Research

Original Investigation

Laboratory Monitoring During Isotretinoin Therapy for Acne

A Systematic Review and Meta-analysis
Young H. Lee, MD; Thomas P. Scharnitz, BS; Joshua Muscat, PhD; Allshine Chen, MS; Gaytri Gupta-Elera, BS;
Joslyn S. Kirby, MD, MEd, MS

Editorial page 17
IMPORTANCE Oral isotretinoin has been associated with several adverse effects, but Author Audio Interview at
evidence-based estimates of laboratory changes during isotretinoin therapy in large patient jamadermatology.com
samples are limited.
Supplemental content at
jamadermatology.com
OBJECTIVE To develop estimates of the laboratory changes that occur during isotretinoin
therapy for acne using extant data and meta-analytic methods.

DATA SOURCES A comprehensive search strategy using Ovid/MEDLINE, EMBASE, and gray
literature was conducted (1960-August 1, 2013) to identify all relevant studies of isotretinoin
use in acne vulgaris. Terms related to acne treatment, isotretinoin, and diagnostic procedures
were searched with all available synonyms.

STUDY SELECTION Inclusion criteria consisted of clinical trials using oral isotretinoin, doses of
40 mg/d or more, duration of at least 4 weeks, patients aged 9 to 35 years with acne vulgaris,
and 10 or more participants. Studies from all countries published in any language were
included. Exclusion criteria were use of modified isotretinoin products, isotretinoin therapy
for conditions other than acne vulgaris, and concomitant acne therapy. The initial search
yielded 342 records; 116 of these were screened for full-text examination.

DATA EXTRACTION AND SYNTHESIS Two authors independently reviewed the publications to
determine eligibility, and disagreements were resolved by a third author. Generated weighted
means and 99% CIs were calculated using the reported means (SDs or SEs). A random effects
model was created, and statistical heterogeneity was quantified. Data were analyzed from
August 25, 2014, to December 4, 2015.

MAIN OUTCOMES AND MEASURES Laboratory values for lipid levels, hepatic function, and
complete blood cell count were evaluated.

RESULTS Data from 61 of the 116 studies were evaluated; 26 studies (1574 patients) were
included in the meta-analysis. The mean (99% CI) values during treatment (nonbaseline) for
triglycerides was 119.98 mg/dL (98.58-141.39 mg/dL); for total cholesterol, 184.74 mg/dL
(178.17-191.31 mg/dL); for low-density lipoprotein cholesterol, 109.23 mg/dL (103.68-114.79
mg/dL); for high-density lipoprotein cholesterol, 42.80 mg/dL (39.84-45.76 mg/dL); for
aspartate aminotransferase, 22.67 U/L (19.94-25.41 U/L); for alanine aminotransferase, 21.77 Author Affiliations: Division of
Dermatology, Sharp Rees-Stealy
U/L (18.96-24.59 U/L); for alkaline phosphatase, 88.35 U/L (58.94-117.76 U/L); and for white
Medical Group, San Diego, California
blood cell count, 6890/μL (5700/μL-8030/μL). This meta-analysis showed that (1) (Lee); Penn State College of Medicine,
isotretinoin is associated with a statistically significant change in the mean value of several Hershey, Pennsylvania (Scharnitz,
laboratory tests (white blood cell count and hepatic and lipid panels), yet (2) the mean Gupta-Elera); Department of Public
Health Sciences, Penn State Milton S.
changes across a patient group did not meet a priori criteria for high-risk and (3) the
Hershey Medical Center, Hershey,
proportion of patients with laboratory abnormalities was low. Pennsylvania (Muscat, Chen);
Department of Dermatology, Penn
CONCLUSIONS AND RELEVANCE The evidence from this study does not support monthly State Milton S. Hershey Medical
Center, Hershey, Pennsylvania
laboratory testing for use of standard doses of oral isotretinoin for the standard patient with ( Kirby).
acne. Corresponding Author: Joslyn S.
Kirby, MD, MEd, MS, Department of
Dermatology, Penn State Milton S.
Hershey Medical Center, 500
JAMA Dermatol. 2016;152(1):35-44. doi:10.1001/jamadermatol.2015.3091 University Ave, HU 14, Hershey, PA
Published online December 2, 2015. Corrected on January 13, 2016. 17033 (jkirby1@hmc.psu.edu).

(Reprinted) 35

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 11/15/2019

 Research Original Investigation
S
evere nodulocystic acne can be treated with isotreti-
noin, which can result in dramatic improvement within
months. Although very effective, isotretinoin has been
associated1-3 with several adverse effects, including terato-
genicity, hyperlipidemia and associated pancreatitis, leuko-
penia, thrombocytopenia, and transaminitis. Monitoring of
pregnancy during therapy is mandated via the iPLEDGE pro-
gram (https://www.ipledgeprogram.com). The package insert4
recommends baseline fasting lipid and hepatic panels with
repeated testing at weekly or biweekly intervals until “the
response has been established.” There are no specific sugges-
tions in the document for laboratory monitoring.
Prior studies have investigated the usefulness of labora-
tory monitoring during isotretinoin therapy and made recom-
mendations ranging from performance of only baseline testing5
to baseline testing with 1 follow-up set of tests.6,7 The latter
recommendations were based on samples of approximately 140
to 200 patients and at single centers.6,7 In addition, Hansen
et al8 reviewed 574 isotretinoin courses for 515 patients and
found that grade 2 abnormalities were uncommon (0.2%-
1.6% of patients) and 67.7% of the abnormalities occurred
within the first 60 days of treatment. Nevertheless, overall, the
evidence to guide laboratory monitoring during isotretinoin
therapy is limited by differences in tests ordered, testing fre-
quency, and small sample sizes in some studies. The aim of this
systematic review and meta-analysis was to combine data
across multiple published studies to develop estimates of labo-
ratory changes during isotretinoin therapy for acne.
Methods
A systematic review and meta-analysis were performed. The
study was registered with the PROSPERO International pro-
spective register of systematic reviews.9 The PRISMA and
AMSTAR checklists were used to guide the project (eAppen-
dix 1 in the Supplement).
Search Strategy
We conducted a comprehensive search strategy designed by
a Master of Library and Information Science–trained librarian
to identify all relevant studies of oral isotretinoin use in ado-
lescents and adults (age 9-35 years) with acne vulgaris. Ar-
ticles in any language were included; all searches covered 1960
to August 1, 2013. A comprehensive search was performed in
MEDLINE using the Ovid platform. The search terms related
to acne treatment, isotretinoin, and diagnostic procedures were
searched with all available synonyms. A second search of
EMBASE was performed through Proquest. Duplicate cita-
tions were removed. A final search for relevant gray literature
was performed on Google Scholar with citations and patents
removed. A complete description of the search methods is de-
scribed in eAppendix 2 of the Supplement.
Selection Criteria
Inclusion criteria were developed a priori and included studies
of acne vulgaris, use of oral isotretinoin (altered sustained-
release or lipid-enhanced products were excluded), dose regi-
36 JAMA Dermatology January 2016 Volume 152, Number 1 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 11/15/2019
Laboratory Monitoring During Isotretinoin Therapy for Acne
mens of 40 mg or more daily (or ≥0.5 mg/kg), duration of treat-
ment for at least 4 weeks, and treatment of children and adults
(aged 9-35 years). Studies with a cohort or comparison design
as well as case series of 10 or more participants were eligible.
The study must have reported values for the laboratory tests of
interest: complete blood cell count, hepatic panel (aspartate
aminotransferase [AST], alanine aminotransferase [ALT], and
alkaline phosphatase [AP]), and/or lipid panel (triglycerides [TG],
total cholesterol, low-density lipoprotein cholesterol [LDL-C],
and high-density lipoprotein cholesterol [HDL-C]). Studies were
separated into 2 groups; those that reported mean values for
laboratory tests were included in the meta-analysis, and stud-
ies that reported the proportion of patients with an abnormal
test were described separately in a narrative review.
Study Selection
Titles and abstracts from the search results were screened, and
full articles of all citations that met the predefined selection cri-
teria were obtained for review. Subsequently, full articles were
examined for inclusion or exclusion and data extraction. Two
reviewers (T.P.S. and G.G.-E.) independently assessed each
potentially relevant study for eligibility. Disagreements were
resolved by a third reviewer (Y.H.L.).
Data Extraction
The selected studies were reviewed and the data were abstracted
by one of us (T.P.S.); the accuracy was confirmed by another one
of us (Y.H.L.). Information was entered into a Google document
(Google Inc) and included study characteristics (country, design,
sample size, and duration of therapy), patient characteristics
(age and sex), and therapeutic interventions (isotretinoin dose
and treatment duration). Laboratory tests of interest included
the complete blood cell count, hepatic panel (AST, ALT, and AP),
and lipid panel (TG, total cholesterol, HDL-C, and LDL-C). The
timing of laboratory monitoring during isotretinoin therapy (eg,
at week 6, month 1, and month 3) was recorded. The mean (SD)
of the laboratory result and the proportion of patients with ab-
normal results were recorded. Studies that did not report spe-
cific values at identified time points were not included in the
meta-analysis, but their findings are described in a separate nar-
rative. The National Institutes of Health Clinical Center refer-
ence ranges10 were used to define significant or high-risk labo-
ratory changes for white blood cell count, which corresponded
to 3000 cells/μL (to convert to × 109/L, multiply by 0.001), TG
corresponding to 200 mg/dL (to convert to millimoles per liter,
multiply by 0.0113), and total cholesterol, LDL-C, and HDL-C
corresponding to 240, 160, and 40 mg/dL, respectively (to con-
vert to millimoles per liter, multiply by 0.0259). The Common
Terminology Criteria for Adverse Events reference ranges11 were
used to define grade 2 or significant laboratory changes for the
hepatic panel including AP, AST, and ALT corresponding to 367.5
U/L, 108 U/L, and 111 U/L, respectively (to convert to microkatals
per liter, multiply by 0.0167).
Statistical Analysis
Trials reported findings from different laboratory studies and
at varying intervals of repeated measurements in time. The
99% CI for each laboratory test in each study was calculated
jamadermatology.com
 Laboratory Monitoring During Isotretinoin Therapy for Acne
Figure 1. CONSORT Diagram
186 Records identified through 140 Records identified through
Ovid/MEDLINE EMBASE Proquest
342 Records to be screened
116 Records screened
86 Full-text articles assessed
for eligibility
26 Studies included in quantitative synthesis
Quantifiable data recorded at preestablished time
intervals during therapy and available for ANOVA
based on the reported mean (SD). The meta-analytic method
used weighted means (SEs) to estimate the mean and 99% CI
for the pool of participants. Midtreatment and late effects of
isotretinoin therapy on laboratory results were analyzed
whenever possible depending on the data available in pub-
lished studies. Midtreatment was defined as 6 to 8 weeks of
therapy. Late effects of prolonged isotretinoin therapy were
examined for 16 to 20 weeks. A random effects model was
used and statistical heterogeneity was quantified using
the I2 and τ2 statistics. An assessment of the quality of the
evidence was not performed. Data were analyzed from
August 25, 2014, to December 4, 2015, using Stata, version 13
(StataCorp) and Comprehensive Meta-analyses software
(Biostat Inc).
Results
The initial search identified 342 references (Figure 1); 116 of
these (33.9%) were selected for full-text examination. The
meta-analysis of changes in laboratory values included 22 ran-
domized clinical trials and 4 retrospective studies1,7,12,13 with
a total of 1574 participants. The individual studies are de-
scribed in eTable 1 in the Supplement. Seven of these studies
reported discontinuation rates for subjects owing to labora-
tory abnormalities, which ranged from 0.71% (1 of 140)7,12 to
22.5% (9 of 40),14 with a mean (SD) of 4.4 (6.9) (eTable 2 in the
Supplement). There were 25 randomized clinical trials and 10
retrospective studies with a total of 17 915 participants that
lacked data on laboratory values, which are summarized be-
low in a narrative review. The excluded references are listed
in eTable 3 in the Supplement.
jamadermatology.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 11/15/2019
Original Investigation Research
16 Records identified through gray
literature Google Scholar search
226 Records omitted by screening titles
Different therapy, topical preparation,
nonhuman subjects, or not treating acne
30 Records excluded
Nonclinical studies, review articles, book
chapters, case reports, or duplicate
citations
25 Full-text articles excludeda
35 Studies included in qualitative synthesis
Recorded trends or reported percentage of
patients with deranged values without specific ANOVA indicates analysis of variance.
values or time intervals established a
Excluded full-text articles are listed
in eTable 3 in the Supplement.
Lipid Panel
Triglycerides
The mean value of nonbaseline measurements 15-33(Figure 2A)
or those made during isotretinoin therapy was 119.98 mg/dL
(99% CI, 98.58-141.39 mg/dL). The difference in mean values
between baseline and the mean follow-up period (11.3 weeks)
(Figure 2B) was 36.96 mg/dL (99% CI, 22.12-51.79 mg/dL).
To examine midtreatment and later effects of isotreti-
noin therapy, the difference in means between baseline and 8
weeks and 20 weeks (eFigure 1A and B in the Supplement) was
examined. For 8 weeks, the difference from baseline was 45.32
mg/dL (99% CI, 22.73-67.92 mg/dL), and for 20 weeks, the dif-
ference from baseline was 45.63 mg/dL (99% CI, 5.15-80.11 mg/
dL). The 2 analyses consisted of different studies because not
all studies reported values for all time points. However, the
change in TG levels from baseline to 8 weeks and 20 weeks does
not demonstrate a substantial late effect of isotretinoin therapy.
Total Cholesterol
The mean value of nonbaseline measurements (Figure 3A)
or those made during isotretinoin therapy was 184.74 mg/dL
(99% CI, 178.17-191.31 mg/dL). All but one study reported all
observations as within the reference range. In one study13
the 99% CI extended above 240 mg/dL, with a mean of
235.90 mg/dL (99% CI, 206.02-265.78 mg/dL). The differ-
ence in mean values between baseline and the mean
follow-up period (11.1 weeks) (Figure 3B) was 19.73 mg/dL
(99% CI, 16.00-23.47 mg/dL). In 3 studies,19,21,24 there were
patients who had a change in total cholesterol of up to 60
mg/dL. At 16 weeks (eFigure 2A in the Supplement), the dif-
ference from baseline was 23.51 mg/dL (99% CI, 16.84-30.18
mg/dL), and for 20 weeks (eFigure 2B in the Supplement),
(Reprinted) JAMA Dermatology January 2016 Volume 152, Number 1 37
 Research Original Investigation Laboratory Monitoring During Isotretinoin Therapy for Acne

Figure 2. Measures for Triglycerides

A Mean nonbaseline triglyceride values

Study Mean (SE) 99% CI

Buckley et al,13 1990 105.90 (4.89) 93.31 to 118.49
Ragos et al,12 1998 173.91 (5.41) 159.98 to 187.83
Michaëlsson et al,15 1986 112.50 (5.30) 98.49 to 126.15
Bershad et al,16 1985 119.56 (9.33) 95.54 to 143.59
Hanstad and Thune,17 1985 101.67 (8.81) 78.99 to 124.35
Pigatto et al,18 1986 107.81 (11.06) 79.31 to 136.30
Laker et al,19 1987 131.32 (20.67) 78.09 to 184.56
Melnik et al,20 1987 112.40 (6.45) 95.79 to 129.01
Lyons et al,21 1982 194.90 (12.52) 162.66 to 227.14
Jones et al,22 1983 77.61 (8.73) 55.13 to 100.09
Strauss et al,23 1984 153.50 (5.77) 138.65 to 168.35
Ostlere et al,24 1996 85.00 (10.22) 58.68 to 111.32
Strauss et al,25 2001 186.90 (2.81) 179.66 to 194.15
Altman et al,7 2002 168.28 (6.10) 152.56 to 183.99
Ferahbas et al,26 2004 101.87 (10.93) 73.73 to 130.02
Koistinen et al,27 2006 83.30 (8.90) 60.38 to 106.23
Polat et al,28 2008 97.10 (6.19) 81.17 to 113.03
Roodsari et al,29 2010 126.00 (8.83) 103.27 to 148.73
Ertugrul et al,30 2011 121.80 (10.41) 94.99 to 148.61
Dursun et al,31 2011 104.02 (7.08) 85.78 to 122.25
Karadag et al,32 2011 110.03 (8.06) 89.53 to 131.07
Erturan et al,14 2012 119.80 (11.10) 91.21 to 148.39
Vieira et al,1 2012 105.30 (5.83) 90.28 to 120.32
Random model 119.98 (8.31) 98.58 to 141.39
0 150 300
Mean (99% CI)
B Mean difference from baseline to mean follow-up

Study Mean (SE) 99% CI

Buckley et al,13 1990 38.60 (3.24) 30.26 to 46.94
Ragos et al,12 1998 70.31 (3.82) 60.47 to 80.15
Michaëlsson et al,15 1986 18.60 (4.70) 6.50 to 30.70
Bershad et al,16 1985 38.56 (6.19) 22.63 to 54.50
Hanstad and Thune,17 1985 22.87 (5.86) 7.77 to 37.98
Pigatto et al,18 1986 28.81 (7.35) 9.88 to 47.73
Laker et al,19 1987 45.42 (14.85) 7.17 to 83.67
Melnik et al,20 1987 30.60 (4.29) 19.54 to 41.66
Lyons et al,21 1982 115.20 (8.29) 93.94 to 136.56
Jones et al,22 1983 19.56 (5.81) 4.58 to 34.53
Strauss et al,23 1984 56.20 (4.07) 45.72 to 66.67
Ostlere et al,24 1996 23.00 (6.78) 5.54 to 40.46
Strauss et al,25 2001 87.70 (2.09) 82.33 to 93.07
Koistinen et al,33 2001 20.30 (5.34) 6.55 to 34.05
Separate analyses were performed
Altman et al,7 2002 46.18 (4.09) 35.63 to 56.72
for triglyceride values at various
26
Ferahbas et al, 2004 25.97 (7.79) 5.90 to 46.05 points in time, including mean (99%
Koistinen et al,27 2006 23.10 (5.91) 7.89 to 38.31 CI) nonbaseline values (A) and mean
Polat et al,28 2008 27.70 (4.18) 16.93 to 38.47 differences from baseline to mean
Roodsari et al,29 2010 35.00 (5.95) 19.68 to 50.32 follow-up (B). The National Institutes
Ertugrul et al,30 2011 28.80 (7.18) 10.31 to 47.29 of Health Clinical Center reference
Dursun et al,31 2011 26.02 (4.81) 13.62 to 38.41 value for high risk for triglycerides is
Karadag et al,32 2011 26.30 (5.36) 12.48 to 40.12
200 mg/dL. For the graph showing
the mean difference from baseline to
Erturan et al,14 2012 15.10 (7.51) −4.49 to 34.69
mean follow-up (B), a negative value
Vieira et al,1 2012 18.30 (4.10) 7.73 to 28.87
indicates a decreased value at
Random model 36.96 (5.76) 22.12 to 51.79 follow-up; a positive value, an
−150 −75 0 75 150 increased value. SI conversion factor:
Difference in Means (99% CI) To convert to millimoles per liter,
multiply by 0.0113.

the difference was 17.72 mg/dL (99% CI, 6.83-28.61 mg/dL). change in total cholesterol from baseline to 16 weeks and 20
The 2 analyses consisted of different studies because not all weeks did not demonstrate a substantial late effect of
studies reported values for all time points. However, the isotretinoin therapy.

38 JAMA Dermatology January 2016 Volume 152, Number 1 (Reprinted) jamadermatology.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 11/15/2019

 Laboratory Monitoring During Isotretinoin Therapy for Acne Original Investigation Research

Figure 3. Measures for Total Cholesterol (TC)

A Mean nonbaseline total cholesterol values

Study Mean (SE) 99% CI

Buckley et al,13 1990 201.34 (4.40) 189.99 to 212.68
Ragos et al,12 1998 200.51 (3.12) 192.46 to 208.56
Michaëlsson et al,15 1986 192.20 (4.60) 180.35 to 204.05
Hanstad and Thune,17 1985 195.70 (5.26) 182.13 to 209.26
Pigatto et al,18 1986 163.56 (11.69) 133.45 to 193.68
Laker et al,19 1987 197.10 (12.10) 165.93 to 226.27
Melnik et al,20 1987 181.30 (5.88) 166.15 to 196.45
Lyons et al,21 1982 235.90 (11.60) 206.02 to 265.78
Ostlere et al,24 1996 192.60 (7.48) 173.34 to 211.86
Strauss et al,25 2001 185.60 (2.31) 179.64 to 191.56
Koistinen et al,33 2001 167.80 (8.50) 145.91 to 189.70
Altman et al,7 2002 184.57 (3.12) 176.52 to 192.61
Ferahbas et al,26 2004 162.07 (6.76) 144.65 to 179.49
Koistinen et al,27 2006 166.30 (7.70) 146.47 to 186.13
Polat et al,28 2008 175.90 (3.99) 165.60 to 186.20
Roodsari et al,29 2010 181.90 (4.97) 169.09 to 194.71
Ertugrul et al,30 2011 168.20 (4.39) 156.87 to 179.53
Dursun et al,31 2011 173.75 (4.77) 161.46 to 186.04
Karadag et al,32 2011 179.50 (4.02) 169.14 to 189.86
Erturan et al,14 2012 184.40 (5.96) 169.04 to 199.76
Bershad et al,16 1985 (females) 169.97 (5.02) 157.03 to 182.91
Bershad et al,16 1985 (males) 185.13 (5.02) 157.03 to 182.91
Strauss et al,23 1984 (0.5-mg/kg dose) 194.24 (4.47) 182.74 to 205.75
Strauss et al,23 1984 (1.0-mg/kg dose) 203.42 (6.02) 187.92 to 218.91
Random model 184.74 (2.55) 178.17 to 191.31
0 125 250
Mean (99% CI)
B Mean difference from baseline to mean follow-up
Study Mean (SE) 99% CI
Buckley et al,13 1990 26.14 (2.95) 18.53 to 33.74
Ragos et al,12 1998 28.01 (2.27) 22.16 to 33.85
Michaëlsson et al,15 1986 15.90 (3.08) 7.98 to 23.82
Hanstad and Thune,17 1985 27.10 (4.55) 15.39 to 38.81
Pigatto et al,18 1986 7.56 (9.26) −16.28 to 31.41
Laker et al,19 1987 36.60 (8.06) 15.84 to 57.37
Melnik et al,20 1987 7.40 (4.46) −4.10 to 18.89
Lyons et al,21 1982 38.70 (7.74) 18.77 to 58.63
Ostlere et al,24 1996 34.80 (9.52) 10.28 to 59.32
Strauss et al,25 2001 23.20 (1.56) 19.18 to 27.22
Koistinen et al,33 2001 17.40 (5.66) 2.83 to 31.97
Altman et al,7 2002 13.27 (2.20) 7.61 to 18.92
Ferahbas et al,26 2004 12.47 (4.48) 0.92 to 24.02
Koistinen et al,27 2006 19.40 (5.43) 5.42 to 33.38
Separate analyses were performed
Polat et al,28 2008 21.90 (2.72) 14.90 to 28.90
for TC values at various points in time,
29
Roodsari et al, 2010 20.30 (3.43) 11.46 to 29.14 including mean (99% CI) nonbaseline
Ertugrul et al,30 2011 11.30 (2.95) 3.70 to 18.90 values (A) and mean differences from
Dursun et al,31 2011 14.75 (3.24) 6.40 to 23.10 baseline to mean follow-up (B). The
Karadag et al,32 2011 19.50 (2.90) 12.02 to 26.98 National Institutes of Health Clinical
Erturan et al,14 2012 15.10 (4.02) 4.76 to 25.44 Center reference value for high risk
Bershad et al,16 1985 (females) 13.94 (4.10) 3.42 to 24.53 for TC level is 240 mg/dL. For the
Bershad et al,16 1985 (males) 24.13 (5.78) 9.25 to 39.01
graph showing the mean difference
from baseline to mean follow-up (B),
Strauss et al,23 1984 (0.5-mg/kg dose) 13.04 (3.36) 4.38 to 21.71
a negative value indicates a
Strauss et al,23 1984 (1.0-mg/kg dose) 30.72 (4.00) 20.42 to 41.02
decreased value at follow-up; a
Random model 19.73 (1.45) 16.00 to 23.47 positive value, an increased value.
−60 −30 0 30 60 SI conversion factor: To convert to
Difference in Means (99% CI) millimoles per liter, multiply by
0.0259.

Low-Density Lipoprotein Cholesterol line and the mean follow-up period (9.7 weeks) was 16.08
The mean value of nonbaseline measurements or those made mg/dL (99% CI, 13.37-18.78 mg/dL) (eFigure 3A and B in the
during isotretinoin therapy was 109.23 mg/dL (99% CI, 103.68- Supplement). Analyses for late effects could not be made be-
114.79 mg/dL). The difference in mean values between base- cause of lack of available data.

jamadermatology.com (Reprinted) JAMA Dermatology January 2016 Volume 152, Number 1 39

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 11/15/2019

 Research Original Investigation Laboratory Monitoring During Isotretinoin Therapy for Acne

Figure 4. Measures for Aspartate Aminotransferase (AST)

A Mean nonbaseline AST values

Study Mean (SE) 99% CI

Michaëlsson et al,15 1986 26.40 (1.20) 23.31 to 29.49
Lyons et al,21 1982 17.40 (1.70) 13.02 to 21.78
Jones et al,22 1983 20.42 (1.11) 17.57 to 23.26
Strauss et al,23 1984 27.92 (0.84) 25.74 to 30.89
Altman et al,7 2002 25.15 (0.85) 22.96 to 27.34
Ferahbas et al,26 2004 20.64 (1.59) 16.79 to 24.49
Polat et al,28 2008 20.30 (0.71) 18.47 to 22.13
Ertugrul et al,30 2011 21.30 (0.74) 19.41 to 23.19
Karadag et al,32 2011 16.50 (1.16) 13.52 to 19.48
Erturan et al,14 2012 25.20 (1.76) 20.67 to 29.73
Vieira et al,1 2012 24.40 (1.42) 20.74 to 28.06
Roodsari et al,29 2010 26.80 (2.06) 21.50 to 32.10
Random model 22.67 (1.06) 19.94 to 25.41
0 30 60
Mean (99% CI)
B Mean difference for AST from baseline to mean follow-up
Study Mean (SE) 99% CI
Separate analyses were performed
Michaëlsson et al,15 1986 6.00 (0.85) 3.81 to 8.19
for AST values at various points in
Lyons et al,21 1982 3.70 (1.19) 0.65 to 6.75 time, including mean (99% CI)
Jones et al,22 1983 3.87 (0.74) 1.97 to 5.76 nonbaseline values (A) and mean
Strauss et al,23 1984 6.12 (0.62) 4.52 to 7.71 differences from baseline to mean
Altman et al,7 2002 2.15 (0.58) 0.67 to 3.63 follow-up (B). The Common
Ferahbas et al,26 2004 2.34 (1.00) −0.24 to 4.92 Terminology Criteria for Adverse
Roodsari et al,29 2011 6.50 (1.42) 2.83 to 10.17 Events reference value for grade 2
Ertugrul et al,30 2011 2.50 (0.50) 1.21 to 3.79 abnormality for AST is 108 U/L. For
the graph showing the mean
Karadag et al,32 2011 0.70 (0.77) −1.27 to 2.67
difference from baseline to mean
Erturan et al,14 2012 4.60 (1.25) 1.38 to 7.82
follow-up (B), a negative value
Vieira et al,1 2012 4.60 (0.50) 2.44 to 5.01 indicates a decreased value at
Random model 3.72 (0.50) 2.44 to 5.01 follow-up; a positive value, an
−15 −7.5 0 7.5 15 increased value. SI conversion factor:
Difference in Means (99% CI) To convert to microkatals per liter,
multiply by 0.0167.

High-Density Lipoprotein Cholesterol
The mean value of nonbaseline measurements or those made
during isotretinoin therapy was 42.80 mg/dL (99% CI, 39.84
to 45.76 mg/dL). The difference in mean values between base-
line and the mean follow-up period (9.1 weeks) was −4.82
mg/dL (99% CI, −6.72 to −2.92 mg/dL) (eFigure 3C and D in the
Supplement). Analyses for late effects could not be made be-
cause of a lack of available data in the studies.
Hepatic Panel
Aspartate Aminotransferase
The mean value of nonbaseline measurements (Figure 4A) or
those made during isotretinoin therapy was 22.67 U/L (99%
CI, 19.94-25.41 U/L). The difference in mean values between
baseline and the mean follow-up period (6.6 weeks) (Figure 4B)
was 3.72 U/L (99% CI, 2.44-5.01 U/L). Analyses for late effects
could not be made because of a lack of available data. To ex-
amine midtreatment effects of isotretinoin therapy, the dif-
ference in means between baseline and 6 weeks and 8 weeks
(eFigure 4A and B in the Supplement) was examined. For 6
weeks, the difference from baseline was 4.52 U/L (99% CI, 2.91-
6.13 U/L); for 8 weeks, the difference from baseline was 3.72
U/L (99% CI, 2.34-5.09 U/L). The 2 analyses consisted of
different studies because not all studies reported values for
all time points. However, the change in AST from baseline to
6 weeks and 8 weeks does not demonstrate a substantial
midtreatment effect of isotretinoin therapy.
Alanine Aminotransferase
The mean value of nonbaseline measurements (Figure 5A) or
those made during isotretinoin therapy was 21.77 U/L (99% CI,
18.96-24.59 U/L). The difference in mean values between base-
line and the mean follow-up period (6.5 weeks) (Figure 5B) was
3.22 U/L (99% CI, 0.99-5.45 U/L). Analyses for late effects could
not be made because of a lack of available data.
Alkaline Phosphatase
The mean value of nonbaseline measurements (eFigure 5A in
the Supplement) or those made during isotretinoin therapy was
88.35 U/L (99% CI, 58.94-117.76 U/L). The difference in mean
values between baseline and the mean follow-up period (6.6
weeks) (eFigure 5B in the Supplement) was 4.23 U/L (99% CI,
0.70-7.76 U/L). Analyses for late effects could not be made be-
cause of a lack of available data.
Complete Blood Cell Count
Analyses of hemoglobin, hematocrit, and platelet counts were
not performed because of a lack of data. The mean value of non-
baseline measurements of the white blood cell count or those
made during isotretinoin therapy was 6890/μL (99% CI,

40 JAMA Dermatology January 2016 Volume 152, Number 1 (Reprinted) jamadermatology.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 11/15/2019

 Laboratory Monitoring During Isotretinoin Therapy for Acne Original Investigation Research

Figure 5. Measures for Alanine Aminotransferase (ALT)

A Mean nonbaseline ALT values

Study Mean (SE) 99% CI

Michaëlsson et al,15 1986 22.80 (1.80) 18.16 to 27.44
Strauss et al,23 1984 23.14 (1.64) 18.92 to 27.37
Altman et al,7 2002 21.97 (1.30) 18.62 to 25.31
Ferahbas et al,26 2004 17.05 (2.88) 9.62 to 24.48
Polat et al,28 2008 22.90 (2.01) 17.72 to 28.08
Roodsari et al,29 2010 34.11 (4.30) 23.02 to 45.18
Ertugrul et al,30 2011 15.90 (1.12) 13.02 to 18.78
Karadag et al,32 2011 21.80 (0.78) 19.80 to 23.80
Erturan et al,14 2012 21.90 (2.25) 16.12 to 27.68
Vieira et al,1 2012 23.30 (2.39) 17.14 to 29.46
Random model 21.77 (1.09) 18.96 to 24.59
0 22.5 45
Separate analyses were performed
Mean (99% CI)
B Mean difference for ALT from baseline to mean follow-up for ALT and AP values at various
points in time, including mean (99%
Difference in
Study Means (SE) 99% CI CI) nonbaseline ALT values (A) and
mean differences from ALT baseline
Michaëlsson et al,15 1986 4.80 (1.20) 1.71 to 7.89
to follow-up (B). The Common
Strauss et al,23 1984 2.59 (1.19) −0.48 to 5.67
Terminology Criteria for Adverse
Altman et al,7 2002 −1.04 (1.00) −3.61 to 1.55 Events reference values for grade 2
Ferahbas et al,26 2004 0.85 (2.03) −4.39 to 6.09 abnormality for ALT is 111 U/L and for
Polat et al,28 2008 7.00 (1.47) 3.23 to 10.77 AP is 367.5 U/L, and the Merck
Roodsari et al,29 2010 12.60 (3.47) 3.66 to 21.54 Manual reference ranges for ALT and
Ertugrul et al,30 2011 0.30 (0.76) −1.66 to 2.26 AP are 0 to 35 U/L and 36 to 92 U/L,
Karadag et al,32 2011 1.90 (0.54) 0.51 to 3.29 respectively. For the graph showing
Erturan et al,14 2012 5.00 (1.50) 1.13 to 6.87 the mean difference from baseline to
mean follow-up (B), a negative value
Vieira et al,1 2012 5.10 (1.77) 0.54 to 9.67
indicates a decreased value at
Random model 3.22 (0.87) 0.99 to 5.45
follow-up; a positive value, an
−25 −12.5 0 12.5 25 increased value. SI conversion factor:
Difference in Means (99% CI) To convert to microkatals per liter,
multiply by 0.0167.

5700/μL to 8030/μL). The difference in mean values be-
tween baseline and the mean follow-up period (11.5 weeks) was
−1130/μL (99% CI, −2140/μL to −110/μL) (eFigure 6 in the
Supplement). Analyses for late effects could not be made be-
cause of a lack of available data.
Narrative Summary of Remaining Studies
Lipid Panel
Thirty-five studies were included in the qualitative analysis
(Figure 1). A subset of studies reported no significant eleva-
tions in total cholesterol,34-37 TG,35,37-39 HDL-C,40-42 and LDL-C
levels41 but did not report specific laboratory values. Several
studies reported measurable increases in serum lipids43-45 but
did not include details on the lipid type.
Triglyceride level elevations were reported, including in-
creases above 200 mg/dL in 5.0% (20 of 400),46 8.7% (41 of
473, with 3 [0.6%] discontinuing treatment),47 35.9% (75 of
209),6 and 8.3% (5 of 60)48 of the patients; above 300 mg/dL
in 10.0% (1 of 10)49 and 4.3% (4 of 94)50 of the patients; and
above 400 mg/dL in 1.5% (14 of 907),5 3.3% (7 of 209),6 and
10.0% (1 of 10)49 of the patients. Other studies reported sig-
nificant increases in 12.1% (7 of 58)51 and 35.8% (19 of 53)52 of
the patients but did not specify the threshold value.
Kaymak and Ilter53 reported elevated TG levels between
the fourth and eighth week in 22.0% (22 of 100) of the pa-
tients. Sixteen percent (16 of 100) had a TG level of 210 to 350
mg/dL, but 1.0% (1 of 100) had a TG level greater than 730
mg/dL at the fourth month, which decreased with a lowered
dosage. Cyrulnik et al54 reported that 18.8% (15 of 80) of the
patients had elevated TG levels, with 12.5% (10 of 80) be-
tween 150 and 375 mg/dL and 6.3% (5 of 80) between 376 and
750 mg/dL. Zane et al3 reported that 44.0% (4231 of 9620) of
the patients with normal baseline TG levels had an elevation
during treatment: 40.4% (3882) had mild elevations (150-375
mg/dL) and 3.6% (349) had transient and reversible moderate
to severe elevations (>375 mg/dL).
Elevated total cholesterol levels above the high-risk thresh-
old (240 mg/dL) were reported in 3.2% (3 of 94),50 13.8% (55
of 400),46 18.2% (4 of 22),55 5.0% (5 of 100),53 3.2% (2 of 63),48
and 10.5% (22 of 209)6 of the patients; elevations above 300
mg/dL were reported in 0.6% (5 of 907)5 and 1.4% (135 of 9641)
(with 0.1% [19] abnormal at baseline)3 of the patients. For pa-
tients with normal values at baseline testing, Zane et al3 re-
ported mild elevations (201-300 mg/dL) in 31.2% (2283 of 7325)
and severe elevations (≥301 mg/dL) in 0.1% (9 of 7325) of the
patients. Kaymak and Ilter53 reported elevated total choles-
terol levels (278-372 mg/dL) in 5.0% (5 of 100) of the patients.
Two studies reported elevated total cholesterol levels in
8.9% (4 of 45)56 and 7.5% (4 of 53)52 of the patients but did
not define the threshold value.
Studies reported abnormal HDL-C levels in 42.0% (58 of
138)57 and 20.0% (2 of 10) of the patients.49 A few studies com-
mented on a significant40,42,58,59 or slight60 increase in total
cholesterol levels, significant42,58,59 or slight34 increase in TG

jamadermatology.com (Reprinted) JAMA Dermatology January 2016 Volume 152, Number 1 41

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 11/15/2019

 Research Original Investigation
levels, significant increase in LDL-C levels,42,59 and significant
decrease in HDL-C levels59 but did not provide more specific data.
Liver Function Tests
Many studies reported no significant elevations in any of the
liver function tests during treatment.17,18,35,37-39,42,60,61 Several
other studies reported no elevations in individual components
including ALT,42,44 AST,6,42,44 or AP levels.6,15,22,34,51 Two
studies25,43 mentioned that a “liver panel” was performed, and
4 reported that AP levels were determined,44,49,52,53 but spe-
cific information was missing.
Moderate or higher elevations in liver function tests were
reported in 2 studies,3,62 but the thresholds were not consis-
tently defined, so they may not agree with the Common Ter-
minology Criteria for Adverse Events reference ranges. Zane et
al3 described moderate elevations (>101 U/L) in either AST or ALT
levels in 1.5% (179 of 11 676) of the patients; in comparison, 0.4%
(49 of 12 503) had a moderate abnormality at baseline. McElwee
et al62 reported moderate elevations in 1.8% (6 of 341) of the pa-
tients without baseline abnormalities (0.9% [3] discontinued the
medication). One patient (0.3%) with an elevated baseline AST
level had a transient rise to 7 times the upper limit of normal,
but treatment was not discontinued. Two studies reported a
small percentage of patients who withdrew owing to eleva-
tions in ALT or AST levels. Strauss et al25 reported 3.1% (9 of 295)
of the patients withdrew owing to elevated TG, ALT, or AST lev-
els, and Ertam et al42 indicated that 1.1% (1 of 91) of the pa-
tients discontinued therapy owing to increased ALT or AST lev-
els; the exact value was not reported.
Several studies reported elevations in liver function tests
without specific values. Four studies did not specify the com-
ponent (ALT, AST, or AP) but reported an increase in 3.8% (3 of
78),45 17.8% (8 of 45),56 2.4% (3 of 127),63 6.0% (6 of 100),53 and
3.7% (1 of 27)44 of the patients. Other studies reported eleva-
tions in ALT in 7.9% (18 of 228),57 2.1% (2 of 94),50 2.5% (10 of
400),46 and 24.5% (13 of 53)52 of the patients; AST elevation in
7.0% (16 of 228)57 and 6.3% (25 of 400)46 of the patients; and
AP elevation in 3.4% (7 of 206)57 of the patients. No patients in
any of the above studies required a reduction in isotretinoin dose
or discontinuation of therapy.
Discussion
This study was performed with the intent to shed more light
on laboratory monitoring for isotretinoin therapy since there
are major differences between the suggestions in the package
insert and multiple studies that suggest less frequent testing.5-7
This meta-analysis showed that (1) isotretinoin is associated
with a statistically significant change in the mean value of sev-
eral laboratory tests (white blood cell count and hepatic and
lipid panels), yet (2) the mean changes across a patient group
ARTICLE INFORMATION Correction: This article was corrected on January
Accepted for Publication: July 23, 2015. 13, 2016, to fix the first author’s affiliation.
Author Contributions: Drs Lee and Kirby had full
Published Online: December 2, 2015.
doi:10.1001/jamadermatol.2015.3091. access to all the data in the study and take
42 JAMA Dermatology January 2016 Volume 152, Number 1 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 11/15/2019
Laboratory Monitoring During Isotretinoin Therapy for Acne
did not meet a priori criteria for high-risk and (3) the propor-
tion of patients with laboratory abnormalities was low.
All of the 99% CIs calculated in the meta-analyses showed
a change from baseline; however, none of the intervals crossed
the predefined thresholds for high-risk or grade 2 abnormalities.
This finding indicated that 0.5% of patients, similar in charac-
teristics and treatment to study participants, are expected to have
a test result above or below the boundaries of the 99% CI. The
results of the narrative review also indicated that laboratory
changes are frequent, especially in TG and total cholesterol lev-
els, yet high-risk or severe abnormalities are infrequent. The
meta-analysis determined that changes in total cholesterol and
TG levels were similar alterations from baseline to 8 weeks or 20
weeks. These findings support the suggestions by Barth et al6 and
Altman et al7 to perform laboratory monitoring at baseline and
during the first 1 to 2 months of isotretinoin therapy rather than
continue monitoring throughout the course of treatment.
The results of this study should be considered in the con-
text of its limitations. The meta-analysis is limited by the avail-
ability of extant data and the completeness of the reports. We
did not have access to information about the patients or the
treatment, so associations between isotretinoin doses or dose
changes could not be correlated with specific laboratory
abnormalities. Similarly, we were not able to investigate the
fasting or nonfasting status of patients at the time of testing
and correlation with laboratory results since these data
were limited.
The findings of this study suggest that less frequent labo-
ratory monitoring may be safe, with few missed high-risk labo-
ratory changes, for many patients with acne who are receiv-
ing typical doses of isotretinoin. Clinical judgment should be
used to determine monitoring frequency for each patient based
on baseline laboratory findings and concomitant conditions,
such as preexisting liver disease, concomitant use of hepato-
toxic medications, or metabolic syndrome, which may in-
crease the risk of laboratory abnormalities.
Conclusions
The results of this study do not support the use of monthly
laboratory tests for all patients with acne who receive stan-
dard doses of isotretinoin. A decrease in the frequency of labo-
ratory monitoring for some patients could help to decrease
health care spending and potential anxiety-provoking blood
sampling. At our institution, we perform a lipid and hepatic
panel at baseline and after 2 months of isotretinoin treat-
ment, with more frequent monitoring dictated by baseline ab-
normalities and medical history. Further studies may be needed
to investigate the influence of patient characteristics, which
may allow risk stratification and, subsequently, clinically in-
dicated and cost-efficient monitoring.
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Lee.
jamadermatology.com
 Laboratory Monitoring During Isotretinoin Therapy for Acne
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Lee, Scharnitz, Chen,
Gupta-Elera, Kirby.
Critical revision of the manuscript for important
intellectual content: Lee, Scharnitz, Muscat.
Statistical analysis: Lee, Scharnitz, Muscat, Chen,
Gupta-Elera.
Obtained funding: Lee, Kirby.
Administrative, technical, or material support: Kirby.
Study supervision: Kirby.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by
grant 106485 from the American Acne and Rosacea
Society.
Role of the Funder/Sponsor: The funding
organization had no role in the design and conduct
of the study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Previous Presentation: Parts of this work were
presented as an abstract at the Society for
Investigative Dermatology Annual Meeting; May 7,
2015; Atlanta, Georgia.
REFERENCES
1. Vieira AS, Beijamini V, Melchiors AC. The effect of
isotretinoin on triglycerides and liver
aminotransferases. An Bras Dermatol. 2012;87(3):
382-387.
2. Flynn WJ, Freeman PG, Wickboldt LG.
Pancreatitis associated with isotretinoin-induced
hypertriglyceridemia. Ann Intern Med. 1987;107(1):
63.
3. Zane LT, Leyden WA, Marqueling AL, Manos MM.
A population-based analysis of laboratory
abnormalities during isotretinoin therapy for acne
vulgaris. Arch Dermatol. 2006;142(8):1016-1022.
4. Roche Laboratories. Accutane (isotretinoin
capsules). http://www.accessdata.fda.gov/drugsatfda
_docs/label/2008/018662s059lbl.pdf. Published
November 2008. Accessed July 5, 2014.
5. Alcalay J, Landau M, Zucker A. Analysis of
laboratory data in acne patients treated with
isotretinoin: is there really a need to perform
routine laboratory tests? J Dermatolog Treat. 2001;
12(1):9-12.
6. Barth JH, Macdonald-Hull SP, Mark J, Jones RG,
Cunliffe WJ. Isotretinoin therapy for acne vulgaris:
a re-evaluation of the need for measurements of
plasma lipids and liver function tests. Br J Dermatol.
1993;129(6):704-707.
7. 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.
8. Hansen T, Zaenglein A, Miller J. Standardizing
laboratory monitoring of patients undergoing
isotretinoin treatment using a cost-effective and
best evidence approach [abstract]. J Am Acad
Dermatol. 2013;68(4)(suppl 1):AB6.
9. University of York Centres for Reviews and
Dissemination. PROSPERO database: laboratory
monitoring during treatment with isotretinoin.
Registration CRD42014010494. http://www.crd.york
.ac.uk/prospero. Accessed July 3, 2014.
jamadermatology.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 11/15/2019
10. National Institutes of Health. Clinical Center
Test Guide: Lipid Panel. Washington, DC: US Dept of
Health and Human Services; 2015.
11. National Institutes of Health. Clinical Center Test
Guide: Hepatic Panel. Washington, DC: US Dept of
Health and Human Services; 2015.
12. Ragos G, Houlden R, Danby FW. Effect of
isotretinoin therapy on serum total cholesterol and
triglycerides. Can J Clin Pharmacol. 1998;5(1):43-47.
13. Buckley D, Rogers S, Daly P. Isotretinoin therapy
for acne vulgaris: results in an Irish population. Ir J
Med Sci. 1990;159(1):2-5.
14. Erturan İ, Naziroğlu M, Akkaya VB. Isotretinoin
treatment induces oxidative toxicity in blood of
patients with acne vulgaris: a clinical pilot study. Cell
Biochem Funct. 2012;30(7):552-557.
15. 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.
16. Bershad S, Rubinstein A, Paterniti JR, et al.
Changes in plasma lipids and lipoproteins during
isotretinoin therapy for acne. N Engl J Med. 1985;
313(16):981-985.
17. Hanstad IK, Thune P. Nodulocystic acne:
treatment with isotretinoin (Roaccutan)—
quantitative measures of skin lipids [in Norwegian].
Tidsskr Nor Laegeforen. 1985;105(23):1497-1500.
18. 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.
19. Laker MF, Green C, Bhuiyan AK, Shuster S.
Isotretinoin and serum lipids: studies on fatty acid,
apolipoprotein and intermediary metabolism. Br J
Dermatol. 1987;117(2):203-206.
20. Melnik B, Bros U, Plewig G. Characterization of
apoprotein metabolism and atherogenic
lipoproteins during oral isotretinoin treatment.
Dermatologica. 1987;175(suppl 1):158-168.
21. Lyons F, Laker MF, Marsden JR, Manuel R,
Shuster S. Effect of oral 13-cis-retinoic acid on
serum lipids. Br J Dermatol. 1982;107(5):591-595.
22. Jones DH, King K, Miller AJ, Cunliffe WJ.
A dose-response study of I3-cis-retinoic acid in acne
vulgaris. Br J Dermatol. 1983;108(3):333-343.
23. Strauss JS, Rapini RP, Shalita AR, et al.
Isotretinoin therapy for acne: results of a
multicenter dose-response study. J Am Acad
Dermatol. 1984;10(3):490-496.
24. 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. 1996;35(3):216-218.
25. 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. 2001;45(2):196-207.
26. 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. 2004;15(3):153-157.
27. 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. 2006;49(2):383-386.
(Reprinted) JAMA Dermatology January 2016 Volume 152, Number 1
Original Investigation Research
28. Polat M, Lenk N, Bingöl 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.
29. 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. 2010;35(6):624-626.
30. Ertugrul DT, Karadag AS, Tutal E, Akin KO.
Isotretinoin does not induce insulin resistance in
patients with acne. Clin Exp Dermatol. 2011;36(2):
124-128.
31. 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. 2011;10(7):710-714.
32. 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. 2011;50(12):1564-1569.
33. 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. 2001;17(5):391-395.
34. Rødland O, Aksnes L, Nilsen A, Morken T.
Serum levels of vitamin D metabolites in
isotretinoin-treated acne patients. Acta Derm
Venereol. 1992;72(3):217-219.
35. Hoting VE, Schütte B, Schirren C. Isotretinoin
treatment of acne conglobate: andrologic follow-up
[in German]. Fortschr Med. 1992;110(23):427-430.
36. Bruhat MA, Mage G, Manhes H, Pouly JL,
Jacquetin B. The indication for laparoscopy in
female infertility [in French]. J Gynecol Obstet Biol
Reprod (Paris). 1980;9(3):337-340.
37. Meigel W, Gollnick H, Wokalek H, Plewig G. Oral
treatment of acne conglobata using 13-cis-retinoic
acid: results of the German multicentric study
following 24 weeks of treatment [in German].
Hautarzt. 1983;34(8):387-397.
38. Plewig G, Gollnick H, Meigel W, Wokalek H.
13-Cis retinoic acid in the oral therapy of acne
conglobate: results of a multi-center study [in
German]. Hautarzt. 1981;32(12):634-646.
39. Wagner A, Plewig G. 13-Cis-retinoic acid:
pharmacologic and toxicologic findings in
treatment of severe forms of acne [in German].
MMW Munch Med Wochenschr. 1980;122(38):1294-
1300.
40. Effects of isotretinoin on plasma lipids and
lipoproteins. Nutr Rev. 1986;44(6):196-198.
41. Zech LA, Gross EG, Peck GL, Brewer HB.
Changes in plasma cholesterol and triglyceride
levels after treatment with oral isotretinoin:
a prospective study. Arch Dermatol. 1983;119(12):
987-993.
42. Ertam I, Alper S, Unal I. Is it necessary to have
routine blood tests in patients treated with
isotretinoin? J Dermatolog Treat. 2006;17(4):214-216.
43. Wahab R, Rahman M, Monamie N, Jamaluddin
M, Khondker L, Afroz W. Isotretinoin vs weekly
pulse dose azithromycin in the treatment of acne—a
comparative study. J Pak Assoc Dermatol. 2008;18:
9-14.
43
 Research Original Investigation
44. Agarwal US, Besarwal RK, Bhola K. Oral
isotretinoin in different dose regimens for acne
vulgaris: a randomized comparative trial. Indian J
Dermatol Venereol Leprol. 2011;77(6):688-694.
45. Ahmed I, Wahid Z, Nasreen S. Adverse effects
of systemic isotretinoin therapy: a study of 78
patients. J Pak Assoc Dermatol. 2005;15:242-246.
46. Tallab T, Joharji H, Jazei M, Bahamdan K,
Ibrahim K, Karkashan E. Isotretinoin therapy: any
need for laboratory assessment? West Afr J Med.
2004;23(4):273-275.
47. Sadick NA. Practitioner’s 10-year experience
with isotretinoin and side effect profiles. Int J
Cosmet Surg Aesthetic Dermatol. 2002;4(2):89-94.
48. Ng PP, Goh CL. Treatment outcome of acne
vulgaris with oral isotretinoin in 89 patients. Int J
Dermatol. 1999;38(3):213-216.
49. Spear KL, Muller SA. Treatment of cystic acne
with 13-cis-retinoic acid. Mayo Clin Proc. 1983;58
(8):509-514.
50. Hermes B, Praetel C, Henz BM. Medium dose
isotretinoin for the treatment of acne. J Eur Acad
Dermatol Venereol. 1998;11(2):117-121.
51. 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.
44 JAMA Dermatology January 2016 Volume 152, Number 1 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 11/15/2019
Laboratory Monitoring During Isotretinoin Therapy for Acne
52. Shahidullah M, Tham SN, Goh CL. Isotretinoin
therapy in acne vulgaris: a 10-year retrospective
study in Singapore. Int J Dermatol. 1994;33(1):60-
63.
53. Kaymak Y, Ilter N. The results and side effects
of systemic isotretinoin treatment in 100 patients
with acne vulgaris. Dermatol Nurs. 2006;18(6):576-
580.
54. Cyrulnik AA, Viola KV, Gewirtzman AJ, Cohen
SR. High-dose isotretinoin in acne vulgaris:
improved treatment outcomes and quality of life.
Int J Dermatol. 2012;51(9):1123-1130.
55. Gandola M. Therapy of severe acne and acne
rosacea with oral 13-cis-retinoic acid (isotretinoin)
[in Italian]. Acta Vitaminol Enzymol. 1984;6(4):325-
337.
56. Bruno NP, Beacham BE, Burnett JW. Adverse
effects of isotretinoin therapy. Cutis.
1984;33(5):484-486, 489.
57. Entezari-Maleki T, Hadjibabaeil M, Salamzadeh
J, Javadil MR, Shalviri G, Gholamil K. Evaluation and
monitoring of isotretinoin use in Iran. Arch Iran Med.
2012;15(7):409-412.
58. Gollnick H, Luley C, Schwartzkopff W, Orfanos
CE. Changes in serum lipid fractions as a side effect
of oral retinoids [in German]. Z Hautkr. 1982;57(17):
1255-1267.
59. O’Leary TJ, Simo IE, Kanigsberg N, Walker J,
Goodall JC, Ooi TC. Changes in serum lipoproteins
and high-density lipoprotein composition during
isotretinoin therapy. Clin Invest Med. 1987;10(4):
355-360.
60. Amblard P, Beani JC, Reymond JL, Didier B,
Coignet M. Our experience of isotretinoin in the
treatment of severe acne for about 421 treated
patients [in French]. Sem Hop Ther Paris. 1986;
62(1-2):61-66.
61. Almond-Roesler B, Blume-Peytavi U, Bisson S,
Krahn M, Rohloff E, Orfanos CE. Monitoring of
isotretinoin therapy by measuring the plasma levels
of isotretinoin and 4-oxo-isotretinoin: a useful tool
for management of severe acne. Dermatology.
1998;196(1):176-181.
62. McElwee NE, Schumacher MC, Johnson SC,
et al. An observational study of isotretinoin
recipients treated for acne in a health maintenance
organization. Arch Dermatol. 1991;127(3):341-346.
63. Al-Mutairi N, Manchanda Y, Nour-Eldin O,
Sultan A. Isotretinoin in acne vulgaris: a prospective
analysis of 160 cases from Kuwait. J Drugs Dermatol.
2005;4(3):369-373.
jamadermatology.com