Topical azelaic acid and the treatment ofacne: a clinical and laboratory comparison with oral tetraeycline

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1 British Journal of Dermatology (1986) 114, 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, lesio were counted and the deity 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 Propionibacterium 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 preparatio 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 remai, 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

2 494 P.T.Bladonetal. azelaic acid exerts its action, at least in part, through an antimicrobial effect (Nazzaro-Porro et al., 1983), deity 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 lesio (Burke & Cunliffe, 1984). The deity 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 No. of patients entering trial Mean age (years) No. of patients completing trial Acne gradei median (range) Facial Total No. of lesio; median (range) Non-infiamed Inflamed A 20",, azelaic acid (topical) O (O-3-6-O) 3'8 ( ) 52 (26-130) 44(13-127) B oral tetraeycline Cl B/day) r-8 (o-2-4'o) 2-6(o-5-9-3) 41 (12-126) 43 (14-116) * Details of the formulation of this cream are not currently available for publication for reaso of patent protection.

3 Azelaic acid in acne i FIGURE I. The effect of azelaic acid ( ) and of tetraeycline ( ) on total lesion counts during 6 months' treatment. Points are media. 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. Intragroup compariso were made using the Wilcoxon matehed-pairs signed rank test. Analysis of laboratory data was carried out using Student's f-test ,o FIGURE 2. The effect of azelaic acid ( ) and of letracycline ( ) on numbers of inflamed lesio (papules, pustules, deep pustules and noduies) during 6 months' treatment. Points are media.

4 496 P. r.bladon et al FIGURE 3. The effect of azelaic acid ( ) and of tetracycline ( ) on numbers of non-inflamed lesio (blackheads and whiteheads) during 6 months' treatment. Points are media, 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 respoe/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 retinoic acid and also responded satisfactorily. No patients left the tetracycline treated group (Group ib). o-" FIGURE 4. The effect of azelaic acid ( ) and of tetracycline ( ) on facial acne grades during 6 months' treatment. Points are media.

5 5i Azelaic acid in acne FIGURE 5. The effect of azelaic acid ( ) and of tetracycline ( ) on total acne grades during 6 months' treatment. Points are media. Azelaic acid and oral tetracycline each produced a significant decrease in total lesion count after a 4-month period (Fig. i) (azelaic acid P<ooi, tetracycline P<oooi) and this was sustained to the sixth month. There were significant reductio in inflamed lesio (Fig. 2) after 2 months in both treatment groups and in non-inflamed lesio (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 Comedones Papules and pustules Nodules and deep pustules Macules Total lesio Facial acne grade Total acne grade P < > P> >P>oos 01 > P>oos 0 I > P>oa5 P>01 P< >P>00$ P>OI P>Ol 01 >P>oos p< D05 = not significant.

6 498 P.T.Bladon et al. Azelaic acid reduced the deity 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 deity 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 deity of micrococcaceae. Azelaic acid produced on 30-fold decreacse in the deity of Propionibacterium sp. on the skin but no decrease was detected with tetracycline treatment. Side effects were seen in both treatment groups. These were traient 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 /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 \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 demotrated 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 inflammatory respoes 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. We thank Schering AG, Berlin. ACKNOWLEDGMENT REFERENCES BHEATHNACH, A.S., NAZZAHO-PORRO, M. & PASSI, S. (1984) Azelaic acid. British Journal of Dermatology, 111, 115.

7 Azelaic acid in acne 499 BURKE, B.M. & CUNLIFFE, W.J. (1984) The assessment of acne vulgaris the Leeds Technique. British Journal of Dermatology, in, 83. COVE, J.H., CUNLIFFE, W.J. & HOLLAND, K.T. (1980) Acne vuigaris: is the bacterial population size significant? Bmn/i Journal of Dermatology, 102, 277. CUNLIFFE, W.J. & BURKE, B.M. (1982) Benzoyl peroxide; lack of seitization. Ai:ta Dermato-Venereologica, 62, 458. CUNLIFFE, W.J., CLAYDEN, A.D., GOULD, D.J. & SIMPSON, N.B. (1981) Acne vulgaris a review. Clinical and Experimental Dermatology, 6, 461. CUNLIFFF, W.J., FORSTHR, R.A., GREENWOOD, N.D., HETHERINGTON, C, HOLLAND, K.T., HOLMES, R.L., KHAN, S., ROBERTS, CD., WILLIAMS, M. & WILLIAMSON, B. (1973) Tetracycline and acne vulgaris: a clinical and laboratory investigation. British Medical Journal, iv, 332. CUNLIFFE, W.J. & HOLLAND, K.T. (1981) The effect of benzoyl peroxide on acne. Acne Dermato- Venereohgica, 61,267. CUNLIFFE, W.J. & SHUSTER, S. ("1969) The rate of sebum excretion in man. British Journal of Dermatology, 81, 697. EADY, E.A., HOLLAND, K.T. & CUNLIFFE, W.J. (1982a) Should topical antibiotics be used for the treatment of acne vulgaris? British Journal of Dermatology, 107, 235. EADY, E.A., HOLLAND, K.T. & CUNLIFFE, W.J. (1982b) The use of antibiotics in acne therapy: oral or topical administration? Journal of Antimicrobial Chemotherapy, 10, 89. FULTON, J.E. & PABLO, G. {1974) Topical antibacterial therapy for acne. Study ofthe family of erythromyci. Archives of Dermatology, no, 83. MARPLES, R.R. & KLIGMAN, A.M. (1971) F,cological effects of oral antibiotics on the microflora of human skin. Archives of Dermatology, 103, 148. MARSDEN, J.R. & SHUSTER, S. (1983) The effect of azelaic acid on acne. (Correspondence) British Journal of Dermatology, 109, 723. MILLS, OH., MARPLES, R.R. & KLIGMAN, A.M. (1972) Acne vuigaris oral therapy with tetracycline and topical therapy with vitamin A. Archives of Dermatology, 106, 200. NAZZARO-PORRO, M., PASSI, S., PICARDO, M., BREATHNACH, A., C:LAYTON, R. & ZINA, G. (1983) Beneficial effect of i5"o azelaic acid cream on acne vulgaris. British Journal of Dermatology, 109, 45. STRAUSS, J.S. & POCHI, P.E. (1961) The quantitative gravimetric determination of sebum production. Journal of Investigative Dermatology, 36, 293. TAAFFE, A., CUNLIFFE, W.J., COVE, J., EADY, A. & HOLLAND, K.T. (1981) Topical erythromycin in acne a doubleblind study. (Abstract) British Journal of Dermatology, 105, Suppl. t9, 19. THOMSEN, R.J.,STRANIERI, A.,KNUTSON,D.& STRAUSS, J.S. (1980) Topical clindamycin treatment of acne./ Dermatology, 116, 1031.

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