Retinoids in dermatology practice - concepts and concerns - deNovo Medica
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Leader in digital CPD
Earn 3
for Southern African
free CEUs Dermatology
healthcare professionals
The view today on acne and ageing
Retinoids in dermatology
practice – concepts and
Reviewed by
concerns
Learning objectives
You will learn:
• The pathogenesis and classification of acne vulgaris
• The basis for selection of treatment for acne and the role of retinoids
• The prescribing principles for oral isotretinoin, which were developed and harmonised for
different formulations, particularly with regard to prevention of pregnancy while on treatment
• Current views on the use of retinoids for the reversal of skin ageing.
Dr Jonathan Smith
MBChB, MMed
Dermatologist Introduction
Cape Town Acne vulgaris is the most common disorder for which patients seek dermatological
care. Affecting mostly adolescents and young adults, acne may persist into the
30s and 40s. Acne can result in significant morbidity, and potential effects include
scarring, dyspigmentation, depression, anxiety and low self-esteem.
Multiple treatment agents and formulations are available for the treatment of
acne, with each agent targeting a specific area within acne pathogenesis. Treatment
selection is based on disease severity, patient preference and tolerability. Topical
retinoids are indicated for acne of any severity and for maintenance therapy.
Systemic and topical antibiotics should be used only in combination with benzoyl
peroxide and retinoids and for a maximum of 12 weeks. Isotretinoin is used for
severe, recalcitrant acne. There is limited evidence for physical modalities (e.g. laser
therapy, light therapy, chemical peels) and complementary therapies as treatment
for acne vulgaris.1
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© 2021 deNovo Medica MAY 2021 I 1
Retinoids in dermatology practice – concepts and concerns
What is the pathogenesis of acne?
Acne vulgaris is a chronic disease originating There may be a genetic component to acne.
within the pilosebaceous follicles. Four inter- Certain foods and drinks, particularly those
related processes are involved: sebum overpro- with a high glycaemic index, appear to affect
duction due to excessive androgen hormones severity; other factors that may be involved
or heightened sebaceous gland sensitivity to in the development or progression of acne
normal levels of androgen hormones; abnor- include psychological stress, tobacco smoke
mal shedding of follicular epithelium; fol- and damaged or unhealthy skin. The patho-
licular colonisation by Cutibacterium acnes genesis in adult women is particularly com-
(previously called Propionibacterium acnes); plex; androgens play a major role.1,2
and inflammation, with inflammatory path
activation at all stages of acne progression.1,2
How is acne classified?
Acne lesions typically occur on the face, chest there is currently no universally accepted
and upper back. Based on the extent and grading system for acne and the grading sys-
types of lesions (Table 1), acne may be clas- tems used in clinical trials vary greatly.1,2
sified as mild, moderate or severe although
There is Table 1. Types of acne lesion
currently no
Non-inflammatory closed comedones
universally
accepted
grading system
for acne Papules formed by the accumulation of sebum/keratin
within the hair follicle, also called whiteheads
Open comedones
Distension of the hair follicle with keratin leads
to opening of the follicle, oxidation of lipids and
deposition of melanin, also called blackheads
Inflammatory papules, nodules,
pustules and cysts
Inflammatory lesions arise from follicle rupture
triggering an inflammatory response
2 I MAY 2021
Retinoids in dermatology practice – concepts and concerns
What is the role of retinoids in the treatment of
acne?
Acne treatment is based on the severity of nonhormonal and nonantimicrobial treat-
the lesions and where they are located on ment option for adult women with acne.1,2
the skin (Figure 1). Retinoids are vitamin A
“I have derivatives recommended as a component of “I have been using isotretinoin formulations
the primary treatment of non-inflammatory in South Africa, both originator and generic
been using and inflammatory acne, being effective formulations; my experience is that they are
isotretinoin against microcomedo and comedo formation. the most cost-effective treatments for moder-
formulations Retinoids also have anti-inflammatory effects. ate to severe acne,” Dr Smith comments.
in South Africa, Topical retinoids are recommended as mono-
both originator therapy for the treatment of mild comedonal Isotretinoin is believed to act on all
acne, and in combination with other topical proposed mechanisms of acne development.
and generic and oral agents for the treatment of moderate Direct inhibition of sebaceous gland
formulations; to severe acne. Topical retinoids are also used function results in decreased sebum
my experience as maintenance therapy once treatment goals production and comedolysis, with the
is that they have been achieved and oral agents have been consequences of decreasing C. acnes
are the most discontinued.1 proliferation and diminished chemotactic
inflammatory modulator release, which
cost-effective Oral isotretinoin is the unique treatment for lessens inflammation. The effectiveness of
treatments for cure or prolonged remission of moderate and isotretinoin is well established; it is approved
moderate to severe acne; if there is no absolute contrain- for the management of severe, recalcitrant
severe acne” dication, isotretinoin should be the first-line nodular acne and relapse-prone acne, and is
Dr Smith treatment for moderate to severe inflam- also endorsed for use in acne that is causing
matory acne. Isotretinoin is an important significant psychosocial distress or scarring.1-3
Determine lesion type and severity
Mild inflammatory B Moderate inflammatory papules and Severe inflammatory papules and
Comedones
papules and pustules pustules with or without a few nodules pustules with or without a few nodules
Topical retinoid plus
Topical retinoids A
benzoyl peroxide*
Nodules Papules and pustules Nodules Papules and pustules
Effective? Effective
Topical retinoid plus Topical retinoid plus
benzoyl peroxide plus benzoyl peroxide
No Yes No Yes topical antibiotic† plus oral antibiotic
Go to A Maintenance Go to B Maintenance
therapy: topical therapy: topical Effective Effective
retinoid retinoid
No Yes No Yes
Topical retinoid plus Maintenance therapy: Oral isotretinoin
benzoyl peroxide topical retinoid plus
plus oral antibiotic† benzoyl peroxide Maintenance therapy: topical
retinoid plus benzoyl peroxide
Maintenance therapy: plus topical antibiotic
topical retinoid plus or
benzoyl peroxide Topical retinoid plus benzoyl
peroxide plus oral antibiotic
Note: Combined oral contraceptives and spironlactone may be considered for females who are unresponsive to or intolerant of past therapies, for
temporal association of acne outbreaks with menses, or for females with signs and symptoms of hyperandrogenism (acne, hirsutism, oligomenorrhoea).
* Alternatively, topical benzoyl peroxide may be used with a topical antibiotic for mild acne, however, combining with a retanoid is preferred.
†
If ineffective, consider alternative antibiotic therapies.
Figure 1. Severity-based approach to treating acne vulgaris1
MAY 2021 I 3Retinoids in dermatology practice – concepts and concerns
Prescribing principles of oral isotretinoin
Dosage
Some guidance recommends starting dosages may be initiated. Long-term use of isotreti-
for moderate acne of 0.25-0.4mg/kg daily, noin has not been studied extensively, but
If, after a in two divided doses, titrated to 0.5mg/kg one study has shown that the higher the total
according to response of the disease and/or dose, the lower the rate of recurrence.1,2
two-month
the emergence of side effects, for 15-20 weeks.
off-therapy However, Dr Smith advises that in his clini- In patients with severe renal insufficiency,
period, there cal experience, isotretinoin should always be treatment should be initiated at low doses, e.g.
is persistent or given at 0.5-1mg/kg until a cumulative daily 10mg daily, and titrated up to the maximum
recurring severe dose of 150mg is achieved. tolerated dose or 1mg/kg daily. Isotretinoin
is not recommended for use in children
nodular acne, a
For severe recalcitrant acne, a 0.5mg/kg daily younger than 12 years due to a lack of data
second course of dose should be titrated to 1mg/kg daily, as on efficacy and safety. Failure to take isotreti-
therapy may be tolerated. If, after a two-month off-therapy noin with food will significantly decrease
initiated period, there is persistent or recurring severe absorption.1
nodular acne, a second course of therapy
Toxicities and tolerability
Oral isotretinoin is effective despite common, side effects. Serious adverse events are rare
controllable and reversible mucocutaneous and represent individual reactions.
Teratogenicity
All female patients who may become preg- treatment, the isotretinoin should be discon-
nant must have contraceptive counselling tinued immediately and the patient referred
and pregnancy testing prior to initiation to an obstetrician-gynaecologist experienced
of isotretinoin treatment as there is a high in reproductive toxicity for further evaluation
risk of teratogenicity. Pregnancy should be and counselling. Because of the potential for
avoided for one month after discontinuing adverse effects, nursing mothers should not
treatment. If pregnancy does occur during receive isotretinoin.
Dose-dependent adverse effects Table 2. Common dose-dependent
Common dose-dependent adverse effects of adverse effects of isotretinoin1
isotretinoin are listed in Table 2. It is recom-
• Xerosis • Cheilitis
mended that a fasting lipid profile, includ-
• Acne flare-up • Dry eyes
ing triglycerides and liver function tests, be
• Elevated lipid and • Headache
performed prior to initiating isotretinoin.
All female hepatic enzyme levels
patients who Psychiatric disorders
may become Previous concerns regarding the associations recent studies, and some studies have shown
pregnant between isotretinoin and mood disorders and improvement of depressive symptoms in
must have suicidal ideation have not been confirmed in patients taking isotretinoin.1
contraceptive
counselling Drug interactions
and pregnancy It is unknown if hormonal contraceptives Concomitant treatment with isotretinoin and
testing prior differ in their effectiveness when used with tetracyclines should be avoided as a number
to initiation isotretinoin and it is therefore critical that of cases of benign intracranial hypertension
women of childbearing potential use two effec- have been associated with this combination.
of isotretinoin
tive forms of contraception simultaneously; The use of isotretinoin and vitamin A supple-
treatment patients should be prospectively cautioned not ments can lead to additive toxic effects and
as there is a to self-medicate for depressive symptoms with should be avoided.
high risk of St John’s Wort, as there are potential drug
teratogenicity interactions between this herbal supplement
and hormonal contraceptives.
4 I MAY 2021Retinoids in dermatology practice – concepts and concerns
Due to its high Is micronised isotretinoin more effective than the standard formulation?
lipophilicity, oral In a double-blind efficacy study of 600 events and hypertriglyceridaemia.4 However,
absorption of patients randomised either to a micronised a micronised formulation of isotretinoin was
isotretinoin is or standard formulation isotretinoin arm, filed with the United States’ Food and Drug
enhanced when micronised isotretinoin was shown to be clini- Administration and rejected on the basis that
cally equivalent to standard isotretinoin with it offered no further benefit compared to the
given with a
a similar safety profile, although it appeared standard formulation.
high-fat meal to carry a lower risk of mucocutaneous
The pharmacokinetics of isotretinoin
Due to its high lipophilicity, oral absorption the pharmaceutical quality of different
of isotretinoin is enhanced when given with generic and originator oral isotretinoin
a high-fat meal. It is more than 99.9% bound formulations. A manufacturer-sponsored
to plasma proteins, primarily albumin. At (Hoffmann-La Roche) study by Taylor and
least three metabolites have been identified Keenan,6 undertaken 15 years ago, compared
in human plasma following administration pharmaceutical quality, in particular parti-
of isotretinoin, all of which possess retinoid cle size distribution, of the originator oral
activity, which are ultimately excreted in urine isotretinoin to that of 14 registered generic
and faeces. Primary cytochrome P450 iso- formulations. The Taylor study showed that
forms involved in isotretinoin metabolism are the average isotretinoin content of the 14
The Taylor study 2C8, 2C9, 3A4, and 2B6. generic formulations all fell within the United
showed that States’ Pharmacopoeia (USP) standard of
Generic oral isotretinoin was introduced to 90-110% of the originator content while two
the average market in 2001. When generic oral isotreti- of the generics fell outside of the narrower
isotretinoin noin became available, a harmonisation range of 95%-105%. The only time therapeu-
content of the procedure on the summary of product tic content fell below the USP criterion was
14 registered characteristics that are required for registra- when an accelerated shelf-life test was con-
generic oral tion of a medicine was raised in the European ducted on capsules, left without packaging
Union, and this approach is now standard for at 40°C and 75% humidity for three months.
isotretinoin the clinical use of oral isotretinoin.5 Modern packaging of isotretinoin in blister
formulations all packaging is likely to protect against extreme
fell within the There are very few published data comparing climate exposure.
United States’
Pharmacopoeia Particle size
standard of Particle size, as indicated earlier, does not irrelevant. Particle size does not affect the
90-110% of significantly affect bioequivalence; if the absorption or excretion of isotretinoin and its
the originator bioequivalence of the generic is the same as metabolites.
content the originator, then particle size is clinically
What is the current view on the use of retinoids
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CPD POINTS
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Ultraviolet radiation causes direct dam- proteins and antioxidants, this system may
www.denovomedica.com age to the DNA of the skin cells. Resultant be overwhelmed by various factors, including
defects in mitochondrial DNA impair ultraviolet radiation, high metabolic demand,
and start to earn today! oxidative phosphorylation, which leads to smoking and decreased cellular function
further oxidative stress on the entire cell. associated with age.7
Indirect cell damage arising from exposure to
ultraviolet A includes the creation of reac- The ability of retinoids to rejuvenate photo-
tive oxygen species and free radicals. While aged skin was spotlighted in the 1980s.
cells are designed to tolerate an oxidative Retinoids have been shown to increase col-
environment and protect themselves with lagen content in the upper papillary dermis
DNA repair enzymes, enzymatic reduction by preventing matrix metalloproteinase
MAY 2021 I 5Retinoids in dermatology practice – concepts and concerns
Efficacy of oral production, inhibiting collagen degradation find no clinical effect that justifies the side-
and increasing collagen synthesis. Efficacy of effect and safety concerns associated with its
isotretinoin oral isotretinoin therapy in the treatment of use.7-9 “There are more cost-effective and safer
therapy in the photo-aged skin has been investigated, with treatment modalities available to improve the
treatment of equivocal findings. Some report subjective evi- signs of ageing,” Dr Smith cautioned.
photo-aged dence of clinical improvement, whereas others
skin has been
investigated,
Key learnings
with equivocal
findings • Acne vulgaris is a chronic disease arising from four inter-related processes
• Selection of acne treatment is based on disease severity (mild, moderate, severe), patient preference and
tolerability
• Topical retinoids are recommended as monotherapy for treatment of mild acne and in combination with
other topical and oral agents for the treatment of moderate-to-severe acne, as well as for maintenance
therapy
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• Isotretinoin is believed to act on all proposed mechanisms of acne development
CPD POINTS
• Oral isotretinoin should be the first line of treatment for moderate-to-severe inflammatory acne and is an
Are you a member of important nonhormonal and nonantimicrobial treatment option for adult women with acne
Southern Africa’s leading
• Common dose-dependent adverse effects of oral isotretinoin are controllable and reversible
digital Continuing
Professional Development
• Caution should be used in woman of childbearing age, with concomitant use of at least two different
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contraceptive methods, as oral isotretinoin is teratogenic
CPD points with access to • Currently, evidence for the use of oral isotretinoin therapy in the treatment of photo-aged skin is equivocal.
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References
Click on reference to access the scientific article
1. Oge LK, Broussard A, Marshall MD. Acne vulgaris: Diagnosis European Directive for prescribing systemic isotretinoin for acne
and treatment. Am Fam Physician 2019; 100(8): 475-484. vulgaris. J Eur Acad Dermatol Venereol 2006; 20(7): 773-776.
2. Tan AU, Schlosser BJ, Paller AS. A review of diagnosis and 6. Taylor PW, Keenan MHJ. Pharmaceutical quality of generic
treatment of acne in adult female patients. Int J Womens isotretinoin products, compared with Roaccutane. Curr Med
Find us at Dermatol 2018; 4(2): 56-71. Res Opin 2006; 22(3): 603-615.
3. Bagatin E, Costa CS. The use of isotretinoin for acne - an 7. Hubbard BA, Unger JG, Rohrich RJ. Reversal of skin aging with
update on optimal dosing, surveillance, and adverse effects. topical retinoids. Plast Reconstr Surg 2014; 133(4): 481e-490e.
DeNovo Medica
Expert Rev Clin Pharmacol 2020; 13(8): 885-897. 8. Hernandez-Perez E, Khawaja HA, Alvarez TY. Oral isotretinoin
4. Strauss JS, Leyden JJ, Lucky AE, et al. Safety of a new as part of the treatment of cutaneous aging. Dermatol Surg
micronized formulation of isotretinoin in patients with severe 2000; 26(7): 649-652.
@deNovoMedica
recalcitrant nodular acne: A randomized trial comparing 9. Nickle SB, Peterson N, Peterson M. Updated physician’s guide
micronized isotretinoin with standard isotretinoin. J Am Acad to the off-label uses of oral isotretinoin. J Clin Aesthet Dermatol
Dermatol 2001; 45(2): 196-207. 2014; 7(4): 22-34.
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5. Layton AM, Dreno B, Gollnick HPM, et al. A review of the
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The views and opinions expressed in the article are those of the presenters and do not necessarily reflect Reg: 2012/216456/07
Reviewed by Dr Jonathan Smith, those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the 70 Arlington Street, Everglen, Cape Town, 7550
Dermatologist, Tygervalley, Cape Town product insert documentation as approved by relevant control authorities. Tel: (021) 976 0485 I info@denovomedica.com
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