ARTICLE
Acne is a multifactorial dermatosis with a polymorphous clinical appearance.
Particularly in severe forms of acne, comedones, papules, pustules and
deep inflammatory lesions (nodules and cysts) can be present simultaneously.
In addition, haemorrhagic crusts and fistular ducts may be present, and,
almost invariably, a relatively pronounced seborrhoea is noted.
The therapy of acne is oriented to the four known pathogenetic factors
of the disease: Follicular hyperkeratosis, increased sebaceous gland activity
with hyperseborrhoea, microbial hypercolonisation with Propionibacterium
acnes, inflammation and immunological host reaction [5, 18, 21].
The choice of topical and/or systemic therapy is guided by the clinical
symptoms and the severity of the acne. Mild to moderate forms (comedonal
acne, papulopustular acne) are usually treated with topical therapeutics.
With increasing acne severity, the inflammatory processes extend deep
into the skin, and thus use of systemic drugs is the first line therapy
in severe acne. There are at present various approaches to the systemic
treatment of acne. Oral antiandrogens, which reduce sebaceous gland activity
via the hormonal pathway, can only be used in women. Oral antibiotics
(preferably tetracycline, doxycycline or minocycline), which reduce colonisation
with P. acnes and also have an antiinflammatory effect [5, 18,
20, 21], can be employed generally.
Oral isotretinoin has become a mainstay in the treatment of severe and
very severe forms of acne. This retinoid is the only acne therapeutic
which targets all four pathogenetic factors of acne vulgaris. It works
essentially by reducing sebaceous gland activity and sebum production;
this is followed by a significant reduction of bacterial colonisation
with P. acnes [3, 12, 19, 20]. However, it must also be considered
that oral isotretinoin is contraindicated in women of child-bearing age
because of its high teratogenicity, and may be employed in women only
in exceptional cases after a full explanation, with the written consent
of the patient and under full contraceptive cover [5, 16, 18, 19].
Azelaic acid (AA), an aliphatic dicarboxylic acid [HOOC-(CH2)7-COOH],
has been employed as a 20% cream (Skinoren®) in topical
acne therapy since 1989. It is an effective and well-tolerated monotherapy
in mild and moderate forms of acne vulgaris which is comparable in its
efficacy to other established topical acne treatments such as benzoyl
peroxide, erythromycin, and tretinoin [4, 6, 9, 10, 14]. AA inhibits the
growth of P. acnes, and normalises the disturbed follicular keratinisation
process. Possibly AA has a direct antiinflammatory effect [10] which may
account for its therapeutic effect in papulopustular rosacea [2].
Systemic antibiotic therapy is accompanied in most cases by a topical
agent [5, 18]. The primary aim of the present study was to investigate
the efficacy and safety of a combined oral minocycline and topical AA
therapy in severe inflammatory acne compared to oral isotretinoin (study
phase 1). Minocycline is a well-established oral antibiotic in acne therapy.
Previous investigations showed that AA had a distinct effect on deep inflammatory
acne lesions [9, 13], and thus the combination of minocycline with AA
was considered to provide a rational approach in the treatment of severe
forms of acne. In this case, the combined antimicrobial and anti-inflammatory
effects would increase the effect on the inflamed lesions while the antikeratinizing
properties of AA may counteract comedo formation.
The second aim of the study was to establish the efficacy of 20% AA
cream as maintenance therapy after the end of the initial full course
of combination treatment (study phase 2). Since acne is a chronic disease,
maintenance therapy with a mild topical treatment is an important means
of reducing the risk of recurrences.
Patients and methods
Study design
The study was conducted as a parallel group comparison in 10 centres
in Germany, Austria and Switzerland. Since oral isotretinoin is identifiable
by its typical side effects, the study design was essentially open-label.
However, all patients were assigned to treatment at random.
The study comprised two study phases. In the first, 6-month study phase,
patients with severe inflammatory acne were treated with either 20% AA
cream plus oral minocycline (AA/Mino group) or with oral isotretinoin
(Iso group). Patients who during study phase 1 had achieved a very good
therapeutic improvement were eligible for admisson to the second, 3-month
study phase (maintenance treatment) immediately subsequent to study phase
1. Patients in whom a very good clinical improvement was achieved prematurely,
i.e. before completing the 6 months of study phase 1, were transferred
early to study phase 2.
The patients of the initial AA/Mino group admitted to the second study
phase used AA cream twice daily as a maintenance therapy over a period
of 3 months. Since oral isotretinoin frequently induces prolonged remission,
eligible patients of the initial Iso group did not receive any further
maintenance therapy. In lieu of a moisturizer, the occasional and sparing
application of the active substance-free vehicle of the AA cream was permitted
for alleviation of skin dryness.
All patients were examined at baseline and at monthly intervals over
the 6-month treatment period in study phase 1. In the second study phase,
the patients of the initial AA/Mino group were examined at monthly intervals
over the 3-month maintenance treatment period. By contrast, the patients
of the initial Iso group were examined only once, i.e. after completion
of the second 3-month study phase.
At every examination the number of facial lesions, i.e. open
and closed comedones, inflammatory papules and pustules, nodules, nodes
and cysts, was counted. The clinical assessment of the trunk (chest/back)
was optional. The degree of seborrhoea and adverse events were assessed
at each examination.
Study population and medication
Eighty-five male patients with nodular forms of facial acne (acne conglobata,
acne papulopustulosa nodosa (Fig.
6a)) were recruited to the study. Fifty patients were assigned
at random to the AA/Mino group and 35 to the Iso group.
AA cream was applied twice daily to the affected areas. Minocycline
was taken twice daily in a dose of 50 mg (daily dose: 100 mg). The dose
of isotretinoin depended on the weight of the patient. The initial dose
(month 1) was 0.8 mg/kg, decreasing in month 2 to 0.7 mg/kg, in month
3 to 0.5-0.7 mg/kg and in months 4-6 to 0.5 mg/kg per day. This corresponded
to a cumulative isotretinoin dose of 106 to 112 mg/kg over the 6 months.
On average, patients received 8.1 g isotretinoin; the lightest patient
received 6.5 g, the heaviest 11.3 g.
Inclusion/exclusion criteria
Only male patients over 16 years of age with severe inflammatory forms
of facial acne were included in the study. The severity of the acne had
to be at least grade 4 using Cunliffe's classification (Leeds scale).
In addition, the face had to display at least 2 deep inflammatory lesions
(nodes, cysts or nodules) and other papules and pustules.
Excluded were women, patients with milder (comedonal or papulopustular
acne) or more severe (acne fulminans, acne tetrade) forms of acne, photosensitive
patients and patients with contraindications to isotretinoin or minocycline
and those hypersensitive to the excipients contained in the AA cream.
The patients were not to have received any systemic therapy for at least
4 weeks prior to the start of study treatment (in case of previous isotretinoin
therapy: 12 months), the use of topical treatment had to be discontinued
at least 2 weeks before the start of the study treatment.
Included in the second phase of the study were patients in whom the
number of deep inflammatory lesions had decreased by at least 75% in the
first phase and in whom the efficacy of the therapy in the first study
phase had been rated by the patients as "very good".
Efficacy variables
In the first study phase, the number of papules, pustules and deep inflammatory
acne lesions before the start, during and at the end of the study was
defined as the primary variable for the assessment of the efficacy of
the therapy. Secondary efficacy variables included the investigator's
and the patient's subjective global assessment of the therapeutic result
(classified as "very good, good, moderate, no improvement, deterioration").
The same criteria were, in principle, used for the assessment of the
therapeutic result after the second study phase. Additionally at the last
visit, the investigators compared the clinical finding at the end of phase
2 with the condition of acne after the end of phase 1. The changes were
rated as "further improvement", "no change", "slight deterioration" or
"distinct deterioration".
Tolerability and safety
Both the subjective complaints of the patients and the adverse symptoms
established by the investigators were documented by nature, severity and
duration at every visit; the causal association with the study medication
was assessed at the same time. If pronounced local irritation occurred,
the frequency of applications was reduced temporarily to once daily; where
necessary, the study medication was interrupted for a couple of days until
the symptoms had disappeared. The patients of the Iso group underwent
regular clinicochemical checks as per the manufacturer's guidelines.
Ethics
The study was performed in compliance with the Declaration of Helsinki,
the state-specific regulations and the GCP (Good Clinical Practice) Guidelines.
Statistics
All patients who had attended at least one examination after baseline
were included in the statistical evaluation. The differences in efficacy
between the two study medications were analysed by applying the Mann-Whitney
U-Test (Wilcoxon 2-Samples Test) to the primary assessment criteria. Fisher's
test was used to compare the global assessments and to determine the percentage
reduction of the acne lesions. Only the primary observation variables
of phase I were subjected to a confirmatory test in the statistical analysis;
all other data were analysed using descriptive statistics.
Results
Demographic data/baseline findings
The study population consisted of 85 male patients (mean age 19 years).
The demographic data and the baseline characteristics of the patients
are presented in table I.
The treatment groups were comparable with regard to age. The mean duration
of the acne was 4 years in the AA/Mino group and 3 years in the Iso group.
About 86% of the patients had been treated previously with topical and/or
systemic acne therapeutics. Only the face was affected by acne in 49.4%
of the patients, the trunk as well in 50.6%. Nodular papulopustular acne
(Leeds scale > 4) was diagnosed in the majority of patients.
Patient disposition
Of the 85 eligible patients recruited to the study, 77 completed the
first study phase (90.6%). Eight patients (6 from the AA/Mino group, 2
from the Iso group) dropped out of the study because of poor compliance,
adverse reactions, lack of efficacy, infringement of the study protocol
or for other reasons (table
II). All 85 patients were included in the analysis of the efficacy.
The therapy was regarded as completed before the end of the 6 months in
10% of the patients in the AA/Mino group, while 78% of the patients of
this group finished the first study phase as per the schedule after 6
months, the corresponding figures in the Iso group were 14.3% and 77.1%.
Seventy-one of the 85 patients were admitted to the 2nd phase of the
study (41 from the AA/Mino group and 30 from the Iso group; table
II). However, due to a modification of the initial inclusion criteria
for phase 2, only 52 (26 per group) of the 71 cases were valid for this
study phase and included into the analysis of efficacy.
Because of the different inclusion criteria and medications in phases
1 and 2 of the study, the results for the two study phases were considered
separately.
Results of study phase
1
Both study medications led to a pronounced reduction of the comedones,
papules and pustules. As is seen from the time-response relationship,
the number of papules and pustules decreased markedly particularly in
the first 3 months of treatment both under AA/Mino and under isotretinoin
(Fig. 1).
After 6 months treatment the reduction of comedones, and papules and
pustules was significantly greater under isotretinoin than under AA/Mino
(table
III).
By contrast, the AA/Mino combination and isotretinoin proved to be equally
effective in the treatment of deep inflammatory acne lesions (nodes, cysts;
table
III). At the baseline examination, a median number of 7 deep inflammatory
acne lesions was observed in each of the two treatment groups; while a
median number of 0 was found after 6 months. Observation of the progress
over 6 months showed that the onset of action of AA/Mino treatment was
somewhat faster than that of isotretinoin treatment (Fig.
2). However, no significant treatment difference was noted after
6 months.
Seborrhoea decreased in the course of therapy: the number of patients
without seborrhoea increased from 2 to 32% in the AA/Mino group and from
5.7 to 77.1% in the Iso group.
In the investigators' global assessment of improvement both treatments
yielded similar rates of patients with a very good improvement
during the first 3 months while higher rates of good improvement
were achieved with isotretinoin. In the 4th to 6th month of treatment,
the therapeutic result was graded as very good more frequently
for isotretinoin than for AA/Mino. At the 6-month assessment, a very good
or good improvement was observed in 92.3% and 96.4% of the patients under
AA/Mino and isotretinoin therapy, respectively (Fig.
3).
Overall, for the last on-therapy assessment (i.e. incl. the dropouts)
the rate of therapeutically desirable good and very good results was 97.1%
for the isotretinoin patients compared with 90% for the AA/minocycline
patients (Fig. 4). No
significant treatment differences were observed for the overall results
(p > 0.05, Fisher's exact test). The higher rate of very good improvement
might, however, indicate a higher efficacy of isotretinoin treatment.
Results of study phase 2
In the course of the 3-month second study phase, the median number of
comedones and of the sum of papules and pustules increased slightly in
patients receiving AA maintenance treatment (comedones: from 13 to 17;
sum of papules and pustules: from 3 to 7). In the patients of the former
Iso group a further slight reduction in comedones was seen (from 8 to
7) while the papules and pustules remained constant (median number = 2).
In both groups the median number of deep facial lesions remained zero.
Using mean values rather than medians, a small increase from 1.3 to 1.4
was seen in the AA maintenance group. In the former Iso group a small
decrease, i.e. from 0.8 to 0.4, in the mean number of deep lesions
was noted.
Seborrhoea continued to increase in the AA maintenance group during
the 2nd study phase, the number of patients without seborrhoea falling
from 50 to 26.9%. The percentage of patients in the Iso group without
seborrhoea remained constant (61.5%).
The comparison between the patient's clinical appearance at the end
of phase 1 and after completion of phase 2 showed that further improvement
or no change occurred in about half the patients of both treatment groups
(Fig. 5). The clinical
appearance had deteriorated in the other 50% of patients; however, the
two treatment groups differed markedly from each other as regards the
extent of the deterioration (AA maintenance group: 38.5% distinct deterioration;
Iso group: 46.2% slight deterioration). A significant difference between
the treatment groups in favour of isotretinoin (p = 0.0023, Fisher's test)
was observed.
Tolerability and safety
In the first study phase local side effects occurred in a total of 18
patients (36%) of the AA/Mino group and in 23 patients (65.7%) of the
Iso group. In most cases, only one transient and mild symptom (burning,
stinging or itching) occurred in the patients treated with the combination.
In the AA/Mino group, the incidence rate of pronounced skin irritation
was 6%. More than half of the patients treated with isotretinoin exhibited
3-5 skin symptoms (including cheilitis, xerosis, dry mucous membranes,
epistaxis, conjunctivitis, dryness and rhagades of the lips, paronychia);
although mild in most cases, they were also persistent and severe in 20%
of the patients. The local side effects (itching and stinging) led to
termination of the therapy in one patient of the AA/Mino group.
The rate of side effects decreased in the course of therapy (from 24%
in the 1st month to 2.5% in the 5th) in the patients treated with the
AA/Mino combination. Under isotretinoin, the side effects rate was 47.1%
in the first month and remained at this high level (42-48%) throughout
the entire course of the 1st study phase.
Systemic side effects occurred in 6 patients (12%) of the AA/Mino group
(4 x gastrointestinal complaints; discontinuation of the therapy
in one patient because of gastric pain). The rate of systemic side effects
in the Iso group was 17.1% (6 patients: 2 x isotretinoin-induced
changes of the blood lipids or liver enzymes).
In the second study phase local side effects (mild burning or stinging)
were reported by only two patients; no systemic side effects occurred.
Discussion
Isotretinoin is a highly efficacious treatment of severe acne. Its use,
however, is associated with a large number of side effects on various
organ systems including the skin, muscles and bone, the eyes and ears,
and metabolism. In particular, the potent teratogenic property of isotretinoin
and, more recently, psychiatric adverse effects are major safety concerns.
Therefore, there is a need for alternative treatments, particularly in
women of child-bearing potential, that are comparable to isotretinoin
in terms of efficacy but do not entail its risks.
The concomitant use of oral antibiotics with topical medication is a
recommended option in severe acne [3, 5, 18]. The present study, therefore,
compared oral isotretinoin with a combination of 20% AA cream and oral
minocycline. This combination brings about an inhibition of P. acnes
growth, normalisation of the disturbed follicular keratinisation process
and an antiinflammatory effect, and thus targets three of the pathogenetic
mechanisms involved in acne.
The results of the 6-month randomized comparison showed that both the
AA/Mino and isotretinoin treatment was highly effective in severe inflammatory
forms of acne. Thus, over the 6-months period the AA/Mino combination
yielded therapeutically desirable good or very good results in 90% of
the patients. AA/Mino showed a small more rapid effect with regard to
lesion count reduction during the first 3 months. At the end of the 6-month
treatment period, isotretinoin yielded a significantly greater reduction
of comedones, papules and pustules. However, no significant treatment
difference was demonstrable with regard to the reduction of nodes and
cysts which are hallmarks of severe acne. With regard to overall improvement,
only slight treatment differences were found for the sum of therapeutically
desirable, good and very good results. However, isotretinoin yielded a
higher proportion of very good results.
The AA/Mino combination therapy was clearly better tolerated than isotretinoin.
Thus, the rate of local side effects was substantially lower under the
combination treatment (36%) than under isotretinoin (65.7%). Systemic
side effects were also less frequently observed under the combination
treatment (8%) than under isotretinoin (14.3%). Most of the local side
effects under the combination were transient and of mild intensity. Local
side effects of pronounced intensity was low, i.e. 6%. With both
treatment regimens, the rate of local side effects was highest in the
first month. In the combination treatment group the frequency gradually
decreased during the further course of therapy (most likely indicating
a hardening process of the skin) while the incidence rate observed with
isotretinoin remained at a high level throughout the entire treatment
period.
The choice of minocycline and AA for combination therapy has distinct
advantages over other antibiotics and other topicals (e.g. benzoyl
peroxide and tretinoin), respectively [9, 15]. The almost 100% intestinal
absorption of minocycline, even when taken together with a meal, increases
patient compliance [15]. Minocyline is also effective in cases not responding
to other tetracycline derivatives. Its high lipophilicity results in a
greater accumulation of the drug in the sebaceous gland follicle, and
its the antiinflammatory effect appears to have a broader spectrum and
to be more intensive than that of tetracycline [8, 15]. Moreover, minocycline
does not, or only to a slight extent (< 2%), induce P. acnes
resistance [8, 12, 15] which is an increasing problem with topical erythromycin
or clindamycin, and systemic tetracycline, erythromycin and doxycycline.
The selection of AA as the topical component was governed by previous
clinical results showing that 20% AA cream clearly reduced the nodulo-cystic
lesions in patients with acne conglobata [9]. AA is virtually non-toxic,
is not teratogenic [10], and is locally well tolerated causing less irritant
reactions (erythema and scaling) than benzoyl peroxide and tretinoin [18].
Over and above this, the concurrent use of the antibacterial AA, which
per se does not induce P. acnes resistance, can reduce or
might even prevent the induction of resistance to antibiotics [8, 18].
The good local tolerability of 20% AA cream is also of advantage in
maintenance therapy. Acne is a chronic, recurrent disease. Therefore,
it is an important clinical aspect to maintain a low level of acne activity
achieved during the primary course of therapy. This is best achieved using
a well-tolerated topical medication. The results of the second, 3-month
follow-up study phase indeed showed that regular, continued use of AA
cream is of distinct clinical benefit in the maintenance therapy of acne.
CONCLUSION
In summary, the present study showed that the combination of topical
20% AA cream and oral minocycline was a highly effective treatment in
severe forms of acne. Although the combination was somewhat less efficacious
than oral isotretinoin, it is better tolerated and associated with fewer
risks. Thus, the AA/Mino combination can be regarded as a valuable therapeutic
alternative in patients for whom isotretinoin is not indicated, who do
not wish to use or cannot tolerate isotretinoin therapy. Particularly,
the lack of teratogenicity makes therapy with 20% AA cream plus oral minocycline
an optimal alternative to isotretinoin therapy in women of childbearing
potential.
Article accepted on 8/8/01
REFERENCES
1. Berson DS, Shalita AR. The treatment of acne: the role of combination
therapies. J Am Acad Dermatol 1995; 32: S31-41.
2. Bjerke R, Fyrand O, Graupe K. Double-blind comparison of azelaic
acid 20% cream and its vehicle in treatment of papulo-pustular rosacea.
Acta Derm Venereol (Stockh) 1999; 79: 456-9.
3. Bojar RA, Cunliffe WJ, Holland KT. The short term treatment
of acne vulgaris with benzoyl peroxide: effects on the surface follicular
cutaneous microflora. Br J Dermatol 1995; 132: 204-8.
4. Cavicchini S, Caputo R. Long-term treatment of acne with 20%
azelaic acid cream. Acta Derm Venereol (Stockh) 1989; 14
(suppl.): 40-4.
5. Cunliffe WJ, Gollnick HPM, Orfanos CE. Acne. Diagnosis and
Management. Martin Dunitz Publ. London, 2001.
6. Cunliffe WJ, Holland KT. Clinical and laboratory studies of
treatment with 20% azelaic acid cream for acne. Acta Derm Venereol
(Stockh) 1989; 143 (suppl.): 31-4.
7. Fluhr JW, Gloor M, Dietz P, Höffler U. In vitro
activity of 6 antimicrobials against propionibacteria isolates from untreated
acne papulopustulosa. Zentr Bakteriol 1999; 289: 53-61.
8. Gloor M. Antibiotika in der Behandlung der Akne. TW Dermatol
1995; 25: 264-8.
9. Gollnick HPM, Graupe K. Azelaic acid for the treatment of
acne. Comparative trials. J Dermatol Treatm 1989; 1: 27-30.
10. Gollnick HPM, Graupe K, Detmar M, Zaumseil RP. Azelainsäure
für die Behandlung der Akne: Pharmakologie, in vitro- und
in vivo-Effekte, sowie klinische Ergebnisse und Toleranz. Z. Hautkr.
1992; 67: 975-87.
11. Gollnick HPM, Schramm M. Topical drug treatment in acne.
Dermatology 1998; 196: 119-25.
12. Healy E, Simpson N. Acne vulgaris. Br Med J 1994;
308: 831-3.
13. Hjorth N, Graupe K. Azelaic acid for the treatment of acne.
Acta Derm Venereol (Stockh) 1989; 143 (suppl.): 45-8.
14. Katsambas A, Graupe K, Stratigos I. Clinical studies of 20%
azelaic acid cream in the treatment of acne vulgaris: comparison with
vehicle and topical tretinoin. Acta Derm Venereol (Stockh) 1989;
143 (suppl.): 35-9.
15. Knaggs HE, Layton AM, Cunliffe WJ. The role of oral minocycline
and erythromycin in tetracycline therapy-resistant acne - a retrospective
study and a review. J Dermatol Treatm 1993; 4: 53-6.
16. Leyden JJ. Retinoids and acne. J Am Acad Dermatol
1988; 19: 164-8.
17. Leyden JJ. New understandings of the pathogenesis of acne.
J Am Acad Dermatol 1995; 32: S15-25.
18. Orfanos CE, Garbe C (Hrsg.). Therapie der Hautkrankheiten.
Berlin - Heidelberg: Springer, 2001.
19. Orfanos CE, Ehlert R, Gollnick HPM. Retinoide und ihre klinische
Anwendung. Drugs 1987; 34: 459-503.
20. Sykes NL, Webster GF. Acne. A review of optimum treatment.
Drugs 1994; 48: 59-70.
21. Webster GF. Inflammation in acne vulgaris. J Am Acad Dermatol
1995; 33: 247-53.
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