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Azelaic acid and glycolic acid combination therapy for facial hyperpigmentation in darker-skinned patients: a clinical comparison with hydroquinone
CLINICAL THERAPEUTICSVVOL. 20, NO. 5, 1998
Azelaic Acid and Glycolic Acid Combination Therapy for Facial Hyperpigmentation in Darker-Skinned Patients: A Clinical Comparison with Hydroquinone Lenore S. Kakita, MD,’ and Nicholas J. Lowe, MD2 ‘Private practice, Glendale, and 2Clinical Research Specialists, UCLA School of Medicine, Los Angeles, California
ABSTRACT This multicenter, randomized, doublemasked, parallel-group, 24-week clinical study compared the efficacy of the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion with hydroquinone 4% in the treatment of facial hyperpigmentation in darker-skinned patients. At week 24, overall improvement and reduction in lesion area, pigmentary intensity, and disease severity were comparable in the two treatment groups. At some visits, patients treated with an azelaic/glycolic acid combination had slightly greater levels of peeling, burning, stinging, or dryness than did patients treated with hydroquinone, although scores for cutaneous signs and symptoms were always low. The present study demonstrated that the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion was as effective as hydroquinone 4% cream in the treatment of hyperpigmentation in darker-skinned patients, with only a slightly higher rate of
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mild local irritation. These findings suggest that the addition of glycolic acid to azelaic acid treatment for hyperpigmentation is an appropriate alternative in selected darker-skinned patients. Key words: hyperpigmentation, azelaic acid, glycolic acid, hydroquinone.
INTRODUCTION Hyperpigmentary disorders are particularly difficult to treat in darker-skinned patients. The challenge is to diminish the hyperpigmentation without producing an undesirable lightening of the surrounding normally pigmented skin. In addition, care must be taken to avoid excessively irritating treatments, since darker-skinned patients are more likely than lighterskinned patients to develop postinflammatory hyperpigmentation. The most commonly used treatment for all types of hyperpigmentary disorders is topical hydroquinone. 1 Hydroquinone has well-established efficacy against hyperpigmentation but can also lighten nor-
0149.2918/98/$19.00
L.S. KAKITA AND N.J. LOWE
mally pigmented skin and occasionally causes toxic reactions.‘,’ The latter has led to an increased use of topical azelaic acid 20% for the treatment of hyperpigmentation. Azelaic acid 20% cream was shown to be effective in the treatment of hyperpigmentation in darker-skinned patients in two large-scale clinical trials conducted in women with melasma from the Philippines,3 Thailand,3 and South America.4 It was more effective than hydroquinone 2%3 and as effective as hydroquinone 4%.4 Moreover, azelaic acid has not been associated with the adverse events, such as ochronosis, that have been reported with hydroquinone.5 However, both azelaic acid and hydroquinone may require several months to achieve significant lightening of hyperpigmented skin, and some patients never achieve a completely satisfactory result with either treatment.6 This has motivated clinicians to seek new treatments or combinations of treatments that have enhanced efficacy in hyperpigmentary disorders. In our clinic, we have observed that multiple glycolic-acid peels (20% to 70%) in darkerskinned patients can lighten abnormally pigmented skin. Other investigators have also reported beneficial effects with multiple glycolic-acid peels to treat melasma in darker-skinned women. When added to daily treatment with hydroquinone 2%/ glycolic acid 1O%7 or to hydroquinone 2%/glycolic acid lO%/tretinoin 0.05%,s such peels have provided greater and more rapid improvement than either of the daily regimens used alone. These results suggest that the efficacy of glycolic acid as an adjunctive therapy in hyperpigmentation warrants further investigation. In the present study, the efficacy of the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion was
compared with hydroquinone 4% in the treatment of facial hyperpigmentation in darker-skinned patients.
PATIENTS AND METHODS This was a multicenter, randomized, double-masked, parallel-group, 24-week clinical study. Informed consent and photographic release were obtained from all patients before enrollment.
Study Population To be eligible for the study, patients had to have a clinical diagnosis of moderate or more severe melasma or another form of hyperpigmentation, including postinflammatory hyperpigmentation, idiopathic melanosis, or drug-induced hyperpigmentation. Patients were excluded if they were pregnant, nursing, or planning to become pregnant; had an uncontrolled systemic disease; had used a topical preparation of hydroquinone, tretinoin, corticosteroid, kojic acid, glycolic acid or another alpha-hydroxy acid, or medicated cosmetic preparations within 2 weeks of the start of the study; used a systemic corticosteroid or oral contraceptive 30 days before or during the study; had a known allergy or sensitivity to any of the study medications or their components; or had any skin disease that might interfere with the diagnosis or evaluation of hyperpigmentation.
Study Protocol At the initial visit (baseline), patients’ medical histories were taken and their hyperpigmentation and skin condition assessed. All efficacy variables (except those specifically related to response to
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treatment) were evaluated, and facial photographs were taken. All female patients underwent a urine pregnancy test. Patients were then randomized to receive either the combination of azelaic acid 20% cream* and glycolic acid 15%? or 20%* facial lotions or hydroquinone 4% cream5 combined with the vehicle lotion of glycolic acid (Allergan Inc.). In the azelaic/glycolic acid group, all patients received glycolic acid 15% lotion at the beginning of the study and were then switched to glycolic acid 20% lotion after 1 month. Patients applied the assigned study medication for the next 24 weeks according to the following protocol. Each morning and evening, patients washed their face with a nonmedicated soap and thoroughly rinsed and dried their skin. They then applied the cream, followed in 10 to 15 minutes by the lotion. Each morning, approximately 10 to 15 minutes after applying the second study medication, all patients also applied a standardized sunscreen” to their entire face. Overall disease severity and physician’s global evaluation of response to treatment and cutaneous signs and symptoms were recorded at weeks 2, 4, 8, 12, 16, 20, and 24. Lesion area was evaluated, pigmentary intensity determined, and facial photographs taken at baseline and at weeks 8, 16, and 24. Patients’ impressions of the efficacy and cosmetic characteristics of
*Trademark: A.zelex@ (Allergan Inc., Irvine, California). ‘Trademark M.D. Forte I@ (Allergan Inc.). $Trademark: M.D. Forte II@’(Allergan Inc.). *Trademark: Eldoquin Forte@’ (ICN Pharmaceuticals, Inc., Costa Mesa, California). “Trademark Shade@ UVAGuardTM SPF 15 (Schering Corporation, Kenilworth, New Jersey).
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the study medication were surveyed at weeks 12 and 24. All patients completed an exit form at week 24.
Outcome Measures The physician-rated efficacy variables were: pigmentary intensity (on a scale from 0 = none to 5 = severe); disease severity (from 0 = none to 8 = severe); overall global improvement (from 0 = worse to 8 = completely cleared); lesion area (from 0 = none to 5 = severe); and cutaneous signs and symptoms-dryness, erythema, oiliness, peeling, burning, and stinging (from 0 = none to 5 = severe). Patients rated the severity of skin dryness, redness, oiliness, peeling, burning, itching, pain, and hyperpigmentation on a scale from 0 = none to 4 = severe. They also rated the effect of their skin condition on their attractiveness, self-confidence, comfort in social situations, satisfaction with their appearance, comfort in a physical relationship, embarrassment, and performance at work or school on a scale from 0 = not at all to 6 = very much. Patients were also surveyed for their impressions of the efficacy and cosmetic characteristics of the study medication.
Statistical Analysis Statistical significance was set at 0.05 (two-tailed test) for all comparisons between treatment groups. Categorical variables (eg, symptoms, signs, overall disease severity, lesion area, pigment intensity, and patient evaluations) were summarized using descriptive statistics (ie, sample size, mean, standard deviation, and frequency counts) and were analyzed using Wilcoxon rank sum tests. Continuous variables (eg, age and chromometer read-
L.S. KAKITA AND N.J. LOWE
mentation, and had melasma. The majority also had a skin phototype of III or greater. There were no significant between-group differences in any demographic variables. Patient demographics are summarized in Table I. Ninety-four percent (29) of 31 patients in the azelaic/glycolic acid group and 88% (30) of 34 patients in the hydroquinone group completed the study. No patients were terminated because of adverse events or lack of efficacy. Patient disposition is summarized in Table II.
were summarized using descriptive statistics (ie, sample size, mean, standard deviation, minimum, and maximum) and were analyzed using analysis of variance. ings)
RESULTS Patient Characteristics and Disposition A total of 65 adult patients (5 males, 60 females) were enrolled in the study. The majority of patients in both groups were white, had mixed dermal/epidermal pig-
Table I. Demographic
characteristics
of patients (N = 65).
Azelaic/Glycolic (n = 31) Mean age (y) Sex Male Female Race Black White Hispanic Asian Other Missing data Pigmentation type Dermal Epidermal Mixed Skin phototype II III IV V Disorder Drug-induced Idiopathic Melasma Postinflammatory
Acid
Hydroquinone (n = 34)
48
41
2 29
3 31
2 12 8 7 1 1
1 20 5 5 2 1
1 8 22
2 9 23
3 18 9 1
13 12 8 1
2 6 19 4
0 5 25 4
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Table II. Patient disposition
(N = 65). Azelaic/Glycolic Acid
Hydroquinone
29
30
Discontinued Lost to follow-up Missed visits Protocol violation Personal reasons
5 0 1 1 3
5 1 0 3 1
Other*
1
0
Completed the study
*No exit form was completed;
Physician Assessment:
reason for discontinuation
Effiacy
and
safety After 24 weeks of treatment, both azelaic/glycolic acid and hydroquinone were effective in decreasing pigmentary intensity, as evidenced by patient photographs (Figure 1). Mean physician-rated pigmentary intensity at baseline was approximately 3.0 (moderate) in both groups, decreasing to 2.4 (mild-to-moderate) in the azelaic/glycolic acid group and 2.3 (mildto-moderate) in the hydroquinone group at week 24 (Figure 2). There were similar decreases in physician-rated overall disease severity with both treatments; mean scores at baseline were above moderate for both groups (azelaic/glycolic acid = 4.6; hydroquinone = 4.9) and had decreased to mild-to-moderate in both groups (azelaic/glycolic acid = 3.4; hydroquinone = 3.5) by week 24 (Figure 3). Overall global improvement scores increased in both groups throughout the study; by week 24, there was a mean improvement in hyperpigmentation of approximately 25% in both groups -(Figure 4).
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or termination
was listed as unknown
Lesion area decreased in both groups from moderate (covering approximately 33% of the face) at baseline to mild-tomoderate (covering approximately 25% of the face) by week 24. Azelaic/glycolic acid and hydroquinone were associated with similar degrees of dryness (Figure 5), erythema, and oiliness. Mean scores for all three variables were
Patient Assessment As rated by the patients, mean scores for dryness, redness, oiliness, and burning were below mild throughout the treatment period, whereas scores for peeling, itching, and pain were
L.S. KAKITAAND NJ. LOWE
Figure I
Patient photos (A) before azelaic/glycolic acid treatment; (B) after 24 weeks of azelaic/glycolic acid treatment; (C) before hydroquinone treatment; and (D) after 24 weeks of hydroquinone treatment.
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CLINICAL THERAPEUTICS”
Marked (4)
cc1I 0 Hydroquinone
Moderate (3)
$ f z
Mild (2)
E E .F a
Trace (1)
None (0)
1
L
Baseline
Week 8
Week 16
Week 24
Figure 2. Pigmentary intensity was rated on a scale from 0 = none to 5 = severe. Azelaic/glycolic acid and hydroquinone produced equivalent reductions in pigmentary intensity scores (mean + SEM) by week 24. There were no significant between-group differences. Marked (6)
Moderate (4) .s
i
I ._ n
Mild (2)
None (0)
IrI
1
Baseline
n Azelaidglycolic acid 0 Hydroquinone
L
Week 8
Week 16
-i
Week 24
Figure 3. Disease severity was rated on a scale from 0 = none to 8 = severe. Azelaic/glycolic acid and hydroquinone produced equivalent reductions in disease severity scores (mean + SEM) by week 24. There were no significant between-group differences.
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L.S. KAKITAAND N.J. LOWE
~50% Improvement
n Azelaicz’glycolicacid 0 Hydroquinone
-25% Improvement
I
Week 0
Week 16
I
~10% Improvement
-
No Improvement
Week 24
worse to 8 = comFigure 4. Overall global improvement was rated on a scale from 0 pletely cleared. Azelaic/glycolic acid and hydroquinone produced equivalent overall improvement scores (mean + SEM) by week 24. There were no significant between-group differences. Severe (5)
n Azelaic/glycolicacid 0 Hydroquinone
Marked (4)
Moderate (3)
: Mild(2)
Trace (1)
I
None (0) Week 0
Week 16
(
Week 24
Figure 5. Skin dryness was rated on a scale from 0 = none to 5 = severe. Dryness scores (mean + SEM) were ~1 (trace) in both treatment groups at week 8 and decreased as the study continued. There were no significant differences between the azelaic/glycolic acid and hydroquinone groups.
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CLINICAL THERAPEUTIC6
severe (5) -
nAzelaidglycolic
g!
acid
0 Hydroquinone
Marked (4) _
Moderate (3) _
8 Cn F *=
t
tz
Mild (2) 1 Trace (I) 1
t I
*
None (0) Week 0
Week 16
Week 24
Figure 6. Skin burning was rated on a scale from 0 = none to 5 = severe. Although buming scores (mean + SEM) were cl (trace) in both groups throughout the study, azelaic/glycolic acid produced significantly greater burning than hydroquinone at weeks 8 (P = 0.002*), 16 (P < O.OOlt), and 24 (P = 0.018$).
the treatment period. There was slightly but significantly more patient-reported dryness (week 24; P = 0.011) and burning (weeks 0, 12, and 24; P I 0.027) in the azelaic/glycolic acid group than in the hydroquinone group. Mean scores for hyperpigmentation severity were never above moderate at any time point in either group; however, patient-rated severity of hyperpigmentation was slightly but significantly greater in the azelaic/glycolic acid group (week 12; P = 0.046). Patients in both groups had similar opinions about the impact their hyperpigmentation had on their lifestyle and selfesteem and the effect of their treatment on their skin. Patient responses were similar in both groups for the following variables: attractiveness, satisfaction with appearance, embarrassment, and degree to which hyperpigmentation negatively affected
performance at work or school. Although most patient responses were equivalent, at weeks 12 and 24 there were slight but significant differences favoring the hydroquinone group in self-confidence, comfort in social situations, and comfort in a physical relationship (P < 0.035).
DISCUSSION The present study demonstrated that 24week treatment with the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion was as effective as hydroquinone 4% cream-the current standard of care for hyperpigmentary disorders-for decreasing pigmentary intensity, overall disease severity, and lesion area in darker-skinned patients with melasma or another form of facial hyperpigmentation.
L.S. KAKITAAND
N.J. LOWE
These findings build on earlier studies demonstrating that azelaic acid, used alone, was significantly more effective than hydroquinone 2% cream and comparable in efficacy to hydroquinone 4% cream in reducing pigmentary intensity, decreasing lesion size, and affecting overall response in darker-skinned patients with melasma.3*4 In addition, our results show that the addition of glycolic acid 15% or 20% lotion has no detrimental effect on the response of hyperpigmentary disorders to azelaic acid treatment. However, these results do not resolve the question of how, or if, the addition of glycolic acid treatment to a depigmenting regimen improves patient outcomes. When used alone, azelaic acid 20% cream has clear safety advantages over hydroquinone 2% or 4% cream. It does not produce the ochronosis or undesirable lightening of normally pigmented skin that is sometimes associated with hydroquinone1T2 and produces a similarly low level of transient, mild local irritation.3*4 However, the present study demonstrates that the addition of glycolic acid to azelaic acid treatment can produce slightly more local irritation than is observed with hydroquinone 4% treatment. Because this combination has only an equivalent lightening effect to hydroquinone 4% or, by inference, azelaic acid used alone, glycolic acid should be added only if the patient has other skin problems or places a high priority on cosmetic concerns that lead the physician to believe glycolic acid might be beneficial. The most suitable candidates for azelaic/glycolic acid treatment are patients whose skin is not overly prone to irritation who have a combination of hyperpigmentation and other conditions, such as acne vulgaris or rosacea, and those for
whom cosmetic considerations are a high priority. Both azelaic acid and glycolic acid can be of benefit in the treatment of several dermatologic conditions. Azelaic acid has been shown to be effective in the treatment of acne vulgaris and rosacea*O as well as hyperpigmentation.3*4 Various types of glycolic acid treatment are under investigation for acne, l1 hyperpigmentation,7,8 and cosmetic effects.t2J3
CONCLUSIONS Our results demonstrate that the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion is as effective as hydroquinone 4% cream for the treatment of hyperpigmentation in darkerskinned patients, with only a slightly higher rate of mild local irritation. These findings build on earlier studies demonstrating the efficacy of azelaic acid monotherapy in the treatment of hyperpigmentation and suggest that glycolic acid may be an appropriate adjunct to azelaic acid therapy in some patients. This combination may be particularly beneficial for patients whose hyperpigmentation is accompanied by other dermatologic conditions (eg, acne vulgaris or rosacea) or for whom cosmetic concerns are a high priority.
ACKNOWLEDGMENT This research was supported by a grant from Allergan Inc., Irvine, California.
Address correspondence to: Lenore S. Kakita, MD, 18 18 Verdugo Blvd., Glendale, CA 9 1208.
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REFERENCES 1. Frenk E. Treatment of melasma with depigmenting agents. In: Melasma: New Approaches to Treatment. London: Martin Dunitz Ltd.; 19959-U. 2. Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Dermatol. 1995;131:1453-1457. 3. Verallo-Rowe11 WM, Sioson-de 10s Reyes G. South Asian experience with azelaic acid in melasma. Med Prog J. 1993;20 (Suppl):26-30. 4. Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Pharmacol Thel: 1991; 30:893-895. 5. Fitton A, Goa KL. Azelaic acid: A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary disorders. Drugs. 199 1;4 1: 780-791.
8. Bums RL, Prevost-Blank PL, Lawry MA, et al. Glycolic acid peels for postinflammatory hyperpigmentation in black patients. A comparative study. Dermatol Surg. 1997;23:171-174. 9 Graupe K, Cunliffe WJ, Gollnick HPM, Zaumseil R-P Efficacy and safety of topical azelaic acid (20 percent cream): An overview of results from European clinical trials and experimental reports. Cutis. 1996;57(Suppl 1):20-35. 10 Carmichael AJ, Marks R, Graupe KA, Zaumseil Rp. Topical azelaic acid in the treatment of rosacea. J Dermatol Treat. 1993;4(Suppl l):S19-S22. 11. Wang CM, Huang CL, Hu CT, Chan HL. The effect of glycolic acid on the treatment of acne in Asian skin. Dermatol Surg. 1997;23:23-29.
6. Giannotti B, Melli MC. Current approaches to tbe treatment of melasma. Clin Drug Invest. 1995;1O(Suppl 2):57-64.
12 Stiller MJ, Bartolone J, Stem R, et al. Topical 8% glycolic acid and 8% L-lactic acid creams for the treatment of photodamaged skin. A double-blind vehicle-controlled clinical trial. Arch Dernmtol. 1996;132: 63 l-636.
7. Lim JT, Tham SN. Glycolic acid peels in the treatment of melasma among Asian women. Dermatol Surg. 1997;23:177-179.
13 Van Scott EJ, Yu RJ. Alpha hydroxy acids in skin care. Clin Plast Surg. 1996;23: 49-56.
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Azelaic Acid and Glycolic Acid Combination Therapy for Facial Hyperpigmentation in Darker-Skinned Patients: A Clinical Comparison with Hydroquinone Lenore S. Kakita, MD,’ and Nicholas J. Lowe, MD2 ‘Private practice, Glendale, and 2Clinical Research Specialists, UCLA School of Medicine, Los Angeles, California
ABSTRACT This multicenter, randomized, doublemasked, parallel-group, 24-week clinical study compared the efficacy of the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion with hydroquinone 4% in the treatment of facial hyperpigmentation in darker-skinned patients. At week 24, overall improvement and reduction in lesion area, pigmentary intensity, and disease severity were comparable in the two treatment groups. At some visits, patients treated with an azelaic/glycolic acid combination had slightly greater levels of peeling, burning, stinging, or dryness than did patients treated with hydroquinone, although scores for cutaneous signs and symptoms were always low. The present study demonstrated that the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion was as effective as hydroquinone 4% cream in the treatment of hyperpigmentation in darker-skinned patients, with only a slightly higher rate of
960
Santa Monica, and
mild local irritation. These findings suggest that the addition of glycolic acid to azelaic acid treatment for hyperpigmentation is an appropriate alternative in selected darker-skinned patients. Key words: hyperpigmentation, azelaic acid, glycolic acid, hydroquinone.
INTRODUCTION Hyperpigmentary disorders are particularly difficult to treat in darker-skinned patients. The challenge is to diminish the hyperpigmentation without producing an undesirable lightening of the surrounding normally pigmented skin. In addition, care must be taken to avoid excessively irritating treatments, since darker-skinned patients are more likely than lighterskinned patients to develop postinflammatory hyperpigmentation. The most commonly used treatment for all types of hyperpigmentary disorders is topical hydroquinone. 1 Hydroquinone has well-established efficacy against hyperpigmentation but can also lighten nor-
0149.2918/98/$19.00
L.S. KAKITA AND N.J. LOWE
mally pigmented skin and occasionally causes toxic reactions.‘,’ The latter has led to an increased use of topical azelaic acid 20% for the treatment of hyperpigmentation. Azelaic acid 20% cream was shown to be effective in the treatment of hyperpigmentation in darker-skinned patients in two large-scale clinical trials conducted in women with melasma from the Philippines,3 Thailand,3 and South America.4 It was more effective than hydroquinone 2%3 and as effective as hydroquinone 4%.4 Moreover, azelaic acid has not been associated with the adverse events, such as ochronosis, that have been reported with hydroquinone.5 However, both azelaic acid and hydroquinone may require several months to achieve significant lightening of hyperpigmented skin, and some patients never achieve a completely satisfactory result with either treatment.6 This has motivated clinicians to seek new treatments or combinations of treatments that have enhanced efficacy in hyperpigmentary disorders. In our clinic, we have observed that multiple glycolic-acid peels (20% to 70%) in darkerskinned patients can lighten abnormally pigmented skin. Other investigators have also reported beneficial effects with multiple glycolic-acid peels to treat melasma in darker-skinned women. When added to daily treatment with hydroquinone 2%/ glycolic acid 1O%7 or to hydroquinone 2%/glycolic acid lO%/tretinoin 0.05%,s such peels have provided greater and more rapid improvement than either of the daily regimens used alone. These results suggest that the efficacy of glycolic acid as an adjunctive therapy in hyperpigmentation warrants further investigation. In the present study, the efficacy of the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion was
compared with hydroquinone 4% in the treatment of facial hyperpigmentation in darker-skinned patients.
PATIENTS AND METHODS This was a multicenter, randomized, double-masked, parallel-group, 24-week clinical study. Informed consent and photographic release were obtained from all patients before enrollment.
Study Population To be eligible for the study, patients had to have a clinical diagnosis of moderate or more severe melasma or another form of hyperpigmentation, including postinflammatory hyperpigmentation, idiopathic melanosis, or drug-induced hyperpigmentation. Patients were excluded if they were pregnant, nursing, or planning to become pregnant; had an uncontrolled systemic disease; had used a topical preparation of hydroquinone, tretinoin, corticosteroid, kojic acid, glycolic acid or another alpha-hydroxy acid, or medicated cosmetic preparations within 2 weeks of the start of the study; used a systemic corticosteroid or oral contraceptive 30 days before or during the study; had a known allergy or sensitivity to any of the study medications or their components; or had any skin disease that might interfere with the diagnosis or evaluation of hyperpigmentation.
Study Protocol At the initial visit (baseline), patients’ medical histories were taken and their hyperpigmentation and skin condition assessed. All efficacy variables (except those specifically related to response to
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CLINICAL THERAPEUTICS”
treatment) were evaluated, and facial photographs were taken. All female patients underwent a urine pregnancy test. Patients were then randomized to receive either the combination of azelaic acid 20% cream* and glycolic acid 15%? or 20%* facial lotions or hydroquinone 4% cream5 combined with the vehicle lotion of glycolic acid (Allergan Inc.). In the azelaic/glycolic acid group, all patients received glycolic acid 15% lotion at the beginning of the study and were then switched to glycolic acid 20% lotion after 1 month. Patients applied the assigned study medication for the next 24 weeks according to the following protocol. Each morning and evening, patients washed their face with a nonmedicated soap and thoroughly rinsed and dried their skin. They then applied the cream, followed in 10 to 15 minutes by the lotion. Each morning, approximately 10 to 15 minutes after applying the second study medication, all patients also applied a standardized sunscreen” to their entire face. Overall disease severity and physician’s global evaluation of response to treatment and cutaneous signs and symptoms were recorded at weeks 2, 4, 8, 12, 16, 20, and 24. Lesion area was evaluated, pigmentary intensity determined, and facial photographs taken at baseline and at weeks 8, 16, and 24. Patients’ impressions of the efficacy and cosmetic characteristics of
*Trademark: A.zelex@ (Allergan Inc., Irvine, California). ‘Trademark M.D. Forte I@ (Allergan Inc.). $Trademark: M.D. Forte II@’(Allergan Inc.). *Trademark: Eldoquin Forte@’ (ICN Pharmaceuticals, Inc., Costa Mesa, California). “Trademark Shade@ UVAGuardTM SPF 15 (Schering Corporation, Kenilworth, New Jersey).
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the study medication were surveyed at weeks 12 and 24. All patients completed an exit form at week 24.
Outcome Measures The physician-rated efficacy variables were: pigmentary intensity (on a scale from 0 = none to 5 = severe); disease severity (from 0 = none to 8 = severe); overall global improvement (from 0 = worse to 8 = completely cleared); lesion area (from 0 = none to 5 = severe); and cutaneous signs and symptoms-dryness, erythema, oiliness, peeling, burning, and stinging (from 0 = none to 5 = severe). Patients rated the severity of skin dryness, redness, oiliness, peeling, burning, itching, pain, and hyperpigmentation on a scale from 0 = none to 4 = severe. They also rated the effect of their skin condition on their attractiveness, self-confidence, comfort in social situations, satisfaction with their appearance, comfort in a physical relationship, embarrassment, and performance at work or school on a scale from 0 = not at all to 6 = very much. Patients were also surveyed for their impressions of the efficacy and cosmetic characteristics of the study medication.
Statistical Analysis Statistical significance was set at 0.05 (two-tailed test) for all comparisons between treatment groups. Categorical variables (eg, symptoms, signs, overall disease severity, lesion area, pigment intensity, and patient evaluations) were summarized using descriptive statistics (ie, sample size, mean, standard deviation, and frequency counts) and were analyzed using Wilcoxon rank sum tests. Continuous variables (eg, age and chromometer read-
L.S. KAKITA AND N.J. LOWE
mentation, and had melasma. The majority also had a skin phototype of III or greater. There were no significant between-group differences in any demographic variables. Patient demographics are summarized in Table I. Ninety-four percent (29) of 31 patients in the azelaic/glycolic acid group and 88% (30) of 34 patients in the hydroquinone group completed the study. No patients were terminated because of adverse events or lack of efficacy. Patient disposition is summarized in Table II.
were summarized using descriptive statistics (ie, sample size, mean, standard deviation, minimum, and maximum) and were analyzed using analysis of variance. ings)
RESULTS Patient Characteristics and Disposition A total of 65 adult patients (5 males, 60 females) were enrolled in the study. The majority of patients in both groups were white, had mixed dermal/epidermal pig-
Table I. Demographic
characteristics
of patients (N = 65).
Azelaic/Glycolic (n = 31) Mean age (y) Sex Male Female Race Black White Hispanic Asian Other Missing data Pigmentation type Dermal Epidermal Mixed Skin phototype II III IV V Disorder Drug-induced Idiopathic Melasma Postinflammatory
Acid
Hydroquinone (n = 34)
48
41
2 29
3 31
2 12 8 7 1 1
1 20 5 5 2 1
1 8 22
2 9 23
3 18 9 1
13 12 8 1
2 6 19 4
0 5 25 4
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Table II. Patient disposition
(N = 65). Azelaic/Glycolic Acid
Hydroquinone
29
30
Discontinued Lost to follow-up Missed visits Protocol violation Personal reasons
5 0 1 1 3
5 1 0 3 1
Other*
1
0
Completed the study
*No exit form was completed;
Physician Assessment:
reason for discontinuation
Effiacy
and
safety After 24 weeks of treatment, both azelaic/glycolic acid and hydroquinone were effective in decreasing pigmentary intensity, as evidenced by patient photographs (Figure 1). Mean physician-rated pigmentary intensity at baseline was approximately 3.0 (moderate) in both groups, decreasing to 2.4 (mild-to-moderate) in the azelaic/glycolic acid group and 2.3 (mildto-moderate) in the hydroquinone group at week 24 (Figure 2). There were similar decreases in physician-rated overall disease severity with both treatments; mean scores at baseline were above moderate for both groups (azelaic/glycolic acid = 4.6; hydroquinone = 4.9) and had decreased to mild-to-moderate in both groups (azelaic/glycolic acid = 3.4; hydroquinone = 3.5) by week 24 (Figure 3). Overall global improvement scores increased in both groups throughout the study; by week 24, there was a mean improvement in hyperpigmentation of approximately 25% in both groups -(Figure 4).
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or termination
was listed as unknown
Lesion area decreased in both groups from moderate (covering approximately 33% of the face) at baseline to mild-tomoderate (covering approximately 25% of the face) by week 24. Azelaic/glycolic acid and hydroquinone were associated with similar degrees of dryness (Figure 5), erythema, and oiliness. Mean scores for all three variables were
Patient Assessment As rated by the patients, mean scores for dryness, redness, oiliness, and burning were below mild throughout the treatment period, whereas scores for peeling, itching, and pain were
L.S. KAKITAAND NJ. LOWE
Figure I
Patient photos (A) before azelaic/glycolic acid treatment; (B) after 24 weeks of azelaic/glycolic acid treatment; (C) before hydroquinone treatment; and (D) after 24 weeks of hydroquinone treatment.
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Marked (4)
cc1I 0 Hydroquinone
Moderate (3)
$ f z
Mild (2)
E E .F a
Trace (1)
None (0)
1
L
Baseline
Week 8
Week 16
Week 24
Figure 2. Pigmentary intensity was rated on a scale from 0 = none to 5 = severe. Azelaic/glycolic acid and hydroquinone produced equivalent reductions in pigmentary intensity scores (mean + SEM) by week 24. There were no significant between-group differences. Marked (6)
Moderate (4) .s
i
I ._ n
Mild (2)
None (0)
IrI
1
Baseline
n Azelaidglycolic acid 0 Hydroquinone
L
Week 8
Week 16
-i
Week 24
Figure 3. Disease severity was rated on a scale from 0 = none to 8 = severe. Azelaic/glycolic acid and hydroquinone produced equivalent reductions in disease severity scores (mean + SEM) by week 24. There were no significant between-group differences.
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L.S. KAKITAAND N.J. LOWE
~50% Improvement
n Azelaicz’glycolicacid 0 Hydroquinone
-25% Improvement
I
Week 0
Week 16
I
~10% Improvement
-
No Improvement
Week 24
worse to 8 = comFigure 4. Overall global improvement was rated on a scale from 0 pletely cleared. Azelaic/glycolic acid and hydroquinone produced equivalent overall improvement scores (mean + SEM) by week 24. There were no significant between-group differences. Severe (5)
n Azelaic/glycolicacid 0 Hydroquinone
Marked (4)
Moderate (3)
: Mild(2)
Trace (1)
I
None (0) Week 0
Week 16
(
Week 24
Figure 5. Skin dryness was rated on a scale from 0 = none to 5 = severe. Dryness scores (mean + SEM) were ~1 (trace) in both treatment groups at week 8 and decreased as the study continued. There were no significant differences between the azelaic/glycolic acid and hydroquinone groups.
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severe (5) -
nAzelaidglycolic
g!
acid
0 Hydroquinone
Marked (4) _
Moderate (3) _
8 Cn F *=
t
tz
Mild (2) 1 Trace (I) 1
t I
*
None (0) Week 0
Week 16
Week 24
Figure 6. Skin burning was rated on a scale from 0 = none to 5 = severe. Although buming scores (mean + SEM) were cl (trace) in both groups throughout the study, azelaic/glycolic acid produced significantly greater burning than hydroquinone at weeks 8 (P = 0.002*), 16 (P < O.OOlt), and 24 (P = 0.018$).
the treatment period. There was slightly but significantly more patient-reported dryness (week 24; P = 0.011) and burning (weeks 0, 12, and 24; P I 0.027) in the azelaic/glycolic acid group than in the hydroquinone group. Mean scores for hyperpigmentation severity were never above moderate at any time point in either group; however, patient-rated severity of hyperpigmentation was slightly but significantly greater in the azelaic/glycolic acid group (week 12; P = 0.046). Patients in both groups had similar opinions about the impact their hyperpigmentation had on their lifestyle and selfesteem and the effect of their treatment on their skin. Patient responses were similar in both groups for the following variables: attractiveness, satisfaction with appearance, embarrassment, and degree to which hyperpigmentation negatively affected
performance at work or school. Although most patient responses were equivalent, at weeks 12 and 24 there were slight but significant differences favoring the hydroquinone group in self-confidence, comfort in social situations, and comfort in a physical relationship (P < 0.035).
DISCUSSION The present study demonstrated that 24week treatment with the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion was as effective as hydroquinone 4% cream-the current standard of care for hyperpigmentary disorders-for decreasing pigmentary intensity, overall disease severity, and lesion area in darker-skinned patients with melasma or another form of facial hyperpigmentation.
L.S. KAKITAAND
N.J. LOWE
These findings build on earlier studies demonstrating that azelaic acid, used alone, was significantly more effective than hydroquinone 2% cream and comparable in efficacy to hydroquinone 4% cream in reducing pigmentary intensity, decreasing lesion size, and affecting overall response in darker-skinned patients with melasma.3*4 In addition, our results show that the addition of glycolic acid 15% or 20% lotion has no detrimental effect on the response of hyperpigmentary disorders to azelaic acid treatment. However, these results do not resolve the question of how, or if, the addition of glycolic acid treatment to a depigmenting regimen improves patient outcomes. When used alone, azelaic acid 20% cream has clear safety advantages over hydroquinone 2% or 4% cream. It does not produce the ochronosis or undesirable lightening of normally pigmented skin that is sometimes associated with hydroquinone1T2 and produces a similarly low level of transient, mild local irritation.3*4 However, the present study demonstrates that the addition of glycolic acid to azelaic acid treatment can produce slightly more local irritation than is observed with hydroquinone 4% treatment. Because this combination has only an equivalent lightening effect to hydroquinone 4% or, by inference, azelaic acid used alone, glycolic acid should be added only if the patient has other skin problems or places a high priority on cosmetic concerns that lead the physician to believe glycolic acid might be beneficial. The most suitable candidates for azelaic/glycolic acid treatment are patients whose skin is not overly prone to irritation who have a combination of hyperpigmentation and other conditions, such as acne vulgaris or rosacea, and those for
whom cosmetic considerations are a high priority. Both azelaic acid and glycolic acid can be of benefit in the treatment of several dermatologic conditions. Azelaic acid has been shown to be effective in the treatment of acne vulgaris and rosacea*O as well as hyperpigmentation.3*4 Various types of glycolic acid treatment are under investigation for acne, l1 hyperpigmentation,7,8 and cosmetic effects.t2J3
CONCLUSIONS Our results demonstrate that the combination of azelaic acid 20% cream and glycolic acid 15% or 20% lotion is as effective as hydroquinone 4% cream for the treatment of hyperpigmentation in darkerskinned patients, with only a slightly higher rate of mild local irritation. These findings build on earlier studies demonstrating the efficacy of azelaic acid monotherapy in the treatment of hyperpigmentation and suggest that glycolic acid may be an appropriate adjunct to azelaic acid therapy in some patients. This combination may be particularly beneficial for patients whose hyperpigmentation is accompanied by other dermatologic conditions (eg, acne vulgaris or rosacea) or for whom cosmetic concerns are a high priority.
ACKNOWLEDGMENT This research was supported by a grant from Allergan Inc., Irvine, California.
Address correspondence to: Lenore S. Kakita, MD, 18 18 Verdugo Blvd., Glendale, CA 9 1208.
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REFERENCES 1. Frenk E. Treatment of melasma with depigmenting agents. In: Melasma: New Approaches to Treatment. London: Martin Dunitz Ltd.; 19959-U. 2. Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Dermatol. 1995;131:1453-1457. 3. Verallo-Rowe11 WM, Sioson-de 10s Reyes G. South Asian experience with azelaic acid in melasma. Med Prog J. 1993;20 (Suppl):26-30. 4. Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Pharmacol Thel: 1991; 30:893-895. 5. Fitton A, Goa KL. Azelaic acid: A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary disorders. Drugs. 199 1;4 1: 780-791.
8. Bums RL, Prevost-Blank PL, Lawry MA, et al. Glycolic acid peels for postinflammatory hyperpigmentation in black patients. A comparative study. Dermatol Surg. 1997;23:171-174. 9 Graupe K, Cunliffe WJ, Gollnick HPM, Zaumseil R-P Efficacy and safety of topical azelaic acid (20 percent cream): An overview of results from European clinical trials and experimental reports. Cutis. 1996;57(Suppl 1):20-35. 10 Carmichael AJ, Marks R, Graupe KA, Zaumseil Rp. Topical azelaic acid in the treatment of rosacea. J Dermatol Treat. 1993;4(Suppl l):S19-S22. 11. Wang CM, Huang CL, Hu CT, Chan HL. The effect of glycolic acid on the treatment of acne in Asian skin. Dermatol Surg. 1997;23:23-29.
6. Giannotti B, Melli MC. Current approaches to tbe treatment of melasma. Clin Drug Invest. 1995;1O(Suppl 2):57-64.
12 Stiller MJ, Bartolone J, Stem R, et al. Topical 8% glycolic acid and 8% L-lactic acid creams for the treatment of photodamaged skin. A double-blind vehicle-controlled clinical trial. Arch Dernmtol. 1996;132: 63 l-636.
7. Lim JT, Tham SN. Glycolic acid peels in the treatment of melasma among Asian women. Dermatol Surg. 1997;23:177-179.
13 Van Scott EJ, Yu RJ. Alpha hydroxy acids in skin care. Clin Plast Surg. 1996;23: 49-56.
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