlipider. Tidsskr Nor Laegeforen. Aug 20 1985;105(23):1497-1500.

5. Pigatto PD, Finzi AF, Altomare GF, Polenghi MM, Vergani C, Vigotti G. Isotretinoin versus minocycline in cystic acne: a study of lipid metabolism. Dermatologica. 1986;172(3):154-159.

6. Laker MF, Green C, Bhuiyan AK, Shuster S. Isotretinoin and serum lipids: studies on fatty acid, apolipoprotein and intermediary metabolism. Br J Dermatol. Aug 1987;117(2):203-206.

7. Melnik B, Bros U, Plewig G. Characterization of apoprotein metabolism and atherogenic lipoproteins during oral isotretinoin treatment. Dermatologica. 1987;175 Suppl 1:158-168.

8. Lyons F, Laker MF, Marsden JR, Manuel R, Shuster S. Effect of oral 13-cis-retinoic acid on serum lipids. Br J Dermatol. Nov 1982;107(5):591-595.

9. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol. Mar 1984;10(3):490-496.

10. Ostlere LS, Harris D, Morse-Fisher N, Wright S. Effect of systemic administration of isotretinoin on blood lipids and fatty acids in acne patients. Int J Dermatol. Mar 1996;35(3):216-218.

11. Strauss JS, Leyden JJ, Lucky AW, et al. Safety of a new micronized formulation of isotretinoin in patients with severe recalcitrant nodular acne: A randomized trial comparing micronized isotretinoin with standard isotretinoin. J Am Acad Dermatol. Aug 2001;45(2):196-207.

12. Koistinen HA, Remitz A, Gylling H, Miettinen TA, Koivisto VA, Ebeling P. Dyslipidemia and a reversible decrease in insulin sensitivity induced by therapy with 13-cis-retinoic acid. Diabetes Metab Res Rev. Sep-Oct 2001;17(5):391-395.

13. Altman RS, Altman LJ, Altman JS. A proposed set of new guidelines for routine blood tests during isotretinoin therapy for acne vulgaris. Dermatology. 2002;204(3):232-235.

14. Ferahbas A, Turan MT, Esel E, Utas S, Kutlugun C, Kilic CG. A pilot study evaluating anxiety and depressive scores in acne patients treated with isotretinoin. J Dermatolog Treat. Jun 2004;15(3):153-157.

15. Koistinen HA, Remitz A, Koivisto VA, Ebeling P. Paradoxical rise in serum adiponectin concentration in the face of acid-induced insulin resistance 13-cis-retinoic. Diabetologia. Feb 2006;49(2):383-386.

16. Polat M, Lenk N, Bingol S, et al. Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne: a prospective controlled study. J Dermatolog Treat. 2008;19(4):229-232.

17. Roodsari MR, Akbari MR, Sarrafi-rad N, Saeedi M, Gheisari M, Kavand S. The effect of isotretinoin treatment on plasma homocysteine levels in acne vulgaris. Clin Exp Dermatol. Aug 2010;35(6):624-626.

18. Ertugrul DT, Karadag AS, Tutal E, Akin KO. Isotretinoin does not induce insulin resistance in patients with acne. Clin Exp Dermatol. Mar 2011;36(2):124-128.

19. Dursun R, Alpaslan M, Caliskan M, et al. Isotretinoin does not prolong QT intervals and QT dispersion in patients with severe acne: a surprising finding for a drug with numerous side effects. J Drugs Dermatol. Jul 2011;10(7):710-714.

20. Karadag AS, Tutal E, Ertugrul DT, Akin KO. Effect of isotretinoin treatment on plasma holotranscobalamin, vitamin B12, folic acid, and homocysteine levels: non-controlled study. Int J Dermatol. Dec 2011;50(12):1564-1569.

21. Erturan I, Naziroglu M, Akkaya VB. Isotretinoin treatment induces oxidative toxicity in blood of patients with acne vulgaris: a clinical pilot study. Cell Biochem Funct. Oct 2012;30(7):552-557.

22. Buckley D, Rogers S, Daly P. Isotretinoin therapy for acne vulgaris: results in an Irish population. Ir J Med Sci. Jan 1990;159(1):2-5.



23. Jones DH, King K, Miller AJ, Cunliffe WJ. A dose-response study of I3-cis-retinoic acid in acne vulgaris. Br J Dermatol. Mar 1983;108(3):333-343.

24. Vieira AS, Beijamini V, Melchiors AC. The effect of isotretinoin on triglycerides and liver aminotransferases. An Bras Dermatol. May-Jun 2012;87(3):382-387.

25. van der Meeren HL, van der Schroeff JG, Stijnen T, van Duren JA, van der Dries HA, van Voorst Vader PC. Dose-response relationship in isotretinoin therapy for conglobate acne. Dermatologica. 1983;167(6):299-303.

26. Wagner A, Plewig G. 13-cis-Retinsaure. Pharmakologische und toxikologische Untersuchungen bei der Behandlung schwerster Akneformen. MMW Munch Med Wochenschr. Sep 19 1980;122(38):1294-1300.


efigure 2. measures for total cholesterol · 38.80 (32.68 - 44.92) hanstad4 norw ay rct 0.5 38...

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