British Journal of Dermatology (1986) 114, 493-499-

Topical azelaic acid and the treatment ofacne:

a clinical and laboratory comparison with
oral tetraeycline

P.T.BLADON, B.M.BURKE, W.J.CUNLIFFE, R.A.FORSTER,

K.T.HOLLAND* AND K.KING*
Department of Dermatology, The General Infirmary, Leeds LSi 3EX ajnd *Departmem of Microbiology,
University of Leeds, Leeds LS2 9JT, U.K.
Accepted for publication 19 September 1985

SUMMARY
Topical azelaic acid and oral tetraeycline were compared in a 6-month double-blind study for
treatment of acne vulgaris in 45 male subjects with clinical acne. Their acne was graded,
inflamed or non-infiamed, lesions were counted and the density of their skin microflora was
measured. Both treatments were of benefit and produced only a few minor side-effects.
Although oral tetraeycline was more effective than azelaic acid, the differences were only just
significant. The average reduction in numbers of cutaneous micrococcaceae and Propionibacter-
ium sp. with azelaic acid treatment was 224 and 30-fold, respectively.
In a separate group of 11 male subjects with physiological acne the effect of azelaic acid on
sebum excretion rate was assessed, and little change was detected.

The two most commonly used topical preparations for acne in the U.K. are benzoyl peroxide
and retinoic acid. Both are effective (Cunliffe et aL, 1981; Mills, Marples & Kligman, 1972) but
both have disadvantages. They often produce a primary irritant dermatitis (Cunliffe & Burke,
1982) and benzoyl peroxide bleaches hair and clothes.
Topical antibiotics have been used in the U.S.A. for acne (Fulton & Pablo, 1974; Thomsen et
al., 1980; Taaffe et al., 1981), but may induce antibiotic resistance (Eady, Holland & Cunliffe,
1982a).
There remains, therefore, a need for an effective topical therapy with none of these problems.
Nazzaro-Porro et al. (1983) showed, in an open study with 100 patients, that azelaic acid, a
naturally occurring dicarboxylic acid, was effective in acne. The purpose of our investigation
was to compare topical azelaic acid and oral tetraeycline, a common treatment for acne, in a
double-blind trial using acne grade and lesion counts to monitor progress. Since it is likely that
Correspondence: W.J.Cunliffe, Skin Department, Dawson Floor, The General Infirmary, Great George Street,
Leeds, LSi 3EX, U.K.
493
494 P.T.Bladonetal.
azelaic acid exerts its action, at least in part, through an antimicrobial effect (Nazzaro-Porro et
al., 1983), density of cutaneous microflora was also assessed. In addition, azelaic acid may affect
sebaceous gland function (Breathnach, Nazzaro-Porro & Passi, 1984) so measurements of
sebum excretion rate (SER) were made on a separate group of subjects.

METHODS
Group I
Forty-five male acne patients were investigated between November and May. None had used
acne treatment for 6 weeks before entering the study. Clinical and microbiological assessments
were made prior to treatment and after 1,2,4 and 6 months of treatment. Twenty-three patients
(Group iA) were given placebo tablets and 20",, azelaic acid cream.* Twenty-two patients
(Group iB) were given oral tetraeycline (250 mg q.d.s.; tablets being taken with water 30 min
before food) and placebo cream. Topical therapy in Groups i and 2 (see below) was applied
liberally twice a day to face, back and chest. There was no double (tablets and cream) placebo
group.
Clinical assessment was carried out by grading the acne and counting the lesions (Burke &
Cunliffe, 1984). The density of micro-organisms on the skin was determined by the method of
Cove, Cunliffe & Holland (1980). Side effects were assessed at each visit.

Group 2
A group of 11 male subjects with physiological acne were treated with topical 20^,, azelaic acid
over the same period as Group i. No subject had used acne treatment for 6 weeks before starting
the trial. Sebum excretion rate was estimated by the gravimetric technique (Strauss & Pochi,
1961; Cunliffe & Shuster, 1969) before treatment and after i, 2, 4 and 6 months of treatment.

TABLE I. Group I, patient details and pre-treatment acne grades and lesion counts

A B
20",, azelaic acid oral tetraeycline
(topical) Cl B/day)

No. of patients entering trial 23 22

Mean age (years) 18 19
No. of patients completing trial 17 22
Acne gradei median (range)
Facial 2-O (O-3-6-O) r-8 (o-2-4'O)
Total 3'8 (1-5-9-8) 2-6(o-5-9-3)

No. of lesions; median (range)

Non-infiamed 52 (26-130) 41 (12-126)
Inflamed 44(13-127) 43 (14-116)

* Details of the formulation of this cream are not currently available for publication for reasons of patent protection.
 Azelaic acid in acne 495
140i

120

100

80

60

40

20

0 1 2 3 4 5 6
Months
FIGURE I. The effect of azelaic acid (•) and of tetraeycline (•) on total lesion counts during 6 months'
treatment. Points are medians.

Statistical analysis
The Mann Whitney U test was used to evaluate clinical data (total lesion, inflamed lesion and
non-inflamed lesion counts and acne grade) obtained from the different treatment groups. Intra-
group comparisons were made using the Wilcoxon matehed-pairs signed rank test. Analysis of
laboratory data was carried out using Student's f-test.

1001

80

60

,o 40

20

0 1 2 3 4 5 6
Months
FIGURE 2. The effect of azelaic acid (•) and of letracycline (•) on numbers of inflamed lesions (papules,
pustules, deep pustules and noduies) during 6 months' treatment. Points are medians.
496 P. r.Bladon et al.
100

80

60

40

20-

2 3 4
Months
FIGURE 3. The effect of azelaic acid (•) and of tetracycline (•) on numbers of non-inflamed lesions
(blackheads and whiteheads) during 6 months' treatment. Points are medians,

RESULTS
Group t
The treatment code was broken after analysis of the results. Six patients who had been given
azelaic acid (Group i A) left the study prematurely (Table i). One patient left for no given reason
and five patients left because of poor response/compliance to the treatment. Of these patients
four were subsequently given oral tetracycline (i g/day) and 5",, benzoyl peroxide cream and
responded well; one was given oral 13-6-75 retinoic acid and also responded satisfactorily. No
patients left the tetracycline treated group (Group iB).

o-"
0 1 2 3 4 5 6
Months
FIGURE 4. The effect of azelaic acid (•) and of tetracycline (•) on facial acne grades during 6 months'
treatment. Points are medians.
 Azelaic acid in acne 497
5i

0 1 2 3 4 5 6
Months
FIGURE 5. The effect of azelaic acid (•) and of tetracycline (•) on total acne grades during 6 months'
treatment. Points are medians.

Azelaic acid and oral tetracycline each produced a significant decrease in total lesion count
after a 4-month period (Fig. i) (azelaic acid P < o o i , tetracycline P < o o o i ) and this was
sustained to the sixth month. There were significant reductions in inflamed lesions (Fig. 2) after
2 months in both treatment groups and in non-inflamed lesions (Fig. 3) after 2 months in the
tetracycline treated group and after 4 months in the azelaic acid treated group. After 6 months
the median facial acne grade (Fig. 4) was decreased by 66",, in the azelaic acid treated group, and
by 77",, in the tetracycline treated group. Inter-group analysis of total acne grade for face, back
and chest (Fig. 5) showed a significantly lower median grade in the tetracyclinc group compared
with the azelaic acid group after 4 and 6 months (P < 005). Intcr-group analyses of all clinical
data are summarized in Table 2.

TABLE 2. Group i; intergroup comparisonof patients treated with azelaic acid and
with tetracycline

Time of assessment (months)

0 I 2 4 6

Comedones ns ns ns ns ns
Papules and pustules ns ns ns ns ns
Nodules and deep pustules ns ns ns 01 >P>oos 01 >P>00$
Macules ns ns ns 01 > P>oos P>OI
Total lesions ns ns ns 0 I > P>oa5 P>Ol
Facial acne grade ns ns P < 005 P>01 01 > P > o o s
Total acne grade ns ns 01 > P> 0 05 P< 0 05 p< D05

ns = not significant.
498 P.T.Bladon et al.
Azelaic acid reduced the density of the skin microflora, the main effect being a 224-fold
reduction in the numbers of micrococcaceae. After one month, azelaic acid had produced a
significant reduction in the density of micrococcaceae (P<oooi). A further significant
reduction was observed after the second month in comparison with the first (P< 0 025) and
thereafter there was no further decrease. Tetracycline had no signiflcant effect on the density of
micrococcaceae. Azelaic acid produced on 30-fold decreacse in the density of Propionibacterium
sp. on the skin but no decrease was detected with tetracycline treatment.
Side effects were seen in both treatment groups. These were transient and did not cause the
withdrawal of any patient from the study. Minor erythema and scaling was observed in some
patietits receiving azelaic acid. One patient in the tetracycline group reported abdominal pain.

Group 2
Azelaic acid had little effect on the SER. The SER did not differ significantly from the baseline
value at the i, 2 and 6-month visits. The mean SER at the control visit was 089 + 009 /ig/cm" ^/
min " ' (95"u confidence limit) and at 6 months was o 92 ± o 62 /(g/cm " ^/min '. However, there
was a signiflcant but very small decrease in SER at the 4-month visit, mean SER o 84 + 057 \i%\
^/i ' (P< 0-025).

DISCUSSION

Azelaic acid (1,7-heptane dicarboxylic acid, HOi.QCHi)!-COiH) has been reported in an

open study to be of value in the treatment of moderate and severe acne (Nazzaro-Porro et aL,
1983), The present study showed that azelaic acid was beneficial in patients with clinical acne.
However, it did not appear to be as effective as was reported by Nazzaro-Porro et al. (1983), and
was found to be clinically marginally less effective than oral tetracycline. It had few side effects.
The laboratory studies showed that azelaic acid had an antimicrobial effect and that this was
mainly on micrococcaceae. In comparison, tetracycline had no signiflcant effect on the skin
microflora. The mechanism by which tetracycline is effective in the treatment of acne is still
open to discussion. Direct antibacterial effects have been demonstrated using 1000 mg daily,
which reduced the cutaneous microflora (Marples & Kligman, 1971). At a lower dose of 250 mg
daily, indirect effects on the microflora have been shown by Cunliffe et al. (1973) who argued
that the reduction in skin surface free fatty acids was due to the lower production of lipase by
cutaneous bacteria. However, tetracycline has a wide range of activities and lowers inflamma-
tory responses by affecting non-immunological and immunological systems (Eady, Holland &
Cunliffe, 1982b). Azelaic acid had little effect on SER and this finding is in agreement with that
of Marsden & Shuster (1983). During these studies it was not possible to include a placebo
group and it is hoped in future studies that this control can be included.
We conclude that azelaic acid has some potential in the treatment of mild or physiological
acne. Further work on delivery systems, and its mechanism of action, could lead to the
successful use of azelaic acid as a topical treatment for acne vulgaris.

ACKNOWLEDGMENT
We thank Schering AG, Berlin.

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