Oral Isotretinoin For The Treatment of Dermatologic Conditions Other Than Acne: A Systematic Review and Discussion of Future Directions

Archives of Dermatological Research
https://doi.org/10.1007/s00403-020-02152-4
REVIEW
Oral isotretinoin for the treatment of dermatologic conditions other

than acne: a systematic review and discussion of future directions
Sherman Chu1,2 · Lauren Michelle2 · Chloe Ekelem2 · Calvin T. Sung2 · Nathan Rojek2 · Natasha A. Mesinkovska2
Received: 13 June 2020 / Revised: 29 September 2020 / Accepted: 9 October 2020

© Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract
While isotretinoin has been the gold-standard of therapy for severe acne since its approval in 1982, its anti-inflammatory
properties makes it a potentially applicable and versatile therapy for a wide variety of dermatologic conditions yet to be
explored. This systematic review comprehensively recounts the success of oral isotretinoin in non-acne cutaneous diseases
and provide insight into future directions of isotretinoin utility. A systematic literature review was performed using PubMed.
Search terms included “isotretinoin” OR “accutane” AND “skin” OR “dermatology” OR “hair” OR “nails” OR “rosacea”
OR “psoriasis” OR “pityriasis rubra pilaris” OR “condyloma acuminata” OR “granuloma annulare” OR “darier’s disease”
OR “non-melanoma skin cancer” OR “frontal fibrosing alopecia” OR “cutaneous lupus erythematosus” OR “hidradenitis
suppurativa” OR “photodamaged skin” OR “skin aging” OR “wart” OR “flat warts” OR “plane warts” OR “lichen planus”
OR “dissecting cellulitis” OR “folliculitis decalvans” OR “sebaceous hyperplasia” OR “cutaneous t-cell lymphoma” OR
“mycosis fungoides.” A total of 169 studies discuss the use of oral isotretinoin for 16 non-acne dermatologic conditions,
the most common being non-melanoma skin cancers (0.2–8.2 mg/kg/day), cutaneous T-cell lymphomas (0.5–2 mg/kg/day),
and rosacea (0.22–1 mg/kg/day). Inflammatory conditions such as rosacea, granuloma annulare, and hidradenitis suppura-
tiva benefit from lower oral isotretinoin dosage of 0.3–1 mg/kg/day, whereas, hyperkeratotic diseases such as psoriasis and
pityriasis rubra pilaris, consistently respond better to higher dosages of up to 2–4 mg/kg/day for lesion clearance. Recur-
rence of disease following discontinuation of isotretinoin have been reported for rosacea, psoriasis, granuloma annulare,
Darier’s disease, dissecting cellulitis, and non-melanoma skin cancers. Disease exacerbation was reported in some patients
with hidradenitis suppurativa. Off-label isotretinoin is an effective treatment choice for dermatological conditions beyond
acne. Further prospective, randomized human trials are needed to clarify when and how to prescribe off-label isotretinoin
for maximum efficacy and safety.
Keywords Isotretinoin · Dermatology · Accutane · Cutaneous
Introduction of sebaceous glands, decrease sebum excretion, and reduce

Cutibacterium acnes make it an effective therapy for acne
Oral isotretinoin (13-cis-retinoic acid) is a synthetic retinol [1, 2]. The strict FDA regulations on prescribers limit its use
analog that was first approved by the US Food and Drug due to teratogenicity, yet isotretinoin prescriptions continue
Administration (FDA) in 1982 for treating severe acne. Ini- to increase not only among dermatologists but also general
tial research on isotretinoin was conducted to explore it as a practitioners, likely because of its pleiotropic effects on a
cancer treatment, but isotretinoin’s ability to cause atrophy host of skin conditions other than acne [3]. An estimated
1.4 million isotretinoin prescriptions are written annually in
the United States alone [3]. Retrospective utilization studies
* Sherman Chu
sherman.chu@westernu.edu have shown that up to 70% of prescriptions for oral isotreti-
noin are given first-line without the recommended trial of
1
College of Osteopathic Medicine of the Pacific, Northwest, topical retinoids, and are being used off-label for conditions
Western University of Health Sciences, 200 Mullins Dr., such as mild-to-moderate acne, acne-related and hyperkera-
Lebanon, OR 97355, USA
totic dermatoses, and cutaneous neoplasms [1, 4–7].
2
Department of Dermatology, University of California, Irvine,
Irvine, CA 92697, USA
13
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Pharmacologic rationale exists for isotretinoin’s anti- were extracted to Table 1. Studies included for review were
inflammatory and immunomodulatory effects on skin con- graded using the Oxford Center for Evidence-Based Medi-
ditions. Retinoic acid isomers were initially discovered cine 2011 Levels of Evidence [13].
because of their role in cell differentiation and prevention
of epithelial tumorigenesis through lysosome stabilization
and regulation of epithelial cell growth [8]. Isotretinoin, like Results
all metabolites of retinoids, binds to nuclear receptors known
as retinoic acid receptors (RAR and RXR) [9]. Once acti- A total of 169 reports were eligible for inclusion in this
vated, these receptors regulate gene transcription leading to review. Of these studies, 20 are randomized control trials
cellular activity changes ranging from cell-cycle progres- (RCTs), 112 are case reports or series, 18 are prospective
sion, differentiation of keratinocytes, and apoptosis [1] to cohort studies, and 19 are retrospective cohort studies.
modulation of interleukin-2 (IL-2), interferon γ (IFN-γ), and Retrieved number of studies and patients in the different
T and B lymphocyte function [5, 10–12] Further, isotretinoin conditions found is detailed in Table 2. The selection pro-
can be exploited for keratolysis and decreased neutrophil cess of these included articles is shown in the PRISMA flow
migration, a trait useful in conditions such as psoriasis and diagram in Fig. 1.
hidradenitis suppurativa. It can also be used to modulate
signaling factors, such as epidermal growth factor (EGF) Non‑melanoma skin cancer (NMSC)
and cyclic adenosine monophosphate (cAMP), responsible
for epidermal proliferation and differentiation in cutaneous Study demographics
neoplasms [5, 10].
Given the breadth of where isotretinoin can be useful, this The keratinocyte carcinomas, including basal cell carcinoma
systematic review aims to describe the evidence for the use (BCC) and squamous cell carcinoma (SCC), are two types of
of oral isotretinoin in the treatment of dermatologic condi- NMSC that are caused by uncontrolled or atypical keratino-
tions other than acne. cyte proliferation [14]. Retinoids have been used for chemo-
prevention and suppression through its ability to induce cell
differentiation and apoptosis, modulate cell growth, and
Materials and methods restore to near-normal levels of nuclear retinoid receptor
beta (RAR beta) [15]. Thirty-one studies described the use
A search for peer-reviewed articles was performed in Sep- of isotretinoin for the treatment of non-melanoma skin can-
tember 2019 using the PubMed and Web of Science data- cer in 2620 patients, dose ranged from 0.2 to 8.2 mg/kg/day
bases according to PRISMA guidelines and using search [16–45]. Over half of patients included in these reports were
terms: (isotretinoin OR accutane) AND (rosacea OR psoria- treated for multiple types of NMSC simultaneously, and with
sis OR pityriasis rubra pilaris OR condyloma acuminata OR the exception of 55 subjects treated for KA, leukoplakia, or
genital warts OR granuloma annulare OR darier’s disease XP, all results pertained to either BCC or SCC clearance and
OR non-melanoma skin cancer OR skin cancer OR fron- prevention. Combination therapies with isotretinoin included
tal fibrosing alopecia OR lichen planopilaris OR cutaneous IFNα-2a, calcitriol, or chemotherapy [19, 20, 22, 33].
lupus erythematosus OR hidradenitis suppurativa OR pho-
todamaged skin OR skin aging OR wart OR flat warts OR Basal cell carcinoma treatment
plane warts OR lichen planus OR dissecting cellulitis OR
sebaceous hyperplasia OR cutaneous T cell lymphoma OR In patients treated for BCC, several case reports/series used
mycosis fungoides). Subsequent review of article bibliogra- oral isotretinoin therapy (0.2–8.2 mg/kg/day) resulted in
phies was also performed. partial or complete regression of 36–50% of lesions after
Retrieved articles were screened based on eligibil- treating for two months to one year, with regression as early
ity criteria. All available studies prior to September 2019 as three weeks [16–18]. However, a RCT of 981 patients
were considered for inclusion. The inclusion criteria were reported therapy with 10 mg/day oral isotretinoin showed no
relevant articles discussing the treatment of humans with difference in the annual rate of BCC annual formation when
oral isotretinoin and clearly stating non-acne dermatologic compared to placebo [46].
diagnoses. Case reports and series, randomized controlled Squamous Cell Carcinoma Treatment: In patients with
trials, and prospective and retrospective cohort studies were treated for SCC, oral isotretinoin monotherapy dosage
included. Exclusion criteria included: studies written in lan- ranged from 0.5 to 3 mg/kg/day. Twelve of 34 (35.3%)
guages other than English, studies that did not involve the patients treated with isotretinoin monotherapy had malig-
use of oral isotretinoin, reviews, and animal studies were nant lesion regression as soon as two weeks of treatment
excluded. Study design, level of evidence, and outcome data [21, 23–25]. One case series and one prospective study
13
Table 1 Outline of the level of evidence, study design, and outcomes for each study included in the review of oral isotretinoin treatment for non-acne dermatologic conditions
Author and year Level of Study design Sample size (n) Patient demographics and Isotretinoin treatment Course Adverse effects
evidence skin type
Rosacea (15); n = 991

Bostanci et al. (2010) [67] 4 Case series 8 8 M, Mean 62yo 10 mg/d (< 85 kg) or 20 mg/d Failed doxycycline, minocy- Elevated cholesterol, creatinine,
(> 85 kg) × 8 wk cline, topical erythromycin, or GGT (5)
tetracycline, topical isotreti-
noin, and/or topical steroids.
All pts showed improvement
at 4–8 wk. 1/8 w/complete
remission
Erdogan et al. (1998) [74] 2 Prospective 22 4 M, 18 F, Mean 49.1yo 10 mg/d × 16 wk Mean duration illness 6.5 yrs; Dry eyes (18), facial xerosis
previously failed topical (14), erythema (5), burning
steroids (n = 18), topical eyes (5), elevated TG (5)
metronidazole (n = 11),
systemic tetracycline and/
or metronidazole (n = 22).
Significant improvement of
erythema, telangiectasia,
and papules at 9 and 16 wks.
Pustular decrease plateaued
at 9 wks
Ertl et al. (1994) [64] 1 RCT 20 10 M, 10F, Mean 59yo 10 mg/d oral vs. 0.025% topi- Mean duration disease 6.6 yrs. Mild cheilitis, facial xerosis,
(34–77 yo) cal vs. combination × 32 wk One prior tx (n = 8), two epistaxis (1), conjunctivitis (1)
prior tx (n = 4), three prior
tx (n = 5); all unknown. Peak
effect at 16 weeks: 3 subjects
combination pts, 1 isotreti-
noin, and 1 topical showed
resolution
Gollnick et al. (2010) [65] 1 RCT 549 259 M, 290 F, 20–91 yo 0.1 mg/kg vs. 0.3 mg/kg vs. 24% 0.3 mg/kg/d pts w/com- Cheilitis (4), headache (5),
0.5 mg/kg × 12 wk plete remission after 12 wks weakness or fatigue (3),
(vs 13.6% doxycycline pts) leg pain (1), vertigo (1), GI
upset (6)
Hoting et al. (1986) [75] 2 Prospective 92 51 M (Mean 45.2yo; 17–74), 0.5 mg/kg/d × 20 wk Mean duration disease 6.9 yrs. Cheilitis, mouth, or skin (92),
41 F (Mean 47.2 yo; 25–73) 79 pts received various failed conjunctivitis (40), skin
treatments. Mean number thinning (34), pruritus (30),
of papules at baseline: 42, myalgia or arthralgia (17),
wk 12: 9, wk 20: 5. Edema, hair loss (7), epistaxis (5),
erythema, telangiectasia headache (4)
improved
Debroy et al. (2016) [68] 4 Case study 1 1 M, 37 yo 20–60 mg/d + trimethioprim Skin was clear after 6 mo Adverse events not discussed
300 mg BID + oral predniso- 60 mg/d isotretinoin and
lone 0.5 mg/kg/d × 1 wk remained clear at 1 yr w/
trimethoprim alone. Pred-
nisolone dosage reduced
overtime
13
Table 1 (continued)
evidence skin type
13
Marsden et al. (1984) [69] 4 Case series 7 2 M, 5 F, 29-60 yo 1 mg/kg/d × 12 wk Mean duration disease 4.6 yrs, Cheilitis (7), dermatitis (4),
failed tetracycline (n = 7). Cheilitis of eyes (2)
Significant decrease in
papules/plaques w/ response
plateau at 6 wk. Relapse at
8 weeks post therapy, but
severity still lower than
pretreatment
McFalda and Roebuck 4 Case report 1 1 M, 78 yo, FST II 40 mg 2 × /wk w/ 15% azelaic Failed topical metronidazole. Adverse events not discussed
(2011) [78] acid gel BID Significant reduction of
papules, pustules, erythema
nasal phymatous, and scaling
at 3 mo
Rademaker (2018) [76] 3 Retrospective 52 19 M, 33 F, Mean 48 yo 10-40 mg/day × 57 wk Failed topical anti-inflam- Cheilitis (29, 1 pt discontinued
(18–86 yo) matories and systemic from severity), eczema (4),
tetracyclines. 42/46 (91%) infections (2; Herpes zoster,
pts cleared or had 75–99% breast infection), muscle ache
reduction of papulopustules (1), mood change (1), epistaxis
after a mean of 57 wks (1), skin fragility (1)
Sbidian et al. (2016) [66] 1 RCT 156 56 M, 100 F, Median 47.5 yo 0.22–0.26 mg/kg/d vs pla- Median duration disease 5 yrs; Cheilitis, skin, or eyes (33),
(20.9–80.7 yo) cebo × 4 mo 49 pts in isotretinoin group headache (4), abdominal pain
failed cyclines. 57.4% of (11), myalgias/arthralgias (6),
isotretinoin pts had > 90% epistaxis (8), elevated TG or
decrease in lesions at 4mos. LFTs (8)
58.3% isotretinoin relapse 15
wk post-treatment
Schmidt et al. (1984) [70] 4 Case series 12 8 M, 5 F, 39–80 yo 60 mg/d × 16 wk Average duration disease 7 yrs; Cheilitis (10), dry mucosa (4),
8 pts failed oral tetracycline. pruritus (6)
Reduction in lesions as
early as 2 wks; a significant
decrease in papules/pustules
at 4–6 wk
> 50% reduction in sebaceous
gland size w/ 20% decrease
in dermal thickness
Turjanmaa and Reunala 4 Case series 20 10 M, 10 F, 32–76 yo 0.5–1 mg/kg/d × 3–6 mo Mean disease duration 10 yrs; Dryness of lips/nose (20), tin-
(1987) [71] 20 pts failed oral tetracy- nitus/headache (1)
cline, 5 failed metronidazole,
5 failed chloroquine. Papu-
lopustular lesions cleared
rapidly in all pts, as early as
1mo. 17/20 pts no relapse at
1 yr FU
Table 1 (continued)
evidence skin type
Uslu et al. (2012) [72] 4 Case series 25 7 M, 18 F, Mean 46.2 yo 20 mg/d × 4 mo w/6 mo taper Mean disease duration 4.8 Cheilitis (23), dry face (3),
(28–65 yo) off after yrs; 5 pts failed topical pruritic dermatitis (2)
metronidazole, azelaic acid,
tetracycle; 20 failed systemic
doxycycline, tetraycline. Sig-
nificant reduction in papule/
pustule counts, erythema,
sebum score at 1 mo. 45%
relapse at 11 mo FU
Wee and Tan. (2017) [73] 4 Case report 1 1 M, 48 yo 20 mg/d × 32 wk w/ 10 mg/d Reduced sebaceous hyperpla- Adverse events not discussed
maintenance indefinitely sia and induration at 2 mo
Reduced forehead/cheek folds
at 6 mo
Kwon et al. (2019) [77] 3 Retrospective 25 10 M, 15 F; 26–55 yo; FST III 10 mg/d × 8 wk w/3 consecu- All patients failed doxy- Skin dryness (8), cheilitis (8)
(n = 13), FST IV (n = 12) tive weeks of PDL and FMR cycline, minocycline,
at 4 wk intervals topical pimecrolimus, topical
metronidazole, topical
ivermectin, or pulsed dye
laser. Papulopustular lesions
decreased by 78.3% after 3
sessions of PDL and FMR
w/ daily isotretinoin, 70.5%
reduction remained at 24wk
follow-up
Psoriasis (8); n = 184
Al-Shobaili et al. (2007) 4 Case report 1 1 F, 16 yo 0.75 mg/kg/d w/topical steroid Generalized pustular variant. Adverse events not discussed
[153] Failed methotrexate. Lesions
cleared, maintained excellent
control of disease
Anstey and Hawk (1997) 4 Case series 4 4 F, 22–30 yo 0.4–0.6 mg/kg/d w/PUVA Palmoplantar pustulosis Adverse events not discussed
[154] variant. Inadequate therapy
with PUVA. All patients
cleared, relapsed 2–3 mo
post-treatment
Gahalaut et al. (2014) [151] 1 RCT 35 29 M (Mean 40.55 yo), 11F 0.5 mg/kg/d w/PUVAsol vs Plaque variant. Duration of Cheilitis (14), nausea (12),
(Mean 35.65 yo); 5 pts PUVAsol × 12 wk disease 3.95 yrs (M), 5 yrs erythema (1), pruritus (1)
excluded, FST IV (F). Washout of 2 and 4wks
prior to therapy. PASI 75:
63.15% isotretinoin pts at
8wk vs 12.5% control pts
after 10wk
Honigsmann & Wolff (1983) 4 Case series 60 N/A 1 mg/kg/d w/PUVA × vs etreti- Unknown variant. No signifi- Adverse events not discussed
[155] nate 1 mg/kg/d × 5 days cant difference between the
isotretinoin and etreinate
groups
13
Table 1 (continued)
evidence skin type
13
Mortazavi et al. (2011) [152] 1 RCT 37 25 M, 12 F; 2 pts excluded; 0.5 mg/kg/d w/NBUVB vs Plaque variant. Mean disease Mild erythema, pruritus and
Mean 37.47 yo placebo w/NBUVB × 14 wks duration 10.94 yrs. 14/17 nausea
isotretinoin vs 13/20 placebo
w/ complete clearance with
a significant difference in
mean sessions (38.15 vs
30.29, respectively). PASI
not significant after 10wk.
(p = 0.324)
Moy et al. (1985) [158] 2 Prospective 40 29 M, 11 F, 24–85 yo 1.5–2 mg/kg/d vs etretinate Generalized pustular psoriasis Adverse events not discussed
0.75 mg/kg/d (n = 11), chronic plaque pso-
riasis (n = 29). Generalized
pustular psoriasis pts failed
methotrexate, PUVA, topi-
cal/intramuscular steroids.
Isotretinoin pts cleared:
10/11 pustular pts after mean
3.4 days and 4/10 plaque pts
after 8 wks. Etretinate: 18/19
pts cleared after 8wk
Sofen et al. (1984) [156] 4 Case series 5 4 M (24–66 yo), 1 yo 1.2–1.75 mg/kg/d Generalized pustular variant. Adverse events not discussed
Failed parenteral/topical/
intramuscular corticoster-
oids, PUVA, UVB, and/
or methotrexate. Pustules
resolved in 1 week for all
cases. Recurrence of pus-
tules with taper to 0.75 mg/
kg/d in one case
Wilken et al. (2015) [157] 4 Case series 2 1 M 56 yo, 1 F 64 yo 30-40 mg/d Palmoplantar pustulosis vari- Facial dryness (2), cheilitis (2)
ant. Failed topical clobetasol.
Near complete resolution of
palmar plaques at 4 wk and
plantar at 6 wk
Lichen planopilaris (6); n = 61
Pedrosa et al. (2017) [184] 4 Case series 10 9 F, 1 M, Mean 44.5 yo 10 mg eod w/ finasteride Median disease duration 12mo. Adverse events not discussed
(29–60 yo) 2.5–5 mg/d or spirono- Decreased facial papules and
lactone 25–50 mg/d w/ skin roughness at 2 mo
vitamins and pimecrolimus 10/10 pts w/ no further pro-
cream × ≥ 12 mo gression after post-treatment
at 12 mo
Pirmez et al. (2017) [185] 4 Case series 3 3 F, 49–53 yo 20 mg/d × 1 mo, titrated to 1 pt failed oral doxycycline, Adverse events not discussed
0.5 mg/kg/d × 2 mo topical tacrolimus, triam-
cinolone injections. Facial
papules completely resolved,
w/ perifollicular erythema
and scaling unchanged 3/3
after 3 mos. Improvement
seen after 1 mo
Table 1 (continued)
evidence skin type
Rakowska et al. (2017) [182] 3 Retrospective 29 29 F 20 mg/d × 24 mo Previously tried finasteride or Adverse events not discussed
retinoid treatment. 22/29 pts
w/ no further progression of
hair loss after 12 mo. 21/29
w/ no further progression
after post-treatment
Babahosseini et al. (2018) 3 Retrospective 11 N/A 20 mg/d or 20 mg/d w/5-alpha 5aRIs and isotretinoin most Xerosis (3), hyperlipidemia (1),
[180] reductase inhibitors (5aRI; effective drugs for FFA. GI upset (1), 1 pt discontinued
finasteride, dutasteride) 6/7 pts with isotretinoin due to xerosis

monotherapy had a complete
response to therapy. 3/4 pts
with combination isotreti-
noin and 5aRI therapy had
a complete response, while
1 pt had partial response.
Response weighed by the
improvement of symptoms,
negative pull test, and
decrease in facial papules
Namazi et al. (2018) [186] 4 Case series 4 1 M 30 yo, 3 F (35–50 yo) 20 mg/d w/finasteride 5 mg/d Failed hydroxychloroquine, Adverse events not discussed
(n = 1), isotretinoin 20 mg/d cyclosporine, mycopheno-
(n = 3) late, topical corticosteroids,
and/or laser therapy. 1 pt
responded to isotretinoin
and finasteride combina-
tion therapy; FFA progress
stopping with improved
perifollicular erythema and
scaling. 2 pts responded well
to isotretinoin monotherapy
(facial lesions disappeared).
1 pt did not respond
Mardones and Shapiro 3 Retrospective 4 N/A 20 mg/d w/cetirizine 5 mg/d Used in pts w/classic lichen Adverse effects not discussed
(2017) [181] and topical clobetasol planopilaris suffering from
0.05% × 12mo scalp hyperseborrhoea;
no pts achieved complete
remission
Pityriasis rubra pilaris (11); n = 122
Allison et al. (2002) [110] 4 Case series 6 16–19 yo 0.75–1.5 mg/kg/d × 6 mo Type III PRP. 5 pts w/ Adverse events not discussed
complete lesion clearance
at < 6 months
Borok and Lowe (1990) 3 Retrospective 15 14 M (Mean 56 yo), 1 F 1.06–1.64 mg/kg/d × 1–24 mo Mean disease duration Mucocutaneous side effects (15),
[107] (42 yo) 10.8mos. 7/15 pts w/ lesion ectropion (1), elevated TG or
clearance, 3 w/ > 50% cholesterol (11)
clearance, 5 w/ no response.
Clearance occurred
in < 7mos w/ average dose
1.06 mg/kg/day
13
Table 1 (continued)
evidence skin type
13
Clayton et al. (1997) [106] 4 Case series 4 4 M, Mean 60 yo 40 mg BID × 1–10 mo w/ 3 pts failed methotrexate Adverse events not discussed
etretinate 25-75 mg/d or treatment prior. 3/4 pts w/
methotrexate 5-30 mg × 3–25 complete lesion clearance at
mo 28–48 mo
Dicken (1994) [108] 3 Retrospective 15 11 M, 4 F, 16–81 yo 40–60 mg 1–2/d × 4–11 mo Disease duration 2–72 wks. 2 Adverse events not discussed
pts had prior tx with vitamin
A. 10/15 pts w/ complete
lesion clearance after an
average of 25 wks. 2 w/
partial clearance, 3 w/ no
response after 20–24 wks
Dicken and Rochester (1987) 4 Case series 5 4 M, 1 F, 16–81 yo 1.03–1.48 mg/kg/d × 4–6 mo Disease duration 2 wks to 22 Cheilitis, dry skin, and elevated
(Classic Adult, Type I) mos. 4/5 pts w/ lesion clear- TG (5)
[111] ance after 16-24wks
Decreased inflammation by
4 weeks
Gilgor et al. (1980) [112] 4 Case series 4 N/A 0.5-4 mg/kg/d × 16 wk 1/4 pts w/ 75–100% clearance Cheilitis, conjunctivitis, skin
3/4 pts w/ 50–75% clearance fragility, hair loss, rhinitis
Goldsmith et al. (1982) [113] 4 Case series 45 29 M, 16 F, Mean 40.7 yo, 43 1.51–2.13 mg/kg/d × 1–6 mo Mean disease duration of 6.7 Adverse events not discussed
white, 2 black yrs. 40/45 pts w/ improve-
ment for an average duration
of therapy 4 mos. 6/45 pts
w/complete remission post-
therapy
Marrouche et al. (2014) 3 Retrospective 12 19–70 yo 1 mg/kg/d × 3–6 mo Type I and Type III PRP. All Elevated TG (1)
[109] 12 pts w/ > 75% lesion clear-
ance in 3-6mos
Peck et al. (1978) [114] 4 Case series 5 N/A 2 mg/kg/d × 19 wk 3/5 pts w/complete clearance Cheilitis, conjunctivitis, facial
2/5 w/partial clearance dermatitis, xerosis, rhinitis,
skin fragility
Risch et al. (1984) [115] 4 Case series 5 5 M, Mean 43.2 yo (16–67 yo) 1.5–2 mg/kg/d × 6 mo Failed vitamin A, topical Cheilitis, mucosal dryness,
steroids, emollients, PUVA. fatigue, joint pain, hair loss,
3/5 pts w/ lesion clearance elevated TG, decreased HDL
maintained post-treatment.
Duration to relapse 4–12
wks
Sehgal et al. (2006) [116] 4 Case series 6 5 M, 1 F (Mean 28 yo, 0.5–1 mg/kg/d × 2–3 mo Mean duration disease 9.8 Cheilitis, scaling, dryness
11–57 yo) yrs (1–27yrs). All 6 pts w/
complete lesion clearance at
7–12 wks
Table 1 (continued)
evidence skin type
Condylomata acuminata (9); n = 271
Cardamakis et al. (1995) 1 RCT 86 86 M, Mean 26.9 yo 1 mg/kg/d × 3 mo vs 1 mg/kg/d Failed > 2 topical therapies Dry eyes, skin, lips, (86) wart
[118] (18–42 yo) w/ INFα-2a 3MU subq 3x/ and/or surgery. Mean irritation (2), fatigue (4), hair
wk × 8 wk disease duration 3.09 yrs. loss (1), elevated TG or LFTs
26/42 isotretinoin pts w/ (12), flulike symptoms (29)
lesion clearance, 40/44
combination pts w/ lesion
clearance. Duration of
therapy significantly reduced

in combination therapy (2.18
vs 2.5 mos); Recurrence
rate significantly less in the
combination group (4/44 pts
vs 16/42 pts)
Cardamakis et al. (1996) 1 RCT 57 57 F, Mean 23.4 yo (18–29 yo) 1 mg/kg/d × 3 mo vs 1 mg/kg/d Previously treated with topical Dry eyes, skin, lips (57), wart
[119] w/ INFα-2a 3MU subq 3x/ therapies and/or surgery. irritation (4), fatigue (2), hair
wk × 8 wk Mean disease duration of loss (1), elevated TG or LFTs
2.5 yrs (1-5 yrs). 18/24 (8), flu-like symptoms (32)
isotretinoin pts w/ lesion
clearance, 28/33 combina-
tion pts w/ lesion clearance.
Duration of therapy
significantly reduced in
combination therapy (1.9 vs
2.5 mos)
Georgala et al. (2004) [120] 1 RCT 53 53 F, mean 32.3 yo (21–43 yo) 0.5 mg/kg/d vs placebo × 12 Disease duration 7-21mos. Dry eyes, skin, lips (47), hair
wk 9/28 pts w/ lesion clear- loss (6), conjunctivitis (4),
ance, 8/28 w/ no response. elevated TG, cholesterol, or
8/9 complete responders LFTs (14)
remained in remission at
12 mo
Jha et al. (2018) [123] 4 Case series 2 2M 0.75 mg/kg/d w/ topical podo- 2/2 pts w/ lesion clearance Cheilitis
phyllin 20% × 4–6 wk within 4-6wks w/ no recur-
rence at 6 mo follow-up
Olsen et al. (1989) [121] 1 RCT 17 Isotretinoin group: 8 M, Mean 1 mg/kg/d × 6 wk vs INFα-nl Failed 2 prior traditional Dry eyes, skin, lips (8), wart
27.6 yo; 6 white, 1 black, 1 5MU subq/d × 2 wk then therapies. After 6 wks: irritation (4), fatigue (3),
oriental 2×/w × 1 mo 8/8 isotretinoin pts w/ no hair loss (2), joint pain (1),
response, 5/9 INF pts w/ elevated TG (3)
complete or partial clear-
ance, 2 pts w/1 mg/kg/d and
INFα 64.7–98.9% clearance
Pasmatzi et al. (2012) [124] 4 Case report 1 19 F 1 mg/kg/d w/IFN-α 3MU Failed electrocauterization. Mucosal dryness, fever, chills,
3x/wk Lesion clearance at 4 mo myalgia, leukopenia
w/ no recurrence at 3.5 yr
follow-up
13
Table 1 (continued)
evidence skin type
13
Tsambaos et al. (1997) [122] 2 Prospective 53 53 M, 23–47 yo 1 mg/kg/d × 3 mo Failed at least one prior Dry eyes, skin, lips (53),
standard tx. 21/53 pts w/ dermatitis (40), epistaxis (17),
lesion clearance, 25/53 conjunctivitis (14), pruritus
pts w/ no response. Mean (11), elevated TG or choles-
lesion duration highest terol (4),
in non-responders, then
partial, then complete
(12.5mos, 10.4mos, 4.1mos,
respectively). 2/21 complete
responders had recurrences
at 12mo follow-up
Yew and Pan (2014) [125] 4 Case report 1 27 yo F, Chinese 20 mg/d × 8 mo w/surgical Lesion clearance over 8 mos Adverse effects not discussed
debulking w/ no recurrence at > 4 yr
follow-up
Yildirim et al. (2004) [126] 4 Case report 1 27 yo M 0.5 mg/kg/d × 3 mo w/IFNα‐2a Lesion clearance in 3 mos Cheilitis (1)
3MU sibq 3×/wk w/no recurrence at 1 yr
follow-up
Granuloma annulare (12); n = 16
Adams and Hogan (2002) 4 Case report 1 64 yo M, white 40 mg-80/d × 1 yr Generalized variant. Disease Cheilitis and mouth
[100] duration 34 yrs, failed
hydroxychloroquine. Lesion
improvement at 2 mo, near
clear at 1 yr
Arroyo (2003) [101] 4 Case report 1 61 yo F Unknown Generalized variant. Lesions Adverse effects not discussed
improved but stopped
because of adverse effects
profile
Baskan et al. (2007) [105] 4 Case report 1 65 yo M 0.5 mg/kg/d w/ pimecrolimus Generalized variant. Failed Adverse effects not discussed
cream 1% 2x/d topical and oral corticoster-
oids. Complete clearance
at 4 mo
Buendia-Eisman et al. (2003) 4 Case report 1 58 yo F 50 mg/d Generalized variant. Disease Adverse effects not discussed
[102] duration over 10 yrs. Failed
topical corticoid, intral-
esional corticoid, oral corti-
coid, and oral dapsone. 90%
lesion clearance w/total dose
of 120 mg/kg. No recurrence
at 6 mo post-treatment
Erkek et al. (2001) [99] 4 Case report 1 48 yo M, white 1 mg/kg/d Generalized variant. Benefit Adverse effects not discussed
from systemic corticoster-
oids, but the patient had
aggressive diabetes. Lesion
improvement at 3 mo
Table 1 (continued)
evidence skin type
Pasmatzi et al. (2005) [103] 4 Case report 1 58 yo F, white 1 mg/kg/d Generalized variant. Failed Cheilitis, mucosal dryness,
previous conventional txs. elevated TG and cholesterol
90% lesion clearance w/
total dose of 120 mg/kg.
No recurrence at 6 mo post-
treatment
Ratnavel et al. (1995) [96] 4 Case report 1 21 yo F 0.5–0.75 mg/kg/d × 4 mo Perforating variant. Poor Cheilitis, mucosal dryness,
response to topical elevated TG and cholesterol
clobetasol, intralesional
triamcinolone, cryotherapy.
Near-complete clearance at
10 wks. Recurrence at 6 mo
follow-up
Sahin et al. (2006) [104] 4 Case report 1 49 yo M 50 mg/d × 3 mo Generalized variant. Failed Adverse effects not discussed
different topical therapies.
Disease duration 6mo.
Lesion improvement at 2
mo. No recurrence at 3mo
post-treatment
Schleicher and Milstein 4 Case report 1 62 yo F 40 mg 1-2×/d × 3 mo Generalized variant. Failed Cheilitis, elevated TG
(1985) [94] cryosurgery, liquid nitrogen,
anthralin ointment, benzoyl
peroxide, 5-fluorouracil
cream, retinoic acid gel,
triamcinolone cream, oral
dapsone, oral methotrexate,
and oral colchicine. > 95%
lesions cleared after 3 mos.
No relapse after 6mos
Schleicher et al. (1992) [95] 4 Case series 5 5 F, 24–70 yo 40 mg/d × 10 wk Generalized variant. All pts w/ Adverse effects not discussed
complete or partial lesion
clearance. 3 pts w/ recur-
rence several months after
clearance
Tang et al. (1996) [97] 4 Case report 1 72yo M, Chinese 30-50 mg/d × 16 wk Generalized variant. Failed Elevated lipids and cholesterol
dapsone. Lesion improve-
ment at 4 wks. No recur-
rence at 1 yr post-treatment
Young and Coulson (2000) 4 Case report 1 36yo F 40–70 mg (0.5–1 mg/kg/d) × 5 Localized variant. Failed oral Adverse effects not discussed
[98] mo PUVA, oral oxypentifylline,
and oral nicotinamide. Com-
plete clearance at 3 mos, no
recurrence
13
Table 1 (continued)
evidence skin type
13
Darier’s disease (8); n = 119
Del Rosso and Horowitz 4 Case report 1 26 yo M 1.2–1.8 mg/kg/d × 9 mo Failed topical and oral vitamin Cheilitis, elevated TG
(1986) [146] A. 80% lesion clearance at
4 wks. Relapse in 7 days
post-treatment and returned
to pretreatment levels in
4–5 wks
Dicken et al. (1982) [150] 2 Prospective 104 57 M, 47 F, Mean 36.7 yo 0.5 mg/kg/day × 16 wk vs 6mo 85% lesion improvement Cheilitis (104)
(13–86 yo); 101 white, 3 at 5–8 weeks Relapse to
black pretreatment intensity
Gilgor et al. (1980) [112] 4 Case series 4 N/A 0.5–4 mg/kg/d × 16 wk All pts w/75–100% clearing Cheilitis, conjunctivitis, skin
at 6–12 wks, all relapsed fragility, hair loss, rhinitis,
after 8 wks of discontinuing fingertip peeling
therapy but cleared com-
pletely following starting
therapy again
Kim and Fangman (2007) 4 Case report 1 38 yo F 40 mg 1–2×/d w/ salicylic Previously tried isotretinoin Adverse effects not discussed
[147] acid 5% but never completely
resolved. Significant lesion
improvement at 1 mo
Udayashankar et al. (2013) 4 Case report 1 65 yo M 0.5 mg/kg × 2 mo Scaling and plaques decreased Adverse effects not discussed
[148] after 2 mos
Ornelas et al. (2016) [133] 4 Case series 2 2 F, 19–21 yo Unknown One pt failed topical hydro- Suicidal ideation and pain (1)
cortisone, fluocinonide,
pimecrolimus, tretinoin, and
tazarotene. Other pt failed
topical adapalene, tretinoin,
clobetasol, triamcinolone,
and urea. Significant lesion
improvement
Risch et al. (1984) [115] 4 Case series 5 1 M, 4 F, Mean 33.6 yo 1–2 mg/kg/d × 6 mo Failed vitamin A, topical Cheilitis, mouth, and eyes (5),
(13–58 yo) retinoic acid, topical/oral fatigue (5), joint pain (5),
steroids, phlebotomy. All pts hair loss (5), elevated TG (5),
w/ lesion improvement; 2 pts decreased HDL (5)
sustained improvement after
stopping treatment for 6mos.
3/5 pts relapsed at 2–8 weeks
post-treatment
Rotunda et al. (2005) [149] 4 Case report 1 30 yo F, white 0.5 mg/kg/d × 5 mo Complete lesion clearance Adverse effects not discussed
at 2 wk, remained clear
throughout 5mo of treat-
ment. Relapse 6 mo after
discontinuation
Table 1 (continued)
evidence skin type
Non-melanoma skin cancer (31); n = 2620
Basal cell carcinoma
Goldberg et al. (1989) [16] 4 Case report 2 26 yo (twins) 0.2 or 0.4 mg/kg/d × 1 year Both pts w/ decreased in Cheilitis (2), xeroderma (2)
occurrence of new lesions at
1 yr. Recurrence rate higher
at 1 yr post-treatment w/
lower dose
Peck and Gross et al. 4 Case series 3 3 M, 52–72 yo, white 1–3.5 mg/kg/d × 30–38 mos Past therapies included exci- All pts w/ mucosal dryness,
(1982) [17] sion, chemosurgery, x-irra- epistaxis, conjunctivitis,
diation, cobalt irradiation, arthralgias
topical 5-fluorouracil, elec-
trodesiccation and curettage,
and/or cryosurgery. 29/65
tumors underwent > 50%
regression after 30–38mos of
therapy. No new tumors seen
during therapy
Peck et al. (1988) [18] 4 Case series 12 9 M, 3 F, Median 46 yo 1–8.2 mg/kg/d × 8 mo 36% of tumors w/complete All pts w/ mucosal dryness
(29–71 yo) or partial regression after 8 Most common: conjunctivitis
mos. 20% of tumors w/ no (10), arthralgia/myalgia (8)
response
Sollitto and DiGiovanna 4 Case report 1 38 yo F 2 mg/kg/d w/IFNα- 1.5MU 4/5 lesions w/ partial or com- Cheilitis
(1996) [19] 3×/wk × 7 wk plete regression throughout
7 wks
Tangrea et al. (1992) [46] 1 RCT 981 757 M, 224 F, < 60 yo 10 mg/d vs placebo × 3 yr Previously treated, unknown Most common: mucosal dry-
(n = 350), 60–64 yo therapy. No statistically ness (344), elevated TG
(n = 244), 65 yo (n = 387), significant differences in (36), arthralgia/myalgia
FST I–II (n = 603), FST the occurrence of basal (57), progression of existing
III–V (n = 371) cell carcinoma at a new calcification/hyperostosis (56),
site or annual rate of BCC hyperostotic skeletal changes
formation when compared (12)
to placebo after 36mos (327
pts in isotretinoin group and
placebo group developed ≥ 1
new BCC
Squamous cell carcinoma
Lippman and Meyskens 4 Case series 4 4 M, 62–77 yo, white 1 mg/kg/d × 6 mo Patients failed radiation, Elevated creatine kinase (1)
(1987) [21] excision, and/or electrodessi-
cation. All pts w/ lesion
regression at 2 wks with a
resolution at 6 mo
Lippman and Parkinson 4 Case series 28 26 M, 2 F, Median 67 yo 1 mg/kg/d + IFNα-2a subq Failed surgery (n = 26), All pts w/ cheilitis and skin,
et al. (1992) [22] (49–88 yo) 3MU×2 mo radiotherapy (n = 18), elevated TG (14), conjunctivi-
chemotherapy (n = 6). 68% tis (9), epistaxis (3)
lesion regression at 1.5 mo.
25% of lesions w/ complete
resolution
13
Table 1 (continued)
evidence skin type
13
Meyskens et al. (1982) [23] 4 Case series 28 N/A 2–3 mg/kg/d Failed radiation (n = 6), Joint pain (3), cheilitis, der-
methotrexate (n = 1), surgery matitis, or conjunctivitis (8),
(n = 2), and/or multiple headache or elevated TG (7)
drugs. 6/28 pts w/ malignant
lesions regression after an
average of 4mos. 60% pre-
neoplastic lesion regression
after 12–16 mos
Skroza et al. (2014) [24] 4 Case report 1 63 yo M, white 0.5 mg/kg/d × 5 mo Failed excision. Complete Pt denies adverse effect
remission of the malignant
lesion after 5mo. No relapse
at 1 yr follow up
Toma et al. (1994) [20] 2 Prospective 6 43–83 yo 0.6–1 mg/kg/d w/IFNα Pts possibly failed surgery, Mucosa (12) and skin dryness
6MU/d × 3 mo radiotherapy, and/or (8), fatigue (13), anorexia
chemotherapy. 1/6 pts had a (13), fever (10)
complete response, 2/6 had
partial response after median
duration of 28 wks
Bellman et al. (1996) [25] 4 Case report 1 Renal transplant pt 0.5 mg/kg/d up to 1 mg/kg/d 0.5 mg/kg/d isotretinoin No adverse effects
after 2mo reduced number of new
lesions by half within 2mo
Keratoacanthoma
Feldman et al. (2007) [26] 4 Case report 1 27 yo white F Isotretinoin 40 mg/d × 8 Partial resolution of lesions, Dry mouth and eyes, atrophic
mo + topical tazarotene fol- with larger lesions regressing scarring of resolved lesions
lowed by 25–35 mg acitretin into atrophic scars. Acitretin
and 0.1% tazarotene gel helped resolve persistent
lesions
Haydey et al. (1980) [27] 4 Case report 1 43 yo M 2 mg/kg/d (3 wks)-6 mg/ Lesion response seen at 3 Cheilitis, conjunctivitis, ure-
kg/d (13 wks) followed by wk: fully developed lesions thritis; longterm AEs: mild
maintenance dose of 2 mg/ were less tender, and newer cheilitis
kg/d × 18 mos lesions involuted
Recurrence at 8 wk post-
treatment; maintenance dose
started. Surgical excision
resolved remaining lesions
Levine and Miller et al. 4 Case report 1 83 yo F 2 mg/kg/d × 6 mo Multiple SCCs and kerato- Adverse effects not discussed
(1984) [28] kanthomas. Small lesion
regression at 2–6 wks
Large lesion regression at > 6
wks. 36 mos after tx, 3 new
SCCs and one KA developed
and were surgically removed
Table 1 (continued)
evidence skin type
Shaw and White (1986) 4 Case report 1 44 yo M 0.5 mg/kg/d (2 wks)-1.5 mg/ Lesion regression seen at Cheilitis, facial erythema and
[29] kg/d (5 mos) higher doses (1.5 mg/kg/d), scaling, musculoskeletal aches
0.5–1 mg/kg/d did not cause
regression of lesions, but
arrested growth. Lesions
recurred 4 mos after tx
discontinuation, and 1.5 mg/
kg/d was restarted, then
tapered to maintenance dose

of 0.25 mg/kg/d to prevent
new lesions
Schaller et al. (1996) [30] 4 Case report 1 78 yo M 1 mg/kg/d × 3 mo Lesions resolved and new KA Painfully dry skin, frequent
formation was suppressed. nosebleeds; treatment discon-
Within 6 wks of stopping tinued due to AEs
tx, numerous new KAs
developed
Oral leukoplakia
Hong et al. (1986) [31] 1 RCT 44 31 M; 13 F (age 1-2 mg/kg/d (n = 24) vs pla- 16/24 isotretinoin pts w/ lesion Tretinoin group: chelitis, facial
range: < 50– > 70) cebo (n = 20) × 3 mo regression; 2/20 placebo erythema, dryness and peel-
pts w/ lesion regression; ing (19), conjunctivitis (13),
dysplasia reversed in 13/24 elevated TG > 200 mg/dL (17);
isotretinoin pts and 2/20 intolerable conjunctivitis and
placebo pts elevated TGs in 2 pts (2 mg),
and treatment discontinued
after 2 and 4 wks. Photopho-
bia in 1 pt (resolved after dose
lowered)
Xeroderma pigmentosum
Kraemer, DiGiovanna, 2 Prospective 5 3 M; 2 F (age range: 10–39) 2 mg/kg/d × 2 yr Average 63% decrease in All pts w/ cheilitis and skin, con-
Moshell et al. (1988) tumor occurrence; 4/5 pts junctivitis, ectropion, elevated
[32] had reduced tumors after tx TG and LFTs. Mucocutaneous
(improvement starting at 2 symptoms became less promi-
mos); 8.5-fold increase in nent after 6–12 mos of tx
annual tumor occurrence
after treatment cessation
within 3 mos. 3 pts had an
increase in tumor rate after
treatment
Saade et al. (1999) [33] 4 Case report 1 7 yo M 1 mg/kg/d w/IV chemother- Large tumor completely Skin dryness, angular cheilitis
apy × 3 mo resolved with no reported
recurrence
Zaman et al. (2014) [34] 4 Case report 1 15 yo F 1 mg/kg/d w/ Cisplatin 75 mg/ Complete clinical remission of Adverse effects not discussed
m2 and 5-Fluorouracil tumor in 5 cycles of therapy
1000 mg/m2 × 3wk for 5
cycles in 4mo
13
Table 1 (continued)
evidence skin type
13
Multiple NMSCs
Kraemer, DiGiovanna, 4 Case series (XP, BCC, SCC) 5 n/a 0.5–1.5 mg/kg/day × 1 yr All pts w/ decrease in tumor All pts w/ cheilitis and skin,
Peck et al. (1992) [37] occurrence (121 total before elevated TG or LFTs; retinoid
treatment; 25 tumors during hyperostosis (4)
2 years of treatment)
Moon et al. (1997) [35] 1 RCT (BCC, SCC) 719 n/a 5–10 mg/d vs 25,000 IU retinol Isotretinoin reduced SCC Elevated cholesterol and LFTs
vs placebo × 3 yr occurrence rate (17)
No difference in BCC occur-
rence rate
Levine et al. (1997) [36] 1 RCT (BCC, SCC) 525 n/a 5–10 mg/d vs retinol 25,000 IU No difference in number or Mucosal dryness (17), myalgia/
vs placebo × 3 yr occurrence rate of BCC or arthralgia (8), vascular (9),
SCC CNS (3)
Photodamaged skin
Bagatin and Guadanhim 1 RCT 22 FST I-III, age range 50–75 yo 20 mg oral EOD vs 0.05% 82% isotretinoin pts improved Oral: light cheilitis (9/11),
et al. (2014) [38] retinoic acid cream EOD × 6 91% retinoic acid pts xerosis (3/11), eye dryness
mo (both w/ SPF 50) improved; difference not (2/11), nasal dryness (1/11);
significant topical: irritative dermatitis
(10/11) pts
Bagatin and Parada et al. 1 RCT 30 FST 1–III; 30 F (21 tx group, 20 mg qd 3×/wk × 12 wk vs Statistically significant reduc- Mucosal dryness (18), dermatitis
(2010) [39] 11 controls) control (all w/SPF 60) tion of wrinkles, skin elastic- (3), depression (2), elevated
ity, and photoaging grade cholesterol (4)
Bravo et al. (2015) [43] 4 Case series 20 FST II–VI; 20 F (ages 45–50 20 mg BID 3×/wk × 12 wk All pts report improvement; Cheilitis (7), headache (1)
yo; mean 47 yo) Average collagen density
increases from 51.2% to
57.4%
Hernandez-Perez et al. 1 RCT 60 42 F, 18 M (all Hispanic); age 10-20 mg 3×/wk × 2 mo vs. Reduced wrinkles and pig- Cheilitis (5)
(2000) [40] range 35–65 controls mentation; improved skin
elasticity
Kalil et al. (2008) [45] 2 Prospective 30 FST I-III, 30 F 20 mg 3×/wk × 3 mo 20/30 pts reported optimal Dry skin, elevated LDL or
improvement. Decreased TG (6)
collagen degeneration on
histology
Rabello-Fonseca et al. 1 RCT 29 FST II-IV, 29 F 10 vs 20 mg 3×/wk × 3 mo No significant difference in Adverse effects not discussed
(2009) [41] dose
All pts w/ reduced laxity, wrin-
kles, pore size, and increased
collagen via analysis in
photographs and histology.
34.5% self-rated as excellent
results, with remaining rat-
ing average/good
Sander et al. (1997) [44] 4 Case series 27 3 F, 24 M 20 mg/d w/ topical 5% 5-Fluo- Palpable AKs regressed Mild cheilitis, mild dry skin,
rouracil cream BID × 3 wks completely in 22/27 patients mild dry eyes; no major
(81.5%), and almost com- mucocutaneous effects
pletely in remaining 5. At 26
mo f/u, 1–2 new AKs seen in
3 patients
Table 1 (continued)
evidence skin type
Ianhez et al. (2019) [42] 1 RCT 61 (30 in isotreti- n/a Cryotherapy at baseline Reduction in the total amount Retinoid dermatitis (20%),
noin group) and after 120d followed of actinic keratoses related erythema (29%), intolerance
by: 10 mg/d isotretinoin to cryotherapy and sun- to cream (35.5%) in tretinoin
w/ SPF60 q3hr vs topical screen (-39%), isotretinoin group; total cholesterol levels
tretinoin 0.05% cream every combination (-33%), (76%) and triglycerides (61%)
other night w/ SPF 60 q3hr topical tretinoin combina- in isotretinoin group
× 6mo tion (-23%). 2/30 developed
BCC in isotretinoin group;
2/31 developed BCC in the

tretinoin group. Stratum
corneum thickness reduced
in topical group
Cutaneous lupus erythematous (7); n = 19
D’Erme et al. (2012) [167] 4 Case report 1 26 yo F 40 mg /d × 5 mo (0.7 mg/kg/d) Subacute CLE: remarkable Cheilitis. Post-inflammatory
lesion clearance at 1–5 mo hyperpigmentation of some
No relapse at 6 mo post- lesions
treatment
Furner (1990) [160] 4 Case report 1 78 yo M 10-50 mg/d × 1 yr (10 mg pm, Subacute CLE: 90% lesion No adverse effects reported;
40 mg am) clearance at 1 mo; sustained triglycerides and cholesterol
remission for 1 year on low remained within normal limits
dose therapy of 10 mg;
and completely clear after
3 months of treatment ces-
sation
Green and Piette (1987) 4 Case report 1 44 yo F 1 mg/kg/d × 11 wk Topical steroids, oral Adverse effects not discussed
[164] prednisone, and oral
hydroxychloroquine were not
effective. Hypertrophic CLE:
lesion clearance at 3 wk with
isotretinoin
No relapse at 9 mo post-
treatment; no maintenance
therapy
Newton et al. (1986) [162] 4 Case series 8 Mean age 41 yo; 6 F, 2 M 40 mg BID × 16 wk Chronic and Subacute CLE Mucosal and skin dryness,
(7 CCLE, 1 SCLE): Clini- elevated TG
cal benefit in all patients;
decreased lesion size, ery-
thema, scaling with minimal
scarring and PIH
Richardson and Cohen 4 Case report 1 68 yo F 1 mg/kg/d w/clobetasol 0.05% Subacute CLE: Lesion clear- Adverse effects not discussed
(2000) [166] or fluocinonide 0.05% × 1 ance, improvement seen
mo at 2 wk. Failed topical
corticosteroids and hydroxy-
chloroquine
Rubenstein and Huntley 4 Case report 1 75 yo F 40 mg/d w/hydroxychloroquine 17-year history of Hyper- Cheilitis on 40 mg/d, but not
(1986) [163] 400 mg/d × 1 yr trophic CLE: 80% lesion when dosed at 40 mg EOD
clearance
13
Table 1 (continued)
evidence skin type
13
Shornick et al. (1991) [165] 4 Case series 6 Mean age 35 yo; 5 F, 1 M 0.5–1.5 mg/kg/d w/20– Discoid CLE: All pts w/ lesion Dry skin, pruritus
45 mg/d prednisone and improvement at 2 wk
200–600 mg/d hydroxychlo- Lesion resolution at 3 mo
roquine × 3–11 mo Discontinuation of treatment
results in rapid recurrence
of lesions
Hidradenitis suppurativa (9); n = 225
Boer and Gemert (1999) [10] 3 Retrospective 48 59 F, 9 M; age range 15–54 0.50–0.81 mg/kg/d (mean dose 16/48 scored 3 on scale of 0–3, Swelling (6)
(mean 32.6) (20 lost to 0.56 mg/kg/d) × 4–6 mo with 3 = “virtually clear”);
follow-up) 32/48 scored 0–2 (reported
dissatisfaction); overall only
moderately effective for HS
Dicken et al. (1984) [130] 4 Case series 8 Age range 15–57 (mean 35); 0.71–1.2 mg/kg/d × 4 mo Cleared in 1/8, almost cleared Dry skin and lips (8), headache
7 F, 1 M in 3/8, improved in 1/8, not (1), arthralgia (1)
changed in 2/8, worse in 1/8
Huang and Kirchhof (2017) 3 Retrospective 25 Age range 16–55 (mean: 34); 0.14–0.95 mg/kg/d (mean 17/25 pts w/ complete or par- Adverse effects not discussed
[128] 14 F; 11 M 0.45) × 2–22 mo (mean tial lesion clearance; 8/25 no
6.8 mo) response; those with Hurley
I most likely to respond (vs
Hurley stage II/III)
Jones et al. (1982) [131] 4 Case series 3 N/A 1 mg/kg/d × 16 wk 70–90% reduced sebum Adverse effects not discussed
excretion, but no change
in discharge, flare-ups, and
resolution of existing lesions
Norris and Cunliffe (1986) 4 Case series 6 Familial cases (age range 1 mg/kg/d × 4 mo No lesion response; Cheilitis (6), elevated TG or
[132] 14–47 Worsened inflammation/flare- cholesterol (5)
up post-treatment
Ornelas et al. (2016) [133] 4 Case series 2 19 yo F; 21 yo F Unknown Uncertain outcome with Suicidal ideation (1)
isotretinoin treatment in the
first patient. Lesion improve-
ment in the second patient,
isotretinoin and blue-light
phototherapy more effective
than (chlorhexidine, topical
antibiotics, infliximab, and
spironolactone)
Soria et al. (2009) [129] 3 Retrospective 88 Mean age 32 yo 20–140 mg//kg/d (mean 44.0) 14/88 pts w/ lesion improve- Adverse effects not discussed
× mean 7.8 mo ment; 67/88 no effect;
6/88 pts w/ worsened lesions
Jorgensen et al. (2019) [134] 4 Case series 6 3 M, 3F, Age range 19–40 yo 20–40 mg/d × 4-22mo 1/6 patients had a complete or Skin dryness (5), fatigue (1),
(mean: 28 yo) almost complete response. joint pain (1), nosebleed (1)
2/6 patients had no response.
3/6 patients had a larger
number of inflammatory
nodules following tx
Table 1 (continued)
evidence skin type
Patel et al. (2019) [127] 3 Retrospective 39 Age range 17–61 (mean 32); Unknown 35.9% responded to treatment, Adverse effects not discussed
22 F, 17 M with a positive association
found between responders
and pilonidal cyst history;
Hurley stage I and non-obese
patients were more likely to
have a positive response
Flat Warts (6); n = 88
Miljkovic (2012) [171] 4 Case series 2 40 yo white M; 21 yo white F 0.3–0.4 mg/kg/d × 1 mo Total clearance of plane warts No adverse effects
after 1 mo. No relapse at
6–12 mo follow-up
Bialecka et al. (2018) [172] 4 Case report 1 31 yo F 0.5 mg/kg/d × 3 mo Complete remission of hand Dryness and exfoliation of lips,
plane warts after 3 wks dryness of conjunctiva
(initially unresponsive to
cryosurgery, laser surgery,
imiquimod cream, fluoro-
uracil, liquid tretinoin, acetic
acid, and Isoprinosine 4 g)
Kaur et al. (2017) [169] 1 RCT 29 Oral group: age range 20–42 Oral 0.5 mg/kg/d vs topical 69% of patients taking oral Oral group: mild cheilitis (5),
(mean 27) 11 M, 9 F; topical 0.05% daily × 3 mo isotretinoin had complete severe cheilitis (2), xerosis
group: age range 21–55 remission of plane warts, (4), menstrual irregularity (1).
(mean 31), 10 M, 10 F 31% had partial. 38% Topical group: mild erythema
of patients using topical and burning sensation (2),
isotretinoin had complete severe erythema and scaling
remission, 46% had partial. (5)
Statistically significant
difference between the two
groups in response rate (oral
had an earlier and better
response)
Olguin-Garcia et al. (2014) 1 RCT 16 Isotretinoin group: 13 F, 3 M 30 mg/d × 3 mo vs control 87.5% had complete remission Cheilitis (16), pruritus (15), dry
[168] (median age 25); control of facial flat warts, none skin (16), dry eyes (16), rash
group: 8 F, 7 M (mean responded in the placebo (7), muscle pain (9), headache
age 21) group (previous failed (9), diffuse alopecia (5),
treatments were imiquimod, photosensitivity (14), impaired
5-FU, cryosurgery) visual acuity (1)
Al-Hamamy et al. (2012) 2 Prospective 26 Age range 5–35 (mean 15); 15 0.5 mg/kg/d × 2 mo 19/26 (73.07%) patients had Dry lips (26), dry skin (20),
[170] F, 11 M complete remission of facial epistaxis (2), dry nose (8),
plane warts, 7/26 (26.92%) headache (1)
patients had no response at 2
mo. 15/19 (78.94%) still free
from warts at 4 mo follow-up
Dave and Abdelmaksoud 4 Case series 14 4 F, 10 M; age range 7–52 (all 0.1–0.2 mg/kg/d × 3 mo All patients showed a complete Cheilitis (14)
(2019) [173] Indian ethnicity) response with no relapse
over 12 mo follow-up period
and up to 3 yr period in 1
patient
13
Table 1 (continued)
evidence skin type
13
Lichen planus (5); n = 42
Muthu et al. (2016) [187] 2 Prospective 27 10 M, 17F, 20–62 yo, diffuse 20 mg/d (0.3–0.5 mg/ Oral variant. 15/27 (55.7%) Menorrhagia (1), mild cheilitis,
(n = 14), blotchy (n = 10), kg/d) × 60 mo had moderate improve- xerosis, transient transminitis
reticular (n = 3) ment in hyperpigmentation,
7/27 (25.9%) had a good
response, 2/27 (7.4%) had
a mild response. Blotchy
type had the best response
to therapy
Handler (1984) [188] 4 Case report 7 N/A 0.25 mg/kg/d × 2 mo Oral variant. Excellent Mild cheilitis
response in all patients after
2mos
Camisa and Allen (1986) 4 Case series 5 3 M, 2 F, oral erosive type 0.5–1 mg/kg/d × 8 wk Oral variant. Failed topical Cheilitis (5), dry skin (5), head-
[189] and systemic corticosteroids, ache (5), rash (5), joint pain
topical retinoic acid, griseof- (5), pruritus (5)
ulvin. Rating of spontaneous
pain and pain with eating
significantly improved at 8
wks. 4/5 patients improved,
1/5 had no change at 8 wk.
4 pts relapsed after 2 mos
discontinuation
Boyd and King (2001) [190] 4 Case report 1 50 yo F 1 mg/kg/d × 3 mo Oral and vulvar variant. Retinoid dermatitis, cheilitis,
Lichenoid drug reaction after dry eyes
3mos. Oral lesions gradually
resolved; vulvar involvement
subsided after isotretinoin
stopped
Woo (1985) [191] 4 Case series 2 51 yo White F, 63yo White F 0.5–1 mg/kg/d × 4–16 wk Cutaneous and oral variant. Dry skin (2), cheilitis (2),
Failed topical lidocaine, elevated TG (1)
tretinoin, oral lavage
with diphenhydramine,
tetracycline, and prednisone.
Rapid improvement within
3 wks in 1 pt. In other,
90% improvement of oral
lesions, 60% improvement of
cutaneous lesions after 1 mo.
but relapsed occurred if the
dosage was 0.5 mg/kg/d in
one patient
Dissecting cellulitis (14); n = 76
Marquis et al. (2017) [79] 4 Case report 1 Hispanic 18 yo M 0.27 mg/kg/d x 4mo Failed oral antibiotics, topical Adverse effects not discussed
clotrimazole, betamethasone.
Response excellent after 1
mo of therapy, near-complete
resolution after 4 mo. No
recurrence after 7mo
Table 1 (continued)
evidence skin type
Badaoui et al. (2016) [80] 3 Retrospective 35 35 M, mean 26.6 yo, 65% FST 0.5–0.8 mg/kg/d × 3 mo 33/35 (94.3%) had complete Adverse effects not discussed
IV,V,VI remission at 3 mo but
frequent relapses after
discontinuation
Mundi et al. (2012) [82] 4 Case report 1 32 yo M 1 mg/kg/d × 1 mo Failed topical and intralesional Adverse effects not discussed
glucocorticoids and oral
antibiotics. After 1 mo
of therapy, there was an
improvement in the level of

drainage. No relapse after
1 yr
Mihić et al. (2011) [83] 4 Case report 1 N/A 60–80 mg/d × 3.5 mo Failed oral azithromycin, Dry lips and skin
amoxicillin, fluconazole.
Scalp lesions stabilized
under therapy after 3.5mos;
after 2 yrs patient was free
of disease
Scerri et al. (1996) [84] 4 Case series 3 3 M, 23–26 yo Afro-Carribean 0.75-1 mg/kg/d × 9–11 mo Failed systemic antibiotics, Adverse effects not discussed
zinc sulphate. Marked reduc-
tion of scalp swelling within
3–4 months, had regrowth
of hair at end of therapy.
No relapse at 10–30mos
follow-up
Georgala et al. (2008) [85] 4 Case series 4 4 M, 24–34 yo Oral Rifampicin 300 mg 2x/ Failed clindamycin, hydrochlo- Adverse effects not discussed
daily × 4 mo followed by ride, erythromycin, oral anti-
oral isotretinoin 0.5 mg/ fungals, topical clindamycin.
kg/d × 3–4 mo Remission within 3–4 mo.
No relapse at follow up
10-12mo after treatment
Hintze et al. (2016) [86] 4 Case series 2 30 yo Hispanic M; 58 yo Unknown dosage w/dapsone, Failed sulfamethoxazole/ Adverse effects not discussed
African American M Kenalog, clindamycin, trimethoprim, cephalexin,
rifampicin, metronidazole, ciprofloxacin, clindamycin,
adalimumab rifampicin, metronidazole,
adalimumab, dapsone, and
Kenalog injections previ-
ously. Lack of response to
medical treatment led to
surgery intervention
Khaled et al. (2007) [87] 4 Case report 1 25 yo M 0.8 mg/kg/d × 12 mo Failed oral antibiotics, No adverse effects
systemic corticosteroids.
Reduction of abscess forma-
tion at 4 wk. At 6 mo, 95%
of hair regrown. No relapse
after 12 mo of therapy and 6
mo post-therapy
13
Table 1 (continued)
evidence skin type
13
Koca et al. (2002) [88] 4 Case report 1 22 yo White M 0.5–0.75 mg/kg/d × 9 mo Failed systemic antibiotics. Adverse effects not discussed
Resolution of abscesses,
reduction of nodules size,
regrowth of hair seen at 2
mo. No relapse 3 mo post-
therapy
Lee et al. (2018) [81] 3 Retrospective 16 16 M, 12–59yo 40–80 mg/d × 1–16 mo Mean initial response time was Adverse effects not discussed
2 wks. 6/16 had a complete
response, 6 had a partial
response, 4 had no response.
2/16 had disease recurrence
Segurado-Miravalles et al. 4 Case series 8 N/A 30 mg/d Significant reduction in inflam- Adverse effects not discussed
(2016) [89] matory activity in 7/8 (88%)
Wollina et al. (2012) [90] 4 Case report 1 30 yo White M 30 mg/d w/300 mg rifampicin Patient responded with mild Adverse effects not discussed
and 50 mg prednisolone improvement but severity
increased months later.
Started infliximab and saw
significant improvement
Bachynsky et al. (1992) [91] 4 Case report 1 32 yo Black M 1 mg/kg/d × 5 mo Failed antibiotics and intral- Adverse effects not discussed
esional corticosteroids. At
1-year follow-up, disease
totally eradicated and no
recurrence noted
Stites et al. (2001) [92] 4 Case report 1 23 yo White M 1 mg/kg/d × 3 mo Failed amoxicillin, clavulanate, Adverse effects not discussed
ciprofloxacin, azithromy-
cin, topical chlorhexidine
washes. Marked reduction
in inflammation, resolved
abscesses and sinus tracts
after 3mos
Folliculitis decalvans (6); n = 89
Tietze et al. (2015) [174] 3 Retrospective 10 N/A 0.2–0.5 mg/kg/d × 5–7 Dosage tapered after several Adverse effects not discussed
mo ± dapsone mos, 90% had full remission
after therapy, no relapse
reported
Aksoy et al. (2018) [175] 3 Retrospective 39 39 M, mean 37.85yo 0.1–1.02 mg/kg/d × median 82.0% with partial and com- Adverse effects not discussed
2.5 mos plete response after 2.5mos.
20 pts relapsed in the mean
of 9.65mos. 665 of pts that
received ≥ 0.4 mg/kg/day
isotretinoin for ≥ 3mos never
relapsed
Shireen et al. (2018) [178] 4 Case report 1 23 yo African M 60 mg/d × 3 mos, reduced to Isotretinoin stopped after no No adverse effects
20 mg/day × 3 wks improvement; transitioned
to adalimumab therapy,
and remained in remission
for 5 yrs
Table 1 (continued)
evidence skin type
Bunagan et al. (2015) [176] 3 Retrospective 23 16 M (12-42 yo), 7F Unknown dosage with Minimal, unsatisfactory Adverse effects not discussed
(34–74 yo), White (n = 19), cephalexin, minocycline and results; occasional flares
East Indian (n = 3), African other antibiotics with therapy
(n = 1)
Gemmeke et al. (2006) [179] 4 Case report 1 27 yo White M 40 mg/day, reduced to 30 mg/ Failed prednisolone, ampicil- Adverse effects not discussed
day in combination with lin. Marked improvement
daily 20 mg prednisolone for after 3 wks of therapy. No
3 wks and 300 mg clindamy- relapse at 6mo follow-up
cin for 6 wks

Miguel-Gomez et al. (2018) 3 Retrospective 15 N/A Unknown dosage used in Unknown response Epistaxis (3)
[177] combination therapy with
rifampicin, clindamycin,
dapsone, and oral corticos-
teroids
Sebaceous hyperplasia (9); n = 32
McDonald et al. (2011) [140] 4 Case series 2 36 yo M; 45 yo M 0.14–0.29 mg/kg/day × Cyclosporine-induced Minor cheilitis (1)
1 wk–3 mos sebaceous hyperplasia
presented. Complete or
almost complete clearance
of lesions as soon as 1 week,
and no alteration in patient
graft functions (both renal
transplant recipients). Main-
tenance dose of 10–20 mg/
day
Jung et al. (2016) [138] 4 Case report 1 40 yo Korean M 0.29 mg/kg/day × 2 mos Cyclosporine-induced No adverse effects
sebaceous hyperplasia.
Near-complete clearance and
remission after 2 mos. No
recurrence at 9mos
Burton et al. (1985) [135] 4 Case report 1 39 yo White M 40 mg twice per day, then Failed systemic antibiotics, No adverse effects
tapered over 2 wks electrodesiccation, cryosur-
gery, topical trichloroacetic
acid. Complete clearance
within 2 wks, but relapse
within 3 wks of stopping
treatment. Remission
remained with 40 mg every
other day
Grimalt et al. (1997) [136] 4 Case series 3 1 M, 2 F, 22–48 yo 1 mg/kg/day, then topical Marked improvement in skin Adverse effects not mentioned
0.05% texture and reduction in
lesion size after 6 wks. All 3
with no relapse; 2 pts using
isotretinoin gel 0.05% 5mos
after stopping oral
13
Table 1 (continued)
evidence skin type
13
Tagliolatto et al. (2015) 2 Prospective 20 20 F 1 mg/kg/d Average number of sebaceous Mucosal dryness, increased
[142] hyperplasia lesions per serum triglyceride that
patient was reduced from 24 improved with diet and cessa-
to 2 after 2 mos (p < 0.05). tion of protocol (1)
Fewer lesions two after
therapy than prior to starting
therapy
Liu et al. (2016) [139] 4 Case series 2 39 yo Indonesian F; 29 yo 0.2 mg/kg/d 1 pt failed oral minocycline, No adverse effects
Indonesian F topical tretinoin, topical
metronidazole; 1 pt failed
oral doxycycline, topical
metronidazole, topical
fluticasone. Improvement
after 1 month in 1 subject,
and continued treatment over
7 months with a cumulative
41 mg/kg dosage, and remis-
sion maintained for 2 years;
second subject had treatment
for 10 wks before tapering
to 0.1 mg/kg/d for 9 months,
with no recurrence at 19 mos
Gupta et al. (2016) [137] 4 Case report 1 64 yo Indian M 20 mg daily Significant improvement and Mild cheilitis
flattening of lesions over
3 mos; dosage continued
to maintain effects and no
relapse
Wang et al. (2016) [143] 4 Case report 1 44 yo Chinese F 1 mg/kg/d × 12 wks Significant reduction in lesion No adverse effects
size and extent of facial
seborrhea after 12 wks; no
relapse at 3 mo follow-up
Noh et al. (2014) [141] 4 Case report 1 55 yo Korean M 20 mg/day × 1 yr, then 10 mg/ Failed CO2 laser treatment. Adverse effects not reported
day × 1 yr; no recurrence Clearance of lesions and
at 1 yr improvement in skin texture
with no recurrence for 1 year
since discontinuing
Cutaneous T cell lymphoma (17); n = 270
Thomsen (1995) [51] 4 Case series 3 2 M, 1 F, 60–69 yo 40 mg/d and 1 μg calcitriol × 3 Failed topical nitrogen mus- Hair loss (1)
mo tard, PUVA, radiotherapy,
retinoids, methotrexate,
interferon α-2b. All patients
deteriorated on combination
therapy with skin lesions
enlarging or new lesions
appearing
Table 1 (continued)
evidence skin type
Duvic et al. (1996) [47] 2 Prospective 28 19 M, 9 F, median 58.5 yo 1 mg/kg/d w/5 × 106 U/m2/d 3/28 (11%) achieved complete Skin and mucous membranes
interferon alfa × 4 mo fol- remission, 11/28 (39%) dryness, elevated TG (18),
lowed by TSEB (stage I–II) had partial remission elevated hepatic enzymes
or combination chemother- with interferon alfa and (7%), diarrhea (3), thrombocy-
apy (stage III–IV) isotretinoin after 4mo. 20/28 topenia (3)
(71%) achieved complete
remission, 3/28 (11%)
achieved partial remissions
with combined therapy after

4mo. 14 pts had recurrence
of disease between median
time of 5-18mos
Duvic et al. (2003) [48] 2 Prospective 94 58 M, 37 F, median age 1 mg/kg/d w/5 × 106 U/m2/d 79/94 (84%) responded to TG (60), leukopenia (58),
59 yo, White (n = 67), Black interferon alfa-2b × 4 mo combined modality, 56/94 fatigue (45), flu symptoms
(n = 15), Hispanic (n = 12), followed by TSEB (stage Ia- (60%) achieved complete (40), hepatitis (37), thrombo-
Asian (n = 1) IIa) or combination chemo- response. 7/56 (13%) com- cytopenia (23), anorexia (15),
therapy (stage IIb-IVb) plete responses induced by headache (15), nausea (12),
initial IFN-α and isotretinoin mood changes (10), dizziness
induction, with 8% complete (8), diarrhea (7), alopecia
response and 56% partial (6), hypersensitivity rash (2),
response rate hypothyroidism (2), abdomi-
nal pain (2), transient ischemic
attack (1), shortness of breath
(1), injection site cellulitis (1),
sarcoidosis exacerbation (1),
sebopsoriasis (1), impotence
(1)
Knobler et al. (1991) [49] 2 Prospective 7 3 M, 4 F, 43–70 yo 1 mg/kg/d w/2 × 106 IU IFN Failed radiation, chemo- Adverse effects were negligible
alfa-2b 3×/wk × 3 mo therapy, steroids. 2/7 (29%)
had complete response, 2/7
(29%) had a partial response
with a median response time
of 3 mo. Therapeutic effect
was systemic, distant lesions
responded well. No relapse
at 15 mo follow-up
Su et al. (1993) [52] 4 Case report 1 69 yo F 1 mg/kg/d × 3 mo Failed systemic chemotherapy, Dry eyes, slightly elevated
prednisolone, radiotherapy, triglycerides
interferon α. Tumors dimin-
ished 3 weeks after therapy
with complete disappearance
of tumor masses 3 mo later
Wantzin and Thomsen 4 Case series 4 N/A 0.5 mg/kg/d × 2 wk Isotretinoin therapy resulted in Retinoid dermatitis (erythro-
(1985) [53] 3/4 (75%) pts having severe derma) (3)
aggravation of erythroderma
after 2 wk of treatment,
persisted for 2–3 mo
13
Table 1 (continued)
evidence skin type
13
Warrell et al. (1983) [54] 4 Case series 7 N/A 100 mg/d × 4 wk Failed TBSE, cytotoxic chemo- Adverse effects not discussed
therapy, methotrexate. 2/7
(28.6%) had 50% clearing of
plaque lesions. 1/7 (14.3%)
had a total clearing of
erythroderma and enlarged
axillary lymph node. 4/7
(57.1%) did not improve, all
with tumor stage disease
Neely et al. (1987) [55] 4 Case series 6 3 M, 3F, 54-71yo 1-2 mg/kg/d × 8-13mo Failed topical/oral/intralesional Dry mucous membranes (6),
corticosteroids, TBSE, conjunctivitis (2), non-specific
bleomycin, doxorubicin, musculoskeletal complaints
cyclophosphamide, vincris- (2), elevated triglycerides (2)
tine, prednisone. Decreased
pruritus and skin lesion
fading occurred between 2–8
wks. 4/6 (67%) had main-
tained improvement with
dose tapering. 2/6 relapsed
but improved after treatment
started again
Mycosis fungoides
Fitzpatrick and Mellette 4 Case report 1 56 yo M 1 mg/kg/d × 6 mo Failed topical nitrogen Cheilitis, dry skin, elevated
(1986) [60] mustard. Skin was back triglycerides
to normal after 3 mo of
therapy. No relapse 16 mo
post-therapy
Molin et al. (1987) [56] 2 Prospective 34 N/A 0.2-2 mg/kg/d × 2 mo, 1-27mo In patients treated for Retinoid dermatitis (11),
for long-term 2 months, 8/34 (23.5%) were mucosal/skin dryness
complete remission, 14/34
(41.2%) in partial, 12/34
(35.3%) had no response.
For patients undergoing
long-term therapy, 5/28
(17.9%) had complete remis-
sion, 11/28 (39.3%) had
partial, 12/28 (42.9%) had no
response. Relapse occurred
in 10 pts despite continued
therapy
Leverkus et al. (2005) [61] 4 Case report 1 63 yo M 0.2-1 mg/kg/d × 15 mo Failed PUVA with interferon Adverse effects not discussed
alfa-2a. Slow, steady regres-
sion of residual cysts and
comedones with complete
healing over 15mos. No
relapse of follicular mycosis
fungoides
Table 1 (continued)
evidence skin type
Thomsen et al. (1984) [57] 2 Prospective 20 10 M, 10 F, Mean 63.6 yo 0.1-2 mg/kg/d × 2wk-6 mo Response to therapy as early as Adverse effects not discussed
2–4 wks, complete remission
was seen at 2 mos. 6/20
(30%) patients had complete
remission, 10/20 (50%) had
partial remission. 4/20 (20%)
had no convincing response
Wantzin and Thomsen 4 Case series 1 N/A 0.5 mg/kg/d × 4d After 2 days, the patient had Retinoid dermatitis (1)
(1985) [53] universal skin reddening

with exfoliation and pattern
of severe seborrheic derma-
titis. Widespread dermatitis
present at 6wk
Kessler et al. (1983) [62] 4 Case series 4 3 M, 1 F, 39–68 yo 0.1-3 mg/kg/d Failed topical and systemic Skin dryness (4)
corticosteroids, topical nitro-
gen mustard, electron beam
therapy, PUVA, systemic
cytotoxic chemotherapy.
After 1 mo, plaques and pru-
ritus were reduced. Dosage
of therapy decreased due to
skin dryness and scaling
Kessler et al. (1987) [58] 2 Prospective 25 18 M, 7 F, mean 65 yo 1-2 mg/kg/d × 2 wk–8 mo Failed topical steroids, pred- Dry skin (23), cheilitis (15),
nisone, topical mechlore- conjunctivitis (14), fatigue (9),
thamine carmustine, PUVA, arthralgia/myalgia (9), mental
electron beam radiation status change (6), headache (7)
therapy, systemic chemo-
therapy. 3/25 (12%) had total
disappearance of all visible
skin lesions, 8/25 (32%)
had a partial response, 6/25
(24%) had minor responses.
Median duration of response
2mos (2 wks–8 mos)
Thomsen et al. (1989) [59] 2 Prospective 22 N/A 0.5–1.5 mg/kg/d w/etretinate Complete remission in 16/22 Mucosal and skin dryness
0.3–1 mg/kg/d and PUVA (73%), partial remission in
6/22 (27%). Therapy 4×/wk
induced complete remission
after a mean of 15 sessions,
2×/wk therapy had complete
remission after 19 sessions
13
described isotretinoin combined with interferon alpha-2a;
taneous, INF interferon, LFT liver function tests, TG triglycerides, MU million units, KA keratocanthoma, qHS every night, XP xerosis pigmentosa, TSEB total skin electron beam therapy, RCT
randomized controlled trial, PDL pulsed dye laser, FMR fractional microneedling radiofrequency, MF mycosis fungoides, FMF folliculotropic mycosis fungoides, 5aRI 5-alpha reductase inhibi-
Eod every other day, mo month, d day, wk week, yr year, pt patient, RCTrandomized control trial, PUVA psoralen and UVA light, NBUVB narrow-band UVB light, BID twice a day, subq subcu-
Cheilitis (4), xerosis (3), retinoid
dermatitis (2), hypertriglyc-
68% of lesions regressed after 1.5 months of therapy and
headache (1), arthralgia (1)

eridemia (2), myalgia (1),
40.6% of patients were described to have a response to
treatment, respectively [20, 22]. Failed prior treatments
included radiation, excision, electrodessication, chemo-
Adverse effects
therapy, methotrexate, and/or various typical pharmaco-

logical therapies.
achieved complete response.
therapy. Mean time to maxi-

6/8 patients with classic MF
patients with FMF achieved
had a partial response, 2/8

Failed PUVA, NBUVB. 3/4
Mixed basal and squamous cell carcinoma treatment

had the stable disease to
mal response was 6mo

a partial response, 1/4
Two RCTs [35, 36] and one case series [37] described the
use of oral isotretinoin in 1249 patients affected by mul-
tiple NMSCs. Five patients treated with 2 mg/kg/day oral
Course
isotretinoin monotherapy presented with a 63% decrease

in tumor occurrence [37]. Two RCTs described patients
with multiple NMSCs (BCC and SCC) and compared the
0.1–0.7 mg/kg/d × 3.5–55 mo
efficacy of 5–10 mg/day oral isotretinoin, oral retinol,

Isotretinoin treatment
and placebo therapy. Retinol reduced the incidence of

first new SCCs in one study [35], whereas no significant
difference in the first occurrence of NMSCs or in the
total number of tumors was noted between therapies in
the other [36]. In the reported studies assessing photoag-
ing, patients were evaluated for overall skin appearance,
folliculotropic MF (n = 4),
7 M, 5 F, Mean 48 yo, Early
wrinkles, dyspigmentation, texture, elasticity, and amount

Patient demographics and
classical patch (n = 8)
of collagen. Patients were generally FSTI-III and treated

with oral isotretinoin with dosages ranging from 10 to
20 mg [38–45]. Improvement was reported in almost all
patients treated with oral isotretinoin.
skin type
Keratoacanthoma treatment
Sample size (n)
Five patients suffering from keratoacanthoma were

described in five case reports treated with 0.5–6 mg/
kg/day oral isotretinoin [26–30]. Lesion regression was
12
seen as early as two weeks, however, recurrence within

8–12 weeks was common after therapy cessation [27, 30].
One case report using 0.5–1 mg/kg/day isotretinoin was
ineffective in treating existing lesions, whereas regression
only occurred with dosages as high as 1.5 mg/kg/day [29].
Retrospective
Study design
Actinic damage treatment

evidence
Level of
Eight studies with a total of 248 patients reported the use

of oral isotretinoin (10–20 mg/day) for photodamaged
3
skin. A study compared 10 mg/day oral isotretinoin to

topical tretinoin cream and found that isotretinoin reduced
Amitay-Laish et al. (2019)
Table 1 (continued)
a higher amount of actinic keratoses (AK) compared to

topical tretinoin [42]. Bagatin and Guadanhim compared
Author and year
20 mg every other day oral isotretinoin to topical 0.05%

retinoic acid and found that both therapies improved
[50]
overall skin condition with no significant difference [38].

tors
13
Another study combined 20 mg/day oral isotretinoin with 39.3% of patients undergoing short-term therapy (2 months)
topical 5-fluorouracil cream reported AK lesions regressed had complete or partial remission, while only 17.9% patients
completely in 22 (81.5%) patients [44]. While mucosal undergoing long-term therapy had the same response [56].
dryness and cheilitis were the most common adverse Combination therapy with 0.5–1.5 mg/kg/day isotretinoin
effects reported with oral therapy. Depression was reported with etretinate and PUVA reported complete remission in
in two patients treated with 20 mg oral isotretinoin [39]. 16/22 (73%) of patients while 6/22 (27%) patients had partial
remission of their illness [59].
Relapse was reported in 26 patients between a median
Leukoplakia
duration of 5–18 months after stopping therapy. Cheilitis
and mucosal dryness were common side effects in patients.
One RCT treated 44 patients for oral leukoplakia with oral
Dosage reduction was required in some patients treated with
isotretinoin 1–2 mg/kg/day or placebo therapy. Sixty-six
2 mg/kg/day due to severe retinoid dermatitis [56, 58]. One
percent of patients treated with isotretinoin had decreased
study reported uncommon adverse effects in patients treated
lesion size and dysplasia, compared to those who received
with a combination therapy of 1 mg/kg/day isotretinoin,
placebo (10%) [31].
interferon alfa-2b, and TSEB or combination chemotherapy:
leukopenia (n = 58), fatigue (n = 45), mood changes (n = 1),
Xeroderma pigmentosum hypothyroidism (n = 2), transient ischemic attack (n = 1), sar-
coidosis exacerbation (n = 1), and impotence (n = 1) [48].
Three studies with a total of 7 patients have reported the Additionally, one case series reported four patients treated
use of oral isotretinoin (1–2 mg/kg/day) for xeroderma with 0.5 mg/kg/day isotretinoin subsequently had a severe
pigmentosum [32–34]. In a prospective study, isotreti- aggravation of erythroderma following therapy [53]. Other
noin monotherapy (2 mg/kg/day) showed a 63% decrease uncommon side effects reported were myalgias/arthralgias,
in tumor occurrence over two years of treatment, but an mental status changes, and diarrhea [47, 50, 58].
8.5-fold increase in annual tumor occurrence was noted
within 3 months of treatment cessation in 60% of patients Rosacea
[32]. Combination therapy with 1 mg/kg/day isotretinoin
and chemotherapy described in a case report completely Rosacea is a common chronic inflammatory skin disorder
resolved a large tumor with no reported recurrence [33], with strong evidence for the use of isotretinoin.[64–77].
and another case report involving therapy with isotreti- Isotretinoin’s ability to reduce cutaneous blood flow and
noin, cisplatin, and 5-fluorouracil resulted in complete decrease the number of sebaceous glands has been attrib-
clinical remission of a tumor [34]. uted to its success in rosacea [15]. Across 15 studies with a
total of 991 patients, ranges of oral isotretinoin for rosacea
Side effects were from 0.22 to 1 mg/kg/day, with 0.3 mg/kg/day found
to be most effective in achieving complete remission after
Mucosal dryness, cheilitis, and conjunctivitis were com- 12 weeks of therapy [65]. Men and women were about
mon adverse effects in NMSC patients treated with isotreti- equally involved in studies, with most of the patients being
noin. Hyperostotic skeletal changes were noted in two middle-aged.
studies, particularly in the cervical and thoracic spine [37, Oral isotretinoin has been proven to be more effective
46]. Undefined vascular (n = 9) and central nervous system in decreasing symptoms of rosacea compared to placebo,
(n = 3) adverse effects were reported using 0.5–1.5 mg/kg/ topical tretinoin, and doxycycline. However, it does not
day isotretinoin [36]. Other uncommon side effects include serve as a definitive treatment due to the high relapse rates
arthralgia/myalgias, fatigue, and urethritis. (45–58.3%) within three months to a year after treatment
cessation. Two studies show that treatment longer than
Cutaneous T cell lymphoma (CTCL) six months with either 10–40 mg/day oral isotretinoin or
300 mg/day trimethoprim was sufficient for maintaining
Retinoids have a historic role in the management of CTCL remission up to a year after cessation [68, 76].
by influencing multiple signaling pathways in cellular dif- Combination therapies including azelaic acid, oral pred-
ferentiation and apoptosis [47–63]. Oral isotretinoin mono- nisolone, and oral trimethoprim were found to have similar
therapy for CTCL ranged from 0.5 to 2 mg/kg/day, with success compared to oral isotretinoin monotherapy based
1–2 mg/kg/day for 2–3 months being most effecting in lesion on papule and pustule size and amount, erythema, indura-
clearance [52, 53, 56–58, 62]. Combination therapy ranged tion, accentuated skin folds, and sebaceous gland size [68,
from 0.5 to 1.5 mg/kg/day, with 1 mg/kg/day for 3–4 months 78]. Relapse was not commonly reported in patients but
being most effective [47–49, 59]. Molin et al. presented that was noted at follow-up visits 8 weeks to 11 months after
13
Table 2 Retrieved number of studies and patients using oral isotreti- such as various antibiotics, antifungals, and topical/oral/
noin in various dermatological conditions intralesional glucocorticoids.
Dermatologic condition Number of Number of
studies patients Granuloma annulare
Non-melanoma skin cancer 31 2620
Granuloma annulare (GA) is a benign, asymptomatic gran-
Cutaneous T cell lymphoma 17 270
ulomatous skin condition characterized by grouped flesh-
Rosacea 15 991
colored or erythematous annular papules and plaques that
Dissecting cellulitis 14 76
is often localized but can be generalized. The mechanism
Granuloma annulare 12 16
of isotretinoin treating GA is unclear but may be due to its
Pityriasis rubra pilaris 11 122
ability to alter cellular growth and differentiation along with
Condyloma acuminata 9 271
its anti-inflammatory properties [93]. Twelve case reports or
Hidradenitis suppurativa 9 225
series [94–105] describe the outcomes of 0.5–1 mg/kg/day
Sebaceous hyperplasia 9 32
oral isotretinoin in 16 patients with ages ranging from 21 to
Darier’s disease 8 119
65-years-old. Ten of these cases were generalized, one was
Psoriasis 8 184
localized, and one was the less common perforating variant.
Cutaneous lupus erythematous 7 19
Oral isotretinoin was found to effectively clear lesions
Flat warts 6 88
by at least 90% in all patients, regardless of variant type,
Folliculitis decalvans 6 89
where treatment success is defined by clinical resolution
Lichen planopilaris 6 61
of erythema and absence of elevated patches [94–96, 98,
Lichen planus 5 42
102–104]. Improvement in pigment and elevation were seen
as soon as 4 weeks. Most follow-up visits were completed at
three months post-treatment but ranged up to 1 year. Recur-
rence occurred in 25% of patients followed [95, 96, 103].
therapy. Cheilitis was the most common adverse effect One case report combined 0.5 mg/kg/day oral isotreti-
encountered, with less common side effects being hair loss, noin with topical pimecrolimus cream and reported complete
mood changes, myalgias/arthralgias, fatigue, and one case lesion clearance after four months of therapy [105]. Several
of Herpes zoster infection [65, 66, 75, 76]. patients previously failed hydroxychloroquine, oral dapsone,
and/or topical/oral/intralesional corticosteroids. Cheilitis
Dissecting cellulitis was a common adverse effect, and elevated triglycerides
and cholesterol were seen in some case reports although
Dissecting cellulitis, or perifolliculitis capitits abscedens et unsure whether those findings could be directly attributed
suffodiens, is a rare suppurative disease of the scalp char- to isotretinoin [94, 96, 97, 103].
acterized by recurrent pustules, abscesses, and sinus tract
formations leading to scarring and alopecia. The success Pityriasis rubra pilaris
of isotretinoin on dissecting cellulitis may be attributed to
its sebosuppressive and anti-inflammatory effect and nor- Pityriasis rubra pilaris (PRP) is an inflammatory cutane-
malization of follicular keratinization [79]. Fourteen studies ous disorder that forms follicular hyperkeratotic papules
with a total of 76 patients reported oral isotretinoin dosages and plaques. Isotretinoin effectiveness may be attributed to
ranging from 0.27 to 1 mg/kg/day for several months to treat the normalization of keratinization. Eleven studies reported
dissecting cellulitis (n = 77) [79–92]. Thirty-nine percent of outcomes from 122 patients treated with oral isotretinoin
the patient demographic reported FST IV–VI. A majority ranging from 0.5 to 4 mg/kg/day [106–116]. Clinicians
of reported patients (71.1%) had significant improvement monitored induration, scaling, erythema, and lesion clear-
with isotretinoin therapy regardless of dose defined by a ance over treatment courses ranging from 1 to 6 months.
clinical decrease in lesions, reduction in scalp swelling, and A majority (82%) of patients responded to treatment with
regrowth of hair, while others (29.9%) had no improvement 50–90% lesion clearance [107, 109–111, 113, 115, 116] and
and had surgical intervention or infliximab therapy [86, 90]. combination therapy of isotretinoin, etretinate, and metho-
Remission of lesions occurred between 1 and 4 months with trexate entirely clearing lesions in 75% of patients [106].
relapse reported in two patients [81]. Complete lesion clearance reported in patients occurred
One study combined oral rifampicin with 0.5 mg/kg/ between 4 and 48 months of therapy. Relapse was seen
day oral isotretinoin (n = 4 patients) and reported remission between 4 and 12 weeks after the end of treatment [115].
within three to four months with no relapse seen after up to Treatment response was reported as early as four weeks with
a year post-therapy [85]. Most patients failed prior therapies complete resolution observed for up to four years in patients
13
Fig. 1 Schematic showing

selection of articles to include PubMed Web of Science
in review 1949-2019 1921-2019
863 cita ons 886 cita ons
890 nonduplicate cita ons screened
683 ar cles excluded aer

Inclusion/exclusion
tle/abstract screen
criteria applied
207 ar cles retrieved

Full-text ar cles excluded,
with reasons
(n = 38)
Inclusion/exclusion Reasons:
1 Spanish ar cle
criteria applied
9 reviews
1 animal study
8 leers/expert opinions
1 reanalysis paper
1 treatment protocol
17 topical isotre noin only
169 ar cles included
on maintenance etretinate or methotrexate [106]. Cheilitis Isotretinoin was shown to provide better lesion clear-
and mucosal dryness were the most common adverse effects, ance than placebo [118–120, 122], however, combination
and joint pain and hair loss were also reported in separate therapy was shown to be superior to isotretinoin monother-
cases [115]. apy. An average of 96% of patients treated with isotretinoin
combined with IFN alfa-nl, -2a, or podophyllin exhibited
Condyloma acuminata 64.7–100% lesion clearance compared to 61.72% of those
treated with isotretinoin monotherapy [118, 119, 121, 123,
Condyloma acuminata, or genital warts, is a sexually trans- 124, 126]. Duration of therapy was found to be significantly
mitted cutaneous condition caused by human papillomavirus reduced in combination therapies compared to isotretinoin
(HPV). Isotretinoin, through its immunomodulatory effects, monotherapy (2.18 months vs 2.5 months; 1.9 months vs
may be able to inhibit the replication of HPV within infected 2.5 months, respectively) [118, 119]. Additionally, the
cells [117]. Two hundred seventy-one patients (18–47-years- recurrence rate was decreased in combination therapy com-
old) across nine studies reported experiences with 0.5–1 mg/ pared to isotretinoin monotherapy (4/44 patients vs 16/42
kg/day oral isotretinoin [118–126]; several studies presented patients, respectively) [118]. Of the combination therapies
isotretinoin combination therapy with subcutaneous inter- reviewed involving isotretinoin, subcutaneous interferon
feron (IFN) alfa-nl or -2a, surgical debridement, or topi- alfa-2a (3MU) was used in most patients and showed the
cal podophyllin [118, 119, 121, 123, 124, 126]. Treatment best results. Patients reported failed therapies with various
response for isotretinoin monotherapy ranged from 2.5 to traditional topical therapies, electrocauterization, and/or
4.1 months. surgery. Dry eyes, skin, or lips were the most common side
13
effect experienced, with rare reports of hair loss (n = 10), remained on dosages of 20 mg/day or 40 mg every other
fatigue (n = 9), and joint pain (n = 1) [118–121]. day to prevent relapse [135, 137]. Isotretinoin was effective
in resolving sebaceous hyperplasia associated with immu-
Hidradenitis suppurativa nosuppressed renal transplant patients (0.14–0.29 mg/kg/
day) with no adverse effects reported [140]. One patient was
Hidradenitis suppurativa (HS) is a chronic inflammatory dis- reported to relapse within three weeks of treatment discon-
ease affecting apocrine glands, characterized by painful per- tinuation [135].
sistent abscesses, fistulas, and scarring. Isotretinoin has been
theorized to be effective in treating HS by reducing follicu- Darier’s disease
lar plugging [127]. Two hundred twenty-five patients across
four retrospective cohort studies [10, 127–129] and five case Darier’s disease is an autosomal dominant condition that
series reported were treated with isotretinoin [130–133]. often develops in childhood with pruritic, malodorous,
Clinical parameters for improvement were defined in lesion hyperpigmented, keratotic papules of the face, back, and
clearance, reducing sebum excretion, and mitigating flares, chest [144, 145]. Isotretinoin may be efficacious for Dari-
with oral isotretinoin doses ranging from 0.14 to 65 mg/ er’s disease by reducing keratinocyte hyperproliferation. The
kg/day [10, 127–134]. Previous failed treatment attempts use of oral isotretinoin (0.5–4 mg/kg/day) for Darier’s dis-
included chlorhexidine, topical antibiotics, infliximab, and ease was reported for 119 patients across eight studies with
spironolactone. clearance between 4 weeks to 3 months of treatment [112,
Three retrospective studies showed that up to 45% of 115, 133, 146–150]. Clinical endpoints included reduction
patients had lesion improvement as early as four months of hyperkeratotic lesions, erythema, scaling, induration,
and maintained for up to nine years [10, 128, 129]. In a study crusting, and clearance of papules. Oral isotretinoin dis-
of 39 patients with HS, 35.9% responded to oral isotretinoin played efficacy with all patients achieving 75–100% lesion
therapy. Additionally, patient history of the pilonidal cyst clearance as early as one week. However, recurrence was
was significantly associated with the positive response to reported in every case seen for follow-up, with 80–100%
therapy, which occurred in 35.9% of patients [127]. A report lesion relapse within 7 days to 6 months post-treatment [115,
of six patients documented no significant improvement on 146, 149]. One case report used 40 mg oral isotretinoin with
1 mg/kg/day and showed worsened inflammation once ther- 5% salicylic acid and reported significant lesion improve-
apy was discontinued [132]. Similarly, although a dose of ment after 1 month of treatment [147]. Recurrence with oral
1 mg/kg/day led to 70–90% decrease in sebum excretion in isotretinoin therapy occurred as early as seven days and up
three other patients, amount of discharge and flares remained to 6 months after discontinuation. Cheilitis was the most
unchanged after four months [131]. In a subset of patients, common adverse effect, however, a study using 1–2 mg/kg/
isotretinoin therapy worsened lesions in several reports [129, day oral isotretinoin reported cases of joint pain, hair loss,
130, 132, 134]. The most common adverse effects included and fatigue [115].
dry skin and cheilitis, fatigue, hair loss, headache, swell-
ing, and elevated triglycerides or cholesterol (n = 5), with Psoriasis
joint pain (n = 2) and suicidal ideation (n = 1) occurring less
frequently. Psoriasis is characterized by abnormal growth and differenti-
ation of keratinocytes, where isotretinoin can help by modu-
Sebaceous hyperplasia lating keratinocyte hyperproliferation and differentiation and
inflammatory cells if traditional therapies have failed [15].
Sebaceous hyperplasia is characterized by enlargement The use of oral isotretinoin for the treatment of generalized
of the sebaceous glands, particularly affecting patients pustular, palmoplantar pustulosis, and plaque psoriasis has
on immunosuppressive therapy, such as organ transplant been described in two RCTs [151, 152], five case reports or
patients. Isotretinoin is the most effective drug for reduction series [153–157], and one prospective cohort study [158]
of sebaceous gland size by decreasing sebocyte proliferation (n = 184 patients). Overall, oral isotretinoin doses as low as
and suppressing sebum production [117]. Thirty-two sub- 0.5 mg/kg/day [157] and up to 1.75 mg/kg/day were effec-
jects across eight case reports or series and one prospective tive at clearing skin lesions [156]. However, one patient with
study have been treated with oral isotretinoin for facial seba- generalized pustular psoriasis reported recurrence of pus-
ceous hyperplasia [135–143]. Doses ranged from 0.14 to tules with tapering of dosage to 0.75 mg/kg/day [156]. In
1.0 mg/kg/day, with treatment courses of one week to three patients with plaque psoriasis, oral isotretinoin with PUVA
months. In all reported cases, oral isotretinoin resulted in combination therapy has been reported to be successful in
complete or near-complete clearance of lesions after a wide clearing lesions [151, 152]. In one study, patients treated for
range of 1–12 weeks of therapy. In most reports, patients generalized pustular psoriasis presented with higher success
13
rate and shorter treatment time in comparison to chronic indicate its effectiveness in flat warts. Two RCTs [168, 169],
plaque psoriasis patient following 1.5–2 mg/kg/day oral one prospective cohort study [170], and three case reports
isotretinoin [156]. Oral isotretinoin dosages ranging from 0.4 or series [171–173] of 88 total patients described the use
to 2 mg/kg/day was combined with PUVA and narrow band of oral isotretinoin between 0.1 and 0.5 mg/kg/day to treat
ultraviolet B (NBUVB) [151, 152, 154, 155, 158]. In 75% of flat warts. Previously failed treatments included imiqimod,
patients, combinations of isotretinoin and PUVA or NBUVB 5-fluorouracil, and cryosurgery [168, 172]. Oral therapy was
showed minimal additional efficacy with the addition of shown to be effective in providing patients complete clear-
isotretinoin [151, 152, 154]. Isotretinoin (1.5–2 mg/kg/day) ance as soon as one month, with no relapse for follow-up
was shown to be non-inferior to etretinate for the treatment periods ranging from four months up to three years [170,
of generalized pustular psoriasis after eight weeks of therapy 171, 173]. Olguin-Garcia et al. compared 30 mg/day oral
[158]. However, isotretinoin (0.5 mg/kg/day) combined with isotretinoin to a placebo control, presenting that 87.5%
either PUVA or NBUVB showed greater clearance of lesions (n = 16) of patients had complete remission of facial flat
compared to placebo [151, 152]. Patients failed prior thera- warts, while no patients responded in the placebo group
pies with methotrexate, PUVA, UVB, and/or corticosteroids. [168]. One study compared the use of oral isotretinoin to a
Cheilitis and nausea were the most common adverse effects topical 0.05% formula, finding that oral therapy was signifi-
described. cantly better than topical treatment [169].
Cutaneous lupus erythematous Folliculitis decalvans
Cutaneous lupus erythematosus (CLE) refers to a variety Folliculitis decalvans (FD) is a neutrophil-driven primary
of disease subtypes classifying discoid (chronic cutaneous), cicatricial alopecia associated tufted hairs and late-stage
keratotic, and subacute cutaneous variants [159, 160]. Reti- scalp fibrosis. Isotretinoin has direct immunomodulatory
noids are common second-line therapy for CLE by decreas- effects that can inhibit the migration of neutrophils into the
ing inflammation and reducing abnormal differentiation and skin, which makes this an interesting treatment modality
hyperproliferation of keratinocytes [161]. Oral isotretinoin for patients with FD [174]. A total of 89 patients, a majority
monotherapy has been used as a treatment for CLE in 19 of whom were male, were described in four retrospective
patients across seven studies, with dosages ranging from studies [174–177] and two case reports/series [178, 179].
10 to 50 mg/day [160, 162–167]. In patients suffering from Patients were treated with 0.1–1.02 mg/kg/day oral isotreti-
chronic/subacute CLE, 90% lesion improvement was seen as noin for 5–7 months, many in combination with oral and top-
early as one month, whereas clearance was seen after three ical antibiotics (i.e. clindamycin). Most subjects (82–90%)
months of therapy in one patient treated for hypertrophic reached complete remission as soon as two months, and
CLE. remained in remission for four months to two years [175].
Combination therapies included hydroxychloroquine, One case report described symptom relapse within a week
prednisone, topical clobetasol propionate, and fluocinonide of oral isotretinoin discontinuation; however, once treat-
[163, 165, 166]. Oral isotretinoin dose varied from 0.5 to ment was restarted, the subject required adalimumab due
1.5 mg/kg/day, except one patient who was initially treated to a plateau effect [178]. One patient on oral isotretinoin
with 400 mg/day and tapered to 40 mg/day [163]. Lesions therapy worsened, however, dose and duration of treatment
were considered improved if they exhibited decreased ery- were unspecified [176]. Combination therapy with 40 mg/
thema, thickness, or size. All patients experienced lesion day oral isotretinoin, a 3-week prednisolone taper, and 300-
improvement with as little as three weeks of treatment with mg oral clindamycin/day reported marked improvement after
as high as 90% clearance. Those treated with combina- 3 weeks of therapy and no relapse at the 6-month follow-up
tion therapy showed lesion resolution after three months in a patient that previously failed prednisolone and ampicil-
of treatment [165]. In multiple case reports, no relapses lin [179]. The only adverse effect described was epistaxis in
were reported within 3–9 months after treatment cessa- three patients [177].
tion [160, 164, 167]; however, a case series of six patients
reported rapid recurrence of lesions upon discontinuation Lichen planopilaris
of treatment [165]. Cheilitis was reported in several cases
in patients treated for various types of CLE [162, 163, 167]. Lichen planopilaris (LPP) is a primary immune-mediated
cicatricial alopecia characterized by lymphocytic infiltrate
Flat warts and fibrosis [180, 181]. Frontal fibrosis alopecia (FFA) is a
subtype of LPP that predominately affects the frontotem-
As previously mentioned, isotretinoin is suggested to inhibit poral hairline with a concomitant finding of facial papules
the replication of HPV within infected cells, which may [182]. Isotretinoin’s mechanism of action in stabilizing
13
hair loss and reducing inflammation is not clear but may isotretinoin compared to diffuse and reticular types [187].
be due to the normalization of follicular keratinocyte anti- Relapse was reported in four patients after two months of
gen expression and reduction in inflammatory cellular infil- discontinuing therapy [189].
trate [183]. Six small studies reported use of isotretinoin Failed prior therapies include topical and systemic corti-
for lichen planopilaris in a total of 61 patients, including costeroids, topical retinoid acid, and griseofulvin. Oral treat-
three retrospective cohort studies [180–182] and three case ment commonly caused cheilitis or xerosis, whereas topi-
series [184–186]. Patient ages ranged from 29 to 60-years- cal therapy caused soreness, transient burning, and a mild
old with therapy duration ranging from 2 to 24 months and increase in pain in most patients. Menorrhagia, joint pain,
improvement seen as early as one month of treatment [185]. and headaches were reported in some patients [187, 189].
Doses of oral isotretinoin ranged from 10 mg every other
day to 40 mg/day, with 20 mg/day being for monotherapy
in studies [180, 182, 185]. One study presented that 22 of Discussion
29 (75.9%) patients had no further progression of hair loss
after 12 months of oral isotretinoin therapy [182]. Babehos- Clinically, the dosing and duration of therapy of isotreti-
seini et al. reported that 6 of 7 patients treated with oral noin utilized for dermatological diseases range from 0.1 to
isotretinoin monotherapy had a complete response to ther- 8.2 mg/kg/day. Inflammatory conditions such as rosacea,
apy, defined as a negative hair pull test, a complete halt of granuloma annulare, and HS benefit from lower oral isotreti-
hair loss progression, and decrease in facial papules [180]. noin dosage of 0.3–1 mg/kg/day, whereas, hyperkeratotic
No hair regrowth in scarred areas was reported. diseases such as psoriasis and pityriasis rubra pilaris, con-
Combination therapy with isotretinoin was common in sistently respond better to higher dosages of up to 2–4 mg/
the studies reviewed for LPP and FFA. Oral isotretinoin kg/day for lesion clearance. Isotretinoin was found to be a
(20 mg/day) was combined with a 5-alpha reductase inhibi- useful modality following failed standard therapies (i.e. topi-
tor (5aRI) and saw that all four patients with hair loss from cal/intralesional/systemic steroids, antibiotics, antifungals,
FFA treated responded to therapy (three complete respond- antimalarials, laser therapy, other retinoids, radiation, and
ers and one partial responder) [180]. In one LPP study, topical chemotherapeutic agents. Although isotretinoin was
10 mg isotretinoin was combined with finasteride or spirono- found to be effective in most cases, the evidence is weak due
lactone, pimecrolimus cream, and vitamins; a decrease in to the lack of extensive studies, particularly in dissecting
facial papules and skin roughness was seen after 2 months of cellulitis, granuloma annulare, sebaceous hyperplasia, flat
therapy, with no further progression seen 12-month follow- warts, folliculitis decalvans, cutaneous lupus erythematous,
up [184]. Patients reported prior failed conventional treat- and lichen planopilaris).
ment with oral antibiotics, finasteride, topical steroids, tri- Investigators have observed oral isotretinoin effective-
amcinolone injections, and/or laser therapy. Adverse effects ness (with dosages ranging from 0.2 to 8.2 mg/kg/day) for
were only found in one study, with xerosis being the most preventing and improving lesions caused by NMSC and
common [180]. photodamage, though the quality of evidence supporting
these results is variable and conflicting. Several RCTs found
Lichen planus no significant differences in the occurrence rate of BCCs
and SCCs following low dose (5–10 mg/day) therapy [36,
Isotretinoin may be effective in lichen planus by regulating 46], but one large RCT found isotretinoin did decrease the
cellular proliferation and differentiation of the epithelium, incidence of first SCCs in patients, while no difference was
but the specific mechanism is not well understood. Five found for occurrence rate of BCCs [35]. This highlights the
studies with a total of 42 patients reported the use of oral current lack of high-powered studies supporting the suc-
isotretinoin (0.25–1 mg/kg/day) as an effective treatment cess of isotretinoin therapy for the prevention and reduc-
for oral, vulvar, and cutaneous lichen planus; improvement tion of NMSC lesions. Oral (10–20 mg) isotretinoin have
has been observed as soon as two months [187–191]. Two been extensively studied in large clinical trials and found
patients with cutaneous lichen planus reported 60% improve- to be effective in improving skin elasticity, reducing wrin-
ment of cutaneous lesions after one month of therapy with kles, pigmentation, and actinic keratoses [38–42]. Patients
0.5–1 mg/kg/day oral isotretinoin [191]. Specifically, in the reported studies had FST I–III. One trial found no
patients responded with moderate or excellent improvement differences between oral isotretinoin dose ranges (10 mg vs.
(69%) in oral lesions and hyperpigmentation [187–191]. 20 mg) in the ability to improve skin laxity, wrinkles, pore
These improvements were similar with between 0.3 and 0.5 size, and increase collagen production [41].
and 1 mg/kg/day, but a relapse of lesions occurred with a However, one of the greatest clinical challenges for
dosage of 0.5 mg/kg/day in one case [191]. Blotchy-type isotretinoin prescribers for dermatological conditions other
lichen planus was reported to have the best response to oral than acne pertains to duration of recession after treatment
13
cessation (i.e. rosacea, condylomata acuminata, Darier’s dis- debate for its association with psychological and emotional
ease, lichen planus, dissecting cellulitis, cutaneous T cell distress, especially anxiety and depression [194]. Three
lymphoma, and non-melanoma skin cancers). studies reported cases involving depression, mental status
Studies revealed dose-dependent adverse effects, applica- change, and also one case of suicidal ideation causing the
ble to 30–40% of patients studied were mostly mild, includ- therapy to be discontinued [39, 58, 133]. Additionally, there
ing cheilitis, facial xerosis, mucocutaneous dryness, pruritus, have been several reported cases of a lichenoid drug reac-
eczema, conjunctivitis, irritation, and elevated triglycerides tion or retinoid dermatitis caused by isotretinoin in patients
and cholesterol. Less common side effects included myal- treated for lichen planus or cutaneous T cell lymphoma [53,
gias/arthralgias (n = 109 cases), fatigue (n = 85), skeletal 56, 190]. To best address issue, further studies are needed to
hyperostosis (n = 72), hair loss (n = 36), joint pain (n = 27), determine optimal dosing and duration of use.
abdominal pain (n = 13), mental status change (n = 6), rhi-
nitis sicca (n = 3), ectropion (n = 2), and suicidal ideation
(n = 3). Additionally, Isotretinoin therapy was found to
Conclusion
worsen disease in multiple studies on its use in HS patients,
though there was a lack of RCTs and high-powered stud-
Isotretinoin is a retinoid with effectiveness beyond acne vul-
ies of isotretinoin use in this patient population [129, 130,
garis. Current literature presents strong evidence of effec-
132, 134]. In some conditions such as mycosis fungoides,
tiveness of isotretinoin to treat non-melanoma skin cancers
where long-term remission is unlikely to be maintained with
(0.2–8.2 mg/kg/day), rosacea (0.22–1 mg/kg/day), pityria-
isotretinoin therapy alone, initial therapy should still be con-
sis rubra pilaris (0.5–4 mg/kg/day, condyloma acuminata
sidered with isotretinoin or another retinoid [56].
(0.5–1 mg/kg/day), granuloma annulare (0.5–1 mg/kg/day),
Isotretinoin can be used in combination with standard
Darier’s disease (0.5–4 mg/kg/day), flat warts (0.1–0.5 mg/
therapy to improve effectiveness in conditions such as rosa-
kg/day), lichen planus (0.25–1 mg/kg/day), folliculitis
cea, condylomata acuminata, and lichen planopilaris. Subcu-
decalvans (0.1–1.02 mg/kg/day), sebaceous hyperplasia
taneous interferon alfa-2a, interferon alfa-nl, and podophyl-
(0.14–1.0 mg/kg/day), and cutaneous T cell lymphoma
lin combined with isotretinoin presented with a higher rate
(0.5–2 mg/kg/day). The studies reviewed here provide an
of lesion clearance compared to isotretinoin monotherapy in
extensive assessment of isotretinoin therapy benefiting
patients suffering from condylomata acuminata [118, 119,
various dermatological conditions. Additional prospective,
121, 123, 126]. Additionally, one retrospective study evalu-
long-term, high-powered studies remain necessary to opti-
ated oral isotretinoin therapy compared to a combination
mize treatment dosages and further evaluate the efficacy of
of isotretinoin and a 5aRI, reporting that the combination
isotretinoin use.
regimen was the most effective drug in treating patients in
their study with FFA [180].
Isotretinoin use in cutaneous conditions beyond acne is Funding The authors did not receive funding for this research.
continually expanding given its potential for treating addi-
tional conditions rises with an improved understanding of Compliance with ethical standards
dermatologic diseases given its IL-2 immunomodulatory
effects that mitigates lymphocyte activity. These properties Conflict of interest The authors do not have any conflicts of interest
potentiate symptom control of inflammatory skin diseases to disclose.
such as granuloma annulare, FFA, CLE, HS, lichen planus,
and rosacea. Isotretinoin has been effective in treating flat
warts by inhibiting replication of HPV-infected cells through
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Oral Isotretinoin For The Treatment of Dermatologic Conditions Other Than Acne: A Systematic Review and Discussion of Future Directions

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Oral Isotretinoin For The Treatment of Dermatologic Conditions Other Than Acne: A Systematic Review and Discussion of Future Directions

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Archives of Dermatological Research

Oral isotretinoin for the treatment of dermatologic conditions other

Received: 13 June 2020 / Revised: 29 September 2020 / Accepted: 9 October 2020

Keywords Isotretinoin · Dermatology · Accutane · Cutaneous

Introduction of sebaceous glands, decrease sebum excretion, and reduce

Rosacea (15); n = 991

finasteride, dutasteride) 6/7 pts with isotretinoin due to xerosis

therapy significantly reduced

Basal cell carcinoma

tapered to maintenance dose

2/31 developed BCC in the

improvement in the level of

cin for 6 wks

with combined therapy after

(1985) [53] universal skin reddening

described isotretinoin combined with interferon alpha-2a;

headache (1), arthralgia (1)

therapy, methotrexate, and/or various typical pharmaco-

therapy. Mean time to maxi-

had a partial response, 2/8

Mixed basal and squamous cell carcinoma treatment

mal response was 6mo

isotretinoin monotherapy presented with a 63% decrease

efficacy of 5–10 mg/day oral isotretinoin, oral retinol,

and placebo therapy. Retinol reduced the incidence of

wrinkles, dyspigmentation, texture, elasticity, and amount

of collagen. Patients were generally FSTI-III and treated

Five patients suffering from keratoacanthoma were

seen as early as two weeks, however, recurrence within

Actinic damage treatment

Eight studies with a total of 248 patients reported the use

skin. A study compared 10 mg/day oral isotretinoin to

a higher amount of actinic keratoses (AK) compared to

20 mg every other day oral isotretinoin to topical 0.05%

overall skin condition with no significant difference [38].

Fig. 1 Schematic showing

890 nonduplicate cita ons screened

683 ar cles excluded aer

207 ar cles retrieved

Cutaneous lupus erythematous Folliculitis decalvans

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683 ar cles excluded aer