ARTICLE
Auteur(s) : Brigitte
Dréno1, Vincenzo Bettoli2, Falk
Ochsendorf3, Montserrat Perez-Lopez4, Håkan
Mobacken5, Hugo Degreef6, Allison
Layton7
1Department of Dermatology, Hotel Dieu, Place Alexis
Ricordeau, 44093 Nantes Cedex 01, France
2Azienda Ospedaliera Universitaria Di Ferrara –
Arcispedale S. Anna, Sezione di Dermatologia, Corso Giovecca 203,
44100 Ferrara, Italy
3Klinikum der Johann Wolfgang Goethe-Universität,
Zentrum der Dermatologie und Venerologie (ZDV) Theodor-Stern-Kai 7,
D-60590 Frankfurt am Main, Germany
4Hospital de la Santa Creu i Sant Pau de Barcelona,
Servicio de Dermatología, C/Sant Antoni Maria Claret, 167, 08025
Barcelona, Spain
5Department of Dermatology, Sahlgren’s University
Hospital, S-413 45 Göteborg, Sweden
6University Hospital St Rafaël, Department of
Dermatology, Kapucijnenvoer, 33, B3000 Leuven, Belgium
7Harrogate and District Foundation Trust, Lancaster Park
Road, Harrogate, North Yorks, HG2 7SX, UK
accepté le 7 Juin 2006
Oral isotretinoin (13-cis-retinoic acid) is a retinoid compound,
chemically very closely related to natural Vitamin A and has a
differentiating action on sebocytes and keratinocytes [1]. It has
been used to treat acne vulgaris for more than 20 years.
Isotretinoin is the only therapeutic agent with anti-inflammatory
activities that also exhibits activities against the four main
aetiological factors involved in the pathogenesis of acne, in that
it significantly reduces the excretion of sebum, formation of
comedones, inflammation, and colonization of the skin with P. acnes
[2-4].The aim of the present report is to provide recommendations
from an expert perspective on how to prescribe oral isotretinoin
within the context of the new recommendation of the European Agency
for the Evaluation of Medicinal Products (EMEA). The work of the
expert group consisted of the following steps:
- 1. an extensive literature review and;
- 2. an independent expert recommendation on when to
switch from an unsuccessful acne treatment regime consisting of a
combination of oral antibiotics (ATB) and local retinoids and
sometimes topical benzoyl peroxide (BPO), to oral isotretinoin. The
experts further reviewed the maximum dosage and the duration of
combination treatment prior to the switch and discussed those cases
in which oral isotretinoin should be considered for first line
therapy.
Background
In 2002 the French Health Authorities presented a referral to the
EMEA. The main reason for this related to the proposed pregnancy
prevention measures as generic forms of isotretinoin did not have
the same summary product characteristics (SPC) across Member States
of the European Community. Hence, the Committee for Proprietary
Medicinal Products (CPMP) evaluated the different information and
suggested that it should be harmonised and the SPC amended
accordingly.
The final conclusions were converted into a decision by the
European Commission on October 17, 2003 [5].
Amendment to the current summary of product characteristics for
isotretinoin
The CPMP concluded that there was no rational justification for
using oral isotretinoin (OI) as a first line therapy in severe
acne, despite widely published clinical opinion.
Considering that the indications should reflect the risk-benefit
profile of isotretinoin in the intended population and in view of
the teratogenic risk and other serious adverse effects associated
with isotretinoin, the CPMP recommended that:
- – Exclusively severe forms of acne (such as nodular or
conglobate acne or acne at risk of permanent scarring) resistant to
adequate courses of standard therapy with systemic antibacterials
and local therapy should benefit from a systemic treatment with
isotretinoin.
- – The initial therapy in adults should start at a dosing
of 0.5mg/kg daily, followed by dosage adjustment during therapy to
avoid dose-related adverse effects and to optimize the therapeutic
response of the patient, which replaces the recommendation of an
initial dosage between 0.5 mg/kg and 1.0 mg/kg daily.
- – Isotretinoin should no longer be indicated for the
treatment of prepubertal acne and should not be recommended in
patients younger than 12 years of age.
- – Serum lipids (fasting values) should now be checked
“before treatment, 1 month after the start of treatment and
subsequently at 3 month intervals unless more frequent monitoring
is clinically indicated” instead of “before treatment and one month
after the maximal dosage”.
- – Aggressive chemical dermabrasion and cutaneous laser
treatment should be avoided in patients on isotretinoin for a
period of 5 to 6 months after the end of the treatment because of
the risk of hypertrophic scarring in atypical areas and, more
rarely, post-inflammatory hyper- or hypopigmentation in treated
areas. Further, patients should avoid depilation with wax during
treatment and for 6 weeks after stopping treatment. This should now
be avoided for at least 6 months after treatment because of the
risk of epidermal stripping.
- – In addition to the current recommendations, female
patients of childbearing potential should use two complementary
forms of contraception including a barrier method.
Treatment algorithms and recommendations for the use of oral
antibiotics and oral isotretinoin in the treatment of acne
The treatment algorithm developed by Gollnick et al. in 2003 (
(figure 1) )
suggests that oral isotretinoin should only be administered as a
first line therapy in severe forms of acne (nodular/conglobata). In
moderate acne or moderate/severe acne, systemic ATBs combined with
topical retinoids with or without the use of BPO are indicated;
while in mild cases topical retinoids in combination with or
without topical antimicrobials should be prescribed [6].
European recommendations on the use of oral antibiotics for
acne
In 2004, the EEP on antibiotics published their recommendations on
the use of oral ATBs on acne. The group recommended that, based on
their efficacy and safety, as well as on their pharmacokinetic
profile, second generation cyclines with a preference for
lymecycline and doxycycline should be used, when indicated [7].
Dosing and duration of the available oral ATBs should depend on
the type of ATB administered and vary according to the country in
which the drug is prescribed. In general, oral ATBs should be
prescribed for a period of 3 months; however they may be prescribed
for longer than 3 months, if further clinical benefit is likely
[7]. Anti-resistant agents (e.g. BPO) should always be considered
in conjunction with ATBs if the duration of treatment is prolonged.
ATBs should always be used in combination with a topical retinoid
to enhance treatment success.
Methods
Current treatment practice for severe acne includes the
administration of OI as a first line therapy. The new European
Directive now recommends that only those patients with severe or
scarring acne not responding to an appropriate combination
treatment with systemic ATBs and topical treatment should receive
systemic treatment with isotretinoin, suggesting that OI is not
indicated as first line therapy in any clinical situation. This is
not something that many dermatologists dealing with acne would
agree with. In addition, the CPMP fails to give any recommendation
or definition of what should be considered as “appropriate” therapy
prior to OI.
The place of isotretinoin in the treatment of acne
Ozolins et al. reported in 2004 that a maximum improvement with
conventional acne treatments occurred after six weeks of treatment
in patients with mild to moderate acne [8]. In moderate to severe
cases of acne, clinical improvement may continue beyond six weeks
of treatment, and frequently response to treatment will be
acceptable by 3 months [9, 10]. Certain prognostic factors,
including psychosocial disability, should be taken into account and
they should influence the clinical decision on when to transfer
patients onto OI from combination antibiotic/topical therapy.
These prognostic factors should also influence the decision to
opt for oral isotretinoin as first line therapy. The following
report represents cases which provide evidence of successful
treatment with oral isotretinoin as 1st line treatment.
The current European Directive would not advocate the use of OI
first line for these patients and therefore this directive does not
conform to what is considered good clinical practice by many
dermatologists.
A female patient, 14 years of age, with no previous treatment
presented with a rapid evolution of inflammatory acne lesions over
3 months quickly developing into only atrophic scars (ice pick).
A 19-year-old male patient with no previous acne treatment and a
family history of acne presented with nodular acne on the face and
back, causing a severe psychological impact. The patient received a
daily dose of 0.5 mg/kg of oral isotretinoin as first line
therapy for 8 months. At the end of treatment clinical results were
good, a mild relapse after 4 months was controlled with a
combination of lymecycline, adapalene and BPO.
Prognostic factors influencing acne
Based on the experience of the members of the expert group and on
an extensive literature review, the prognostic factors listed in
table 1( Table 1 ) should be taken into
account when prescribing for acne and early use of OI considered.
Family history
Recent research work strongly supports the fact that genetic
factors may play an important role in the development of acne [11].
Various studies conducted in twins suffering from acne showed that
the disease was attributable to additive genetic effects. Family
history of acne was significantly associated with an increased risk
[12-18]. Further references related to family history of acne are
listed in table 2( Table 2 ).
Table 1 Prognostic factors for acne
|
• Family history
|
|
• Persistence and late onset
|
|
• Early onset
|
|
• Hyperseborrhoea and response to therapy
|
|
• Scarring potential
|
|
• Lesion location
|
|
• Severe psychological impact
|
Table 2 Family history of acne: additional references
[48-67]
|
Androgen and lipid metabolism
|
- – Verschoore M. Ann Dermatol Venereol 1987; 114(3):
439-54.
- – Verschoore M. Rev Prat 1993 Nov 15; 43(18):
2363-9.
- – Bekaert C, et al. Dermatology 196; 453-454, 1998
- – Walton S, et al. Br J Dermatol 1988; 118: 393-6.
|
|
Chromosomal abnormalities and acne
|
- – Burket JM, et al. Arch Dermatol 1987; 123(4):
432-3.
- – Marr TJ, et al. Cutis 1981; 27(1): 87-8.
- – Funderburk SJ, et al. Arch Dermatol 1976; 112(6):
859-61.
- – Voorhees JJ, et al. Arch Dermatol 1972; 105:
913-9.
|
|
Twin studies
|
- – Gonzalez T, et al. J Rheumatol 1985; 12(2):
389-91.
- – Stewart ME, et al. J Invest Dermatol 1986; 86(6):
706-8.
|
|
Specific genes and acne
|
- – Schackert K, et al. Arch Dermatol 1974; 110(3):
468.
- – Wong SS, et al. Clin Exp Dermatol. 1992; 17(5):
351-3
- – Paraskevaidis A, et al. Dermatology. 1998; 196(1):
171-5.
- – Wanner R, et al. Pharmacogenetics. 1999; 9(6):
777-80.
- – Ostlere LS, et al. Clin Endocrinol (Oxf). 1998; 48(2):
209-15.
- – Sawaya ME, et al. J Cutan Med Surg 1998; 3(1):
9-15.
- – Hatta N, et al. J Invest Dermatol. 2001; 116(4):
564-70.
- – Andro I, et al. J Dermatol 1998 25; 150-152
- – Blanche H, et al. Hum Genet 1997; 101(1): 56-60.
- – Placzek M, et al. J Am Acad Dermatol 2005; 53(6):
955-8.
- – Munro CS, et al. Lancet. 1998 29;352(9129):
704-5.
- – Bekaert C, et al. Dermatology 1998; 196(4):
453-4.
|
Persistence and Late Onset
Only very few patients suffer from acne in the sixth and seventh
decades of life. These patients have suffered from acne for most of
their lives, 30-60 years, and have often unsuccessfully received
multiple courses of antibiotics over many years [19]. Reasons for
this persistent or late-onset acne may be sought in younger adults
with signs of hyperandrogenism, such as menstrual cycle
difficulties and excess of weight, favouring a hormonal or a
hormone producing tumour origin. In rare cases of acne a tumoral
origin must be sought [20, 21]. A study conducted by Goulden et al.
showed that in relatives of acne patients older than 25 years, the
risk of adult acne was significantly greater (P < 0,001) than
for the relatives of an unaffected individual [22].
Early onset
Lucky et al. demonstrated through a clinical trial that those girls
who had more comedonal and inflammatory lesions as early as 10
years as well as 2.5 years prior to menarche developed more severe
acne in adolescence [23]. These results confirmed an investigation
conducted by Chew et al. in 1990 showing that there is a trend
towards greater severity and higher incidence of acne vulgaris in
teenage years in patients with a history of infantile acne compared
to their peers [24].
Scarring potential
Many patients with inflammatory acne suffer also from significant
physical scarring, which is disfiguring and difficult to treat
[25]. Scarring is a consequence of the damage that occurs in and
around the pilosebaceous follicle during inflammation and only very
little information is available about its prevalence and clinical
development. In a study conducted by Layton et al. in 1994,
scarring was found to be present in 95% of acne patients, while
more significant or clinical scarring ensued in approximately 30%
of patients [26]. Many therapeutic approaches have been used to
treat acne scarring, including invasive (surgical and laser) and
noninvasive methods, but with non-quantified differences in
efficacy and cost, and often lack of success [27].
Hyperseborrhoea and response to therapy
Research has demonstrated that subjects with severe acne tend to
have a higher sebum excretion rate than those with either
physiological or moderate acne [28, 29]. As a correlation between
SER and acne improvement in patients with mild, moderate and severe
acne was demonstrated, it would suggest that the SER does influence
the clinical improvement, regardless of the initial acne grade
[30]. Greenwood et al. suggested that the severity of acne is
influential in determining the response of the individual to
antibiotic treatments; severe acne would respond significantly less
well than moderate acne and the follicular level of the antibiotic
may be a relevant factor in determining improvement in acne [31,
32]. Further, Eady et al. suggested that follicular levels of
antibiotics vary inversely with sebum excretion rates. Thus, a high
sebum excretion rate would result in a dilution of the antibiotic
so that the treatment will be below an optimum therapeutic
concentration.
Conversely, a low sebum excretion rate may be associated with a
higher concentration of the drug being achieved in the
pilosebaceous duct, leading to an improved efficacy [31].
Location of lesions
Acne lesions are commonly located on the face, chest, neck and
back, with severe forms such as acne conglobate mainly located on
the back of white males often leaving extensive, disfiguring scars
[33]. Investigations on the treatment success of acne located in
different areas of the body demonstrated differences in results.
When systemically treating papulopustular acne lesions with the
2nd generation cycline lymecycline in combination with
5% BPO for 6 months, Mobacken found that results were better on the
face than on the trunk [34]. Research work by Cunliffe et al.
confirmed these findings for the trunk and for oral isotretinoin:
subjects with more truncal acne fared less well than those with
predominantly facial acne [35]. Goulden et al. demonstrated that
the incidence of relapse with a treatment regimen of isotretinoin,
0.5 mg/kg per day for 1 week in every 4 weeks for a total period of
6 months was significantly higher in patients with predominantly
truncal acne (P = 0.01) than for patients with acne on the face
[22].
Severe psychological impact
Severe acne may lead to scarring and disfigurement, aggravating the
already present psychosocial aspects of this condition [36]. Thomas
considered that the impact of acne is equivalent to that of asthma
or epilepsy. Anxiety and depression and a reduction in social
functioning were described as a consequence of acne and effective
treatment resulted in improvement of quality-of-life measurement
[37]. Tan provided evidence through recent investigations on the
impact of acne on psychosocial health, including psychological
abnormalities such as depression, suicidal ideation, anxiety,
psychosomatic symptoms, including pain and discomfort,
embarrassment and social inhibition. Effective treatment of acne
was accompanied by improvement in self-esteem, affection,
obsessive-compulsiveness, shame, embarrassment, body image, social
assertiveness and self-confidence [38]. Rapp et al. associated
anger with quality of patients’ lives and with treatment
satisfaction [39]. A similar study to assess the adolescent
students’ attitudes to the perceptions and knowledge of acne and
the effect of acne on daily living, confirmed the significant
impact (P < 0.00002) of the patient perception of the severity
of acne and the lack of enjoyment of and participation in social
activities [40]. Epidemiological studies to date have not confirmed
a causal relationship between oral isotretinoin and depression.
However there is concern that an idiosyncratic reaction may occur
very rarely in some patients. With this in mind it is prudent to
counsel patients about this potential adverse effect [41-43].
Discussion
Acne is a chronic disease of the pilosebaceous unit and its
pathophysiology is multifactorial. The severe form, defined by the
prevalence of facial and truncal deep inflammatory lesions, is a
disfiguring disease that can often result in significant permanent
scarring [21]. Layton reported that it is important to be aware of
the prognostic factors, as lesions which develop into scarring
merit early and effective therapy: when initiating treatment, it is
important to consider the aims of therapy. Treatment should be
aimed at achieving clearance of acne, prevention of scarring and,
where necessary, relief from any psychological stress resulting
from acne. It should be commenced early in the disease process and
it is essential to select appropriate therapies according to the
clinical signs and psychological disability [44].
Oral isotretinoin was until recently advocated as first line
therapy to treat severe acne, scarring acne or infantile acne, as
reported by Sarazin et al. in 2004 [45]. However, due to concerns
of teratogenicity related to oral isotretinoin, the EMEA evaluated
and harmonised the SPC of isotretinoin in 2003. As an result of
this process the EMEA now advises that the use of oral isotretinoin
should be limited to “severe forms of acne (such as nodular or
conglobate acne or acne at risk of permanent scarring) only when it
has proved resistant to adequate courses of standard therapy with
systemic antibacterials and topical therapy”. The duration and
dosage of therapy prior to commencing OI has not been specified
[5].
The primary aim of the present report was to interpret from an
expert point of view the meaning of “adequate courses of standard
therapy” prior to a switch to oral isotretinoin and to provide
examples of when oral isotretinoin should be considered as first
line acne treatment.
Topical retinoids alone or in combination with topical ATBs
and/or BPO are currently recommended first line therapy for mild to
moderate forms of acne. Systemic antibiotics and/or anti-androgen
agents (in females) combined with topical retinoids and sometimes
BPO are indicated as first line therapy for moderate and severe
forms of acne [6].
The excessive use of systemic ATBs has led to an increasing
number of antibiotic-resistant bacteria on the skin of patients
with acne [21]. For that reason oral isotretinoin plays an
important role in the treatment of severe acne due to its
mechanisms of action, relatively rapid onset of action and its high
efficacy reducing more than 90% of the most severe inflammatory
lesions [46, 47].
The treatment algorithm developed by the Global Alliance in 2003
provided for the first time clear recommendations on how to treat
acne in a standardized fashion [6].
In 2004, the European Acne Expert Group recommended that
cyclines should be prescribed first line as oral antibiotics in
acne, due to their efficacy and safety profile. In addition, based
on their pharmacokinetic advantages, second generation cyclines
lymecycline, doxycycline or minocycline should always be preferred
over first generation cyclines (tetracycline HCL or
oxytetracycline). Within these second generation cyclines,
doxycycline and lymecycline are recommended prior to minocycline,
due to their good side effect profiles. The choice of the most
appropriate oral antibiotics should depend on the patient
characteristics, the season, UV exposure and national health
systems. The expert group recommended a daily starting dose
depending on the different cyclines: (i) lymecycline 300-600 mg, or
doxycycline 100 mg as first line and (ii) minocycline as a
second line due to rare but severe side effects reported. Dosage of
200 mg per day for minocycline and doxycycline should be
limited to specific cases such as severe seborrhoea. Further, oral
ATBs should always be prescribed in combination with topical
retinoids and sometimes with BPO, should not be continued for more
than 3 months unless further clinical benefit is likely and
should never be used alone to avoid the risk of resistance and lack
of efficacy [7].
Conclusion
To conclude, the EEP agreed with the decision made by the CPMP that
oral isotretinoin should be administered as 2nd line
therapy in those cases of severe acne which were resistant to, or
which did not respond successfully to the above described regimen.
However, the members emphasised that various prognostic factors and
psychosocial disability should be taken into account when selecting
an acne regimen and suggested that, despite the European Directive
on oral isotretinoin prescribing, there are clinical scenarios
where oral isotretinoin could be usefully employed as a first line
therapy.
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