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Hossein Mortazavi, MD 1,2 Retinoids are synthetic and natural analogues of vitamin A that
Nessa Aghazadeh, MD 1 have various effects on cellular differentiation, cellular proliferation,
Maryam Ghiasi, MD 1 immune system, and embryonic development. The present study
reviews the history of systemic retinoids in medicine, the structure
Vahideh Lajevardi, MD 1
of synthetic retinoids and their mechanisms. The main focus is
on their biologic functions, clinical uses, and the adverse effects
1. Department of Dermatology, Tehran
of isotretinoin, acitretin, and bexarotene representing the most
University of Medical Sciences,
Tehran, Iran
commonly used first, second, and third generation systemic
2. Autoimmune Bullous Diseases retinoids, respectively.
Research Center, Tehran University Keywords: acitretin, bexarotene, etretinate, isotretinoin, retinoids
of Medical Sciences, Tehran, Iran
Transport of retinoids
Retinoic acids are transported in blood stream
by albumin. Two intracellular carriers named
cytosolic retinoic acid binding protein1 and 2
(CRABP1, 2) transport retinoic acids into the
nucleus. These carriers have important regulatory
functions, as well. CRABP-1 regulates the levels
of retinoic acid in different tissues and CRABP-2
is the main form in the human epidermis and
mediates the morphogenic activity of vitamin
A. In fact, CRABP-2 is an important mediator in
epidermal differentiation; extremely high levels
of CRABP-2 are found in the psoriatic skin (800%
Figure 1. Chemical Structure of Retinoids increase compared to normal skin) as well as in
other disorders of keratinization such as ichthyosis, metabolized in the liver 2. Isotretinoin is oxidized
Darier disease, pityriasis rubra pilaris and keratosis to 4-oxo-isotretinoin which is quickly eliminated
pilaris. It has been shown that treatment with by the liver and the kidney 3 . In contrast to
retinoids reduces the expression of epidermal vitamin A, isotretinoin is not stored in the liver or
CRABP-2. Interestingly, higher levels of CRABP adipose tissue 3. Acitretin is metabolized through
may be associated with increased sensitivity of isomerization, forming cis-acitretin 2. Bexarotene
the lesion to retinoids 2. is metabolized by cytochrome P450 3A4 3 . It is
oxidized to 6- and 7-hydroxy-bexarotene and
subsequently to 6- and 7-oxo-bexarotene 2.
Retinoid receptors and mechanism of action
These receptors belong to the superfamily of
Half-Lives
ligand-activated nuclear receptors, including
receptors of vitamin D, thyroid hormone, steroid Teratogenicity is a major concern in the
and peroxisome proliferator activated receptor administration of systemic retinoids. Therefore,
(PPAR) 8. Two distinct families of retinoid receptors the length of the time these drugs are present in
are found: retinoic acid receptor (RARs) and the body is crucial; terminal elimination half-lives
retinoic X receptors (RXRs). Each family has three of retinoids are 10 to 20 hours for isotretinoin, 50
isoforms encoded by different genes: alpha (α), hours for acitretin, 7 to 9 hours for bexarotene and
beta (β) and gamma (γ). Retinoids have different as long as 80 to 160 days for etretinate 2.
receptor binding properties. ATRA binds only to Unlike isotretinoin and acitretin, etretinate is
RAR, while 9-cis-retinoic acid is the only known highly lipophilic, approximately 50 times more
physiologic ligand for RXR. Bexarotene is an lipophilic than acitretin. Therefore, it can be stored in
example of highly selective RXR-binding synthetic adipose tissues for several years. In fact, the serum
retinoids (rexinoids) 2,4,9. Briefly, through three level of etretinate is markedly decreased after the
mechanisms, retinoid receptors modulate gene discontinuation of treatment. However, low levels
expression: first, transactivation via direct binding of circulating etretinate may be detectable for up
to retinoic acid–response elements (RARE)in to 2.9 years after discontinuation of the drug 2. The
target gene promoters; second, transrepression of pharmacologic properties of isotretinoin, acitretin,
activator protein 1 (AP-1) and other transcription etretinate and bexarotene are summarized in Table 1.
factors; third, protein–protein interactions and
competition with other nuclear receptors (Vitamin
Acitretin re-esterification (reverse metabolism)
D Receptor, VDR) 4.
Oral alcohol intake promotes the re-esterification
of acitretin to etretinate. In the human hepatocytes
Pharmacokinetics of systemic retinoids
culture, this conversion only occurs in simultaneous
presence of ethanol and acitretin. In a study on 10
Metabolism
psoriatic patients, the plasma level of etretinate
Generally, the bioavailability of oral retinoids is reached 2.5-56.7 nanograms per milliliter (ng/ml)
increased when administered with food, especially three months after their treatment with a daily
with fatty meals 2. Systemic retinoids are transported acitretin dose of 30 mg.
in the blood stream by albumin, lipoproteins, or In another study, the concentration of etretinate
other plasma proteins and are mainly stored and in subcutaneous fat tissues was 100 times greater
than its plasma level after 4-11 months of treatment. of naive T cells to proinflammatory Th-17 cells and
However, the clinical relevance and importance of promotes anti-inflammatory Treg differentiation;
this finding in not clear. Theoretically, etretinate therefore, retinoids are physiologically involved
can be expelled from fat tissues in certain situations in maintaining the TGF-β-induced immunologic
(e.g. accelerated fat catabolism in response to balance 14.
starvation or thermogenesis or in the presence of Recent studies have revealed that the conversion
some lipophilic drugs). These observations led of vitamin A to retinoic acid in intestinal dendritic
to the extension of the recommended therapeutic cells promotes the differentiation of naive T-cells
contraception period in female patients receiving to Tregs, which are important suppressors of
acitretin up to 2 years by manufacturers and up immune responses. Eventually, this process leads
to 3 years by Food and Drug Administration to the accumulation of Tregs in the intestines. Oral
(FDA); similar to etretinate. Some authors have tolerance is known to be induced by local immune-
suggested measuring etretinate and acitretin levels suppressor cells, making the body immunologically
in subcutaneous fat tissues even when they are unresponsive to certain antigens presented to
undetectable in the plasma 2,10-12. intestinal mucosa. Therefore, retinoids may be
involved in the induction of tolerance 15.
Biologic effect of retinoids
ACITRETIN IN CLINICAL DERMATOLOGY
Retinoids regulate various biologic functions in
the human body; they are involved in the regulation
Psoriasis
of cell proliferation and differentiation, exert anti-
keratinization properties and alter cell cohesiveness. The therapeutic profile of acitretin in the
They also exhibit anti-acne and anti-seborrheic treatment of psoriasis is similar to that of etretinate
effects, have immunologic, anti-inflammatory and although the latter is no longer commercially
anti-proliferative functions and are also involved in available 3. The response of plaque-type psoriasis
the induction of apoptosis, tumor prevention, and to both drugs is variable with complete clearance
affect extracellular matrix 3. The important effects in 30%, significant improvement in 50%, and
of retinoids on the immune system are discussed treatment-failure in 20% of the treated patients and
below in more detail. a 60-70% decrease in Psoriasis Area and Severity
McKerrow et al revealed that the activity of Index (PASI) score after 12 weeks of treatment 3.
natural killer (NK) cells was significantly reduced Double blinded studies have proven the efficacy
in acne patients after 6 and 12 weeks of treatment of higher doses of acitretin at 50-75 mg/day over
with isotretinoin. This effect, however, was not placebo 16. Acitretin is the FDA-approved drug for
observed in psoriasis; in fact, etretinate treatment the treatment of psoriasis 17.
resulted in increasing the number and activity of NK The results of treatment in generalized or
cells in these patients. The authors suggested that palmoplantar pustular psoriasis are more
isotretinoin was the safer of the two retinoids for impressive; four weeks after the treatment with
administration in transplant recipients, particularly acitretin, a five-time reduction was noted in the
in the immediate post-transplant period when NK total number of pustular lesions in the patients
cells are highly active 13. with palmoplantar pustolosis 18. In another study,
Retinoic acid is the key regulator in transforming a 10-time reduction in the number of pustular
growth factor-beta (TGF-β) dependent immune lesions was noted in the patients treated with
responses. TGF-β converts naive T cells into either acitretin or etretinate 19.
regulatory T cells (Treg) that prevent autoimmunity In the treatment of psoriasis, combination
and inflammation. Paradoxically, in the presence of therapies, including acitretin or etretinate with
interleukin (IL)-6, TGF-β promotes the differentiation photochemotherapy, have been shown to be
of naive T lymphocytes into proinflammatory IL- more effective than systemic retinoids alone. Four
17-producing T helper 17 cells (Th-17) which are clinical trials have shown that retinoid PUVA
involved in inflammation and autoimmunity. (Re-PUVA) is associated with earlier and higher
Retinoic acid inhibits the IL-6-induced conversion rates of response and lower cumulative radiation
exposure. Bath-PUVA with acitretin or etretinate suggested acitretin as the first-line treatment for
is more effective than either of the two treatments cutaneous lichen planus. Moreover, acitretin may
given alone. A combination of acitretin and UVB also be preferred in hyperkeratotic lichen planus
has also been advocated. Re-UVB is more effective due to its modulatory effect on keratinization 30.
than acitretin or phototherapy alone 20,21.
Lichen sclerosis
Pityriasis rubra pilaris (PRP)
In a multi-center clinical trial of women with
Anecdotally, acitretin (0.5 mg/kg/day) is vulvar lichen sclerosus, the use of acitretin (20-
considered the first-line treatment for PRP. In a 30mg/day) resulted in clinical response in 14 out
retrospective study, 7 out of 9 patients showed of 22 patients vs. 6 out of 24 patients in the placebo
complete or partial clearance after 18.8 months of group 31. However, due to the high drop-out rate,
treatment with acitretin or etretinate 22. the study had a high risk of bias 16.
adjunctive treatment to circumcision) and lipoid the effect of isotretinoin is limited, especially in
proteinosis 38-40. the former 3.
antitumor activity 75. In comparison with bexarotene, obesity, alcohol intake, or a family history of these
alitretinoin has fewer side effects (lower risk for conditions. A concomitant increase in the total
mucocutaneous side effects and alterations in the amount of cholesterol and low-density lipoprotein
laboratory test, such as an increase in serum lipids, is also common. Bexarotene has been associated
liver enzymes and thyroid hormones). Accordingly, with a higher incidence of acute pancreatitis, as
alitretinoin would be a part of CTCL management well 3. Fulminant pancreatitis has also been reported
in the future. Treatment of CTCL with alitretinoin with acitretin therapy 9.
is beyond the subject of this review. In a study that evaluated 500 Iranian patients on
etretinate therapy, 30.6% had hypertriglyceridemia 79.
The regular monitoring of fasting serum lipids is
THE ADVERSE EFFECTS OF RETINOIDS
required during retinoid therapy (monthly for the
first two months, and every 2-3 months thereafter).
Mucocutaneous adverse effects
Bexarotene requires more intensive monitoring; a
Mucocutaneous side effects are the most common baseline serum lipid is required before initiating
adverse effects observed with oral retinoids and the therapy and every 1-2 weeks until the levels
occur in a dose-dependent fashion. The reduction are stabilized 3.
in sebum production, the alteration in the barrier
function of the skin and the reduction in stratum
Blood toxicity
corneum thickness which are all caused by retinoids
are responsible for these side effects. Cheilitis is Dose-dependent leukopenia has been reported
the most common and the earliest adverse effect. within 2-4 weeks of bexarotene therapy in CTCL 9,80.
Xerosis has been reported in nearly 50% of the One case of agranulocytosis has been reported in a
patients on isotretinoin therapy and it is even 15-year-old girl receiving isotretinoin 81,82. In 1987, a
more common in patients with atopic diathesis 3. case of thrombocytopenia was reported as a result of
Also, the occurrence of staphylococcal infection isotretinoin therapy. In this patient, the rechallenge
of the skin has been reported with isotretinoin of isotretinoin led to thrombocytopenia 82. Thereafter,
therapy 2. Mucocutaneous adverse effects may be several other cases of thrombocytopenia caused by
less common with bexarotene 2. isotretinoin were also reported 83-85.
In a study of 457 Iranian patients on etretinate
therapy, cheilitis was the most common
Renal effects
mucocutaneous side effect (88.1%). In this study,
other adverse effects, in the order of frequency, Retinoids are generally not associated with
were hair loss, dry mouth with thrush, dry mucosa, renal toxicity. Isotretinoin is safely used in end
palmoplantar peeling, dry skin with pruritus, stage renal disease (ESRD) patients undergoing
epistaxis, paronychia, facial dermatitis, conjunctivitis, hemodialysis. However, there are some reports of
hair color change, waving of hair and dyspareunia 78. reversible renal dysfunction while using etretinate.
It is recommended to monitor the renal function
in patients with underlying renal diseases 3.
Systemic adverse effects
has been rarely reported in patients with intense hyperostosis during conventional treatment with
physical activity during isotretinoin therapy 3,86,87. isotretinoin is limited 99.
Retinoid hyperostosis is age dependant; it is also
related to the dosage and the duration of the therapy.
Bone toxicity
Five years after retinoid therapy, hyperostosis can
Osteoporosis is a well-known effect of chronic be observed in most of the patients 100.
hypervitaminosis A 3. Periosteal bone formation Premature epiphyseal closure has been reported in
hyperostosis, resembling diffuse idiopathic skeletal children on etretinate and isotretinoin therapy 100,101.
hyperostosis (DISH) and premature epiphyseal It is related to the dose and the duration of the
closure in children have also been reported with treatment 100. The authors recommended that the
chronic vitamin A toxicity 2. Long-term treatment children on long-term systemic retinoid therapy
with etretinate (> 2 years) has been shown to should be monitored for bone changes 89,101.
decrease bone mineral densitometry (BMD) 88 .
Eight of 10 children on etretinate therapy for
Alopecia
keratinization disorders showed bone abnormalities
(periosteal thickening, periosteal bone resorption, Alopecia and telogen effluvium due to the use
osteoporosis, disc narrowing, and slender long of systemic retinoids have been reported 2,102. Hair
bones) 89. According to a study by McMullen and loss is more frequently seen with acitretin than
his colleagues, acitretin is safe in terms of bone with etretinate. It is also much less frequently
loss even in long-term use (>3 years) 90. In 18 men, reported with isotretinoin and bexarotene 2. Hair
a decrease was reported in their bone density after loss is a dose-dependent effect and is reversible in
6 months of using 1 mg/kg of isotretinoin 91. Some 2 months after reducing the dose or discontinuing
studies have shown that isotretinoin does not bear the treatment 2.
a significant risk of bone loss. In a multicenter
study on 217 acne patients, a single course of
Ocular Toxicity
isotretinoin therapy (1 mg/kg for 16 to 20 weeks)
showed no clinically significant change in BMD Blepharoconjunctivitis can occur in one third
values in adolescents 92 . According to a recent of the patients treated with isotretinoin. Using
preliminary study, deficiency in vitamin D might artificial tears and avoiding the use of contact
be a risk factor for developing bone resorption lenses may prevent this side effect 9. Decreasing
and osteopenic women treated with short-course the night vision appears to be the side effect of
isotretinoin 93 . Skeletal hyperostosis has been isotretinoin therapy 2.
observed in the patients treated with an isotretinoin
dose of 2 mg/kg/day for keratinization disorders,
Teratogenicity
a year after initiating the therapy 94,95. Hyperostosis
will become prominent through the time 95. Other For the first time, Cohlan reported teratogenicity
studies have shown skeletal hyperostosis to be due to high dose vitamin A 103 . Today, the
present in patients receiving long-term therapy teratogenetic potential of retinoids is well
with high-dose isotretinoin (2 years or longer) 96. documented 96. Isotretinoin, etretinate, acitretin,
The spinal changes are similar to DISH 96. and bexarotene are all classified by FDA in category
Multiple hyperostoses at extremities and spine X and are absolutely contraindicated during
including anterior spinal ligament calcification, pregnancy and lactation 43,69.
osteophyte formation, and calcification of the Retinoids have been associated with the following
tendons and ligaments have also been reported embryopathies: microcephaly, hydrocephalus,
with etretinate and isotretinoin 3. Recent studies microphthalmos, micrognathia, cardiac septal defects
suggest that the risk of hyperostosis with short-term and complex heart malformations, abnormalities of
treatment with isotretinoin remains minimal 97. A the ear and acral skeleton, craniofacial and thymus
single course of isotretinoin with a cumulative dose gland anomalies 41. Furthermore, adverse pregnancy
of 120 mg/kg for 4 to 6 months has no significant outcomes such as spontaneous abortion, premature
effect on bone metabolism 98. The risk of DISH-like birth or fetal death have been reported, as well 3.
Pregnancy should be excluded with at least one vascular disease 108. Chanson et al. showed that a
negative pregnancy test (two in the U.S.) 2-4 weeks 28-day supplementation program with isotretinoin
before considering retinoid therapy and at regular decreased plasma folate in both young and old
intervals thereafter (e.g. monthly for isotretinoin) 3. healthy individuals 109. Since hyperhomocysteinemia
Adequate contraception (ideally two methods) and folate deficiency are known to be associated
is mandatory from at least one month prior to the with fetal developmental abnormalities, obstructive
administration of retinoids up to 1 month after the vascular diseases, degenerative neurologic diseases,
cessation of bexarotene therapy, 3 months after and even colorectal cancer, future studies addressing
the cessation of the treatment with isotretinoin these concerns are required.
and 3 years (2 years in Europe) after the cessation
of the treatment with acitretin 41. Etretinate has
Mood Change and Psychiatric Effects
been removed from the market because of its
accumulation in adipose tissues 104. There are few Mood change due to the oral use of isotretinoin is
reports about fetus malformation due to the use of not accepted universally and remains a challenging
isotretinoin by males at the time of conception 2. subject for most of the dermatologists involved in
The available data do not suggest an increased isotretinoin therapy. In 1983, Hazen et al. reported
risk of fetal anomalies due to paternal exposure to depressive symptoms in 6 out of 110 patients
acitretin 2,105. However, it is usually recommended treated with isotretinoin 110 . Bremner and his
that the men who are trying to father a child should colleagues studied the influence of isotretinoin
avoid systemic retinoids 3. on the function of the brain by using positron
emission tomography (PET) scan and concluded
that isotretinoin decreased the brain metabolism in
BEXAROTENE-RELATED SIDE EFFECTS
the orbitofrontal cortex. The orbitofrontal area of
the brain cortex is known to mediate the symptoms
Hypothyroidism
of depression 111,112. However, a large population-
Clinical and subclinical secondary hypothyroidism based cohort study found no evidence that the
(characterized by low serum TSH and thyroxine use of isotretinoin is associated with an increased
concentrations) are seen in 40% of the patients with risk for depression, suicide, or other psychiatric
CTCL treated with bexarotene 3,106. Hypothyroidism disorders 113 . In a systematic review, the rates
is due to thyrotropin suppression by retinoid X of depression among isotretinoin users ranged
receptor. It is more common with higher doses of from 1% to 11% across studies, with similar rates
bexarotene and is rapidly reversible after treatment in oral antibiotic control groups. Some of these
cessation 3,60,106,107. Hypothyroidism is most often studies have reported a decrease in the incidence
clinically symptomatic and thyroxine replacement and severity of depression in the patients treated
is required 107. with isotretinoin 114. To the best of our knowledge,
Azoulay et al showed a significant association
between depression and isotretinoin therapy in a
ISOTRETINOIN-RELATED SIDE EFFECTS
controlled study for the first time 115.
Briefly, according to most authors, our present
Effects on homocysteine and folate
knowledge is not enough to establish a causal
Schulpis et al. showed that the plasma levels relationship between isotretinoin and suicidal
of homocysteine are significantly elevated after behavior and/or depression 114-117 . However,
45 days of treatment with isotretinoin in patients according to a recent comprehensive review by
with cystic acne. This effect could be either due Bremner et al. on the patients receiving isotretinoin,
to the inhibition of cystathionine beta synthase brain imaging studies showed a direct relationship
by isotretinoin or isotretinoin-induced liver between the decreased orbitofrontal function and
dysfunction. The authors recommended daily folate, headache 118. On the other hand, in isotretinoin-
vitamin B6 and B12 supplementation along with treated patients, the patients with headache are
the frequent monitoring of blood levels to prevent more prone to depression 119. As a conclusion, the
homocysteine -associated premature occlusive patients with headache, the patients with a past
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