Mt. sinai sept/oct 4 (page 279)

The Modern Age of Acne Therapy:
A Review of Current Treatment Options
Abstract
This review of current acne treatments begins with the crucial discovery in 1979 of isotretinoin treat-ment for nodulocystic acne. This drug’s approval in 1982 revolutionized therapy, since it was the firstoral acne-specific drug, and it provided prolonged remissions. In addition, it may prevent the emer-gence of resistant bacteria, a problem linked to the traditional use of antibiotics for acne.
Patients who are not candidates for isotretinoin therapy may benefit from one of the other drugs or drug combinations reviewed, including the third-generation topical retinoids adapalene and
tazarotene, retinoic acid reformulated in new vehicles, azelaic acid, and topical antibiotics. Proper
selection and education of patients are essential, since serious consequences may result from poorly
monitored use of antibiotics and retinoids.
Key Words: Acne, review, therapy, treatment, isotretinoin, retinoid, antibiotic, azelaic acid, adapalene,
tazarotene, benzoyl peroxide.
Introduction
Acne: Definition, Demographics and
Pathogenesis
THE PERIOD 1945–1995 has been named the“Golden Age of Treatment” in dermatology by Acne is a chronic inflammatory condition of Thomas B. Fitzpatrick (1). These fifty years the pilosebaceous unit. The comedo, a plug of saw a great number of therapeutic discoveries, sebum and keratin lodged in the follicular duct, ranging from penicillin for syphilis to topical is its primary lesion. Comedones appear clini- corticosteroids for psoriasis. In the field of cally as blackheads and whiteheads. When a acne treatment, the single most important event closed comedo or microcomedo causes the fol- probably was the 1979 report of prolonged re- licular wall to rupture, an inflammatory reac- missions of cystic acne attributable to 13-cis- tion ensues, resulting in clinically evident papules, pustules, nodules and cysts. The term In 1982, the Food and Drug Administration “cyst” is a misnomer that refers to a pus-filled (FDA) approved the use of isotretinoin for acne lesion greater than 5 mm in diameter, in treating recalcitrant nodulocystic acne. Unlike which the wall is composed of inflammatory traditional antibiotic treatment, isotretinoin’s sole approved indication is cystic acne. Its ef- The typical clinical picture of acne is an fect lasts months to years after a 20-week eruption located on the face, with the upper course, a claim that no other acne medication trunk often being affected as well. Adolescents can match. Also, its use does not promote an- and young adults are most often afflicted, with tibiotic-resistant bacteria, an important concern estimates of 85 – 100% of those aged 12 – 24 being affected, at least intermittently, during Since isotretinoin is reserved specifically those years (4, 5). Within the adolescent group, for severe acne, it has not made other acne the frequency and severity of acne, as well as treatments obsolete. Yet it appears to provide an its tendency toward scarring, is greater in males acne treatment that is comfortable, safe, effec- than in females. However, the persistence of acne into adulthood is more common in females(6).
Contrary to popular belief, hygiene plays at most a minor role in the etiology of acne, and Assistant Clinical Professor of Dermatology, The Mount Sinai diet appears to have little or no influence.
Address all correspondence to S. Bershad, 28 South Moun- However, true acne can be exacerbated by ex- ternal factors such as friction (“acne mechan- THE MOUNT SINAI JOURNAL OF MEDICINE Vol. 68 Nos. 4 & 5 September/October 2001 September/October 2001
ica”) (7) and pore-clogging cosmetics (“acne tions in this group include topical tretinoin, cosmetica”) (8). The etiology of acne lies in a adapalene and tazarotene, as well as oral confluence of several factors which together isotretinoin. Considerable current research is produce clinical acne. Research suggests that genetic control, along with the stimulation of Tretinoin preceded the others in this class androgenic hormones, is responsible for abnor- by a decade or more, becoming available as a mal sebum secretion (9, 10). The latter, to- topical acne treatment in the United States in gether with faulty corneocyte occlusion of the 1971. Tretinoin exerts its effects by increasing pilosebaceous orifice, produces comedonal the turnover of follicular epithelial cells, thus acne (11). The anaerobic diphtheroid Propioni- normalizing keratinization (13). This leads to bacterium acnes is believed to play a pivotal the extrusion of comedones and also accelerates role in converting comedonal acne to inflamma- tory acne. Previously P. acnes was thought to incite inflammation by breaking down neutral Early formulations of tretinoin tended to sebaceous lipids into free fatty acids, but newer cause excessive skin irritation, due to the high research favors a direct role for P. acnes in neu- concentration of the active ingredient in a pen- etrating hydroalcoholic vehicle. Now availableare a number of formulations which utilize a Treatment of Acne
lower tretinoin concentration (0.025%) andcream vehicles which are designed to be more Today’s therapeutic modalities for acne are emollient and less penetrating. Two of the aimed at one or more of its pathogenic precipi- newest topical tretinoin products are based on tants, which include androgenic hormonal stimu- slow-release delivery systems (15). One of lation, hypersecretion of sebum, faulty occlusion these contains tretinoin (0.025%) in a gel or of the follicular orifice, P. acnes colonization, cream base containing polyolprepolymer-2, a and inflammation. Combination therapy, there- large-polymer compound that delays absorption fore, is the usual approach, with isotretinoin of the active ingredient into epidermal cells.
treatment being the notable exception.
The second formulation designed to slow deliv-ery is a tretinoin (0.1%) gel, in which the active Comedonal Acne
ingredient is incorporated into microsponges,which are macroporous beads 10 – 25 microns principal manifestations of acne, there is no substitute for the immediate results achieved tretinoin in dermatology practice is often lim- with acne surgery, which is the manual extrac- ited by local skin irritation. In addition, the tion of impacted comedones, performed in the onset of improvement is relatively delayed and physician’s office. Most patients benefit by variable — one to three months is common having this procedure performed at 3 – 6 week (16). Some patients experience clinical wors- intervals until topical medications take effect.
ening after 2 – 4 weeks of treatment (17), when Patients should be discouraged from attempting the extrusion of comedones can elicit a pustular this at home, due to the risk of infection and the reaction. Tretinoin also increases sun sensitiv- potential for scarring due to excessive trauma to ity, necessitating regular sunblock use.
The most effective topical medications for matic retinoids, adapalene and tazarotene, may comedonal acne are the so-called keratolytic provide therapeutic advantages over tretinoin.
agents, which target faulty occlusion of the fol- These new agents have molecular configura- tions that are selective for nuclear retinoic acid retinoids, azelaic acid, and the alpha-hydroxy receptors. It is theorized that these receptors, when activated, affect keratinocyte differentia-tion and block inflammation (17 – 19).
Retinoids
Adapalene is a synthetic naphthoic acid de- rivative. Its mechanism of action is twofold: Topical Vitamin A acid (tretinoin, all-trans- first, it inhibits comedo formation through its retinoic acid) and its synthetic analogs, termed ability to bind to retinoic acid receptors and retinoids, comprise the most potent group of modulate cell differentiation; and second, it currently available keratolytic agents. Medica- possesses direct anti-inflammatory activity Vol. 68 Nos. 4 & 5
(20). Adapalene is available in gel, solution Figure) (23). There was no control group in and cream formulations containing 0.1% active this early study, but subsequent vehicle-con- trolled clinical trials support the efficacy of this In a multicenter study of more than 300 pa- tients, adapalene (0.1% gel) was compared totretinoin (0.025% gel) for efficacy and side ef- Azelaic Acid
fects. Adapalene produced significantly greaterlesion reduction than tretinoin and caused less Azelaic acid is a naturally occurring dicar- boxylic acid. Available in a 20% cream formu- Adapalene shares with other retinoids the lation, it has been demonstrated to prevent fol- adverse effect, in certain patients, of an inflam- licular hyperkeratosis, thereby inhibiting come- matory acne flare toward the end of the first dogenesis (14). It also has antimicrobial activ- month of therapy. This risk can be reduced by ity, being bacteriostatic against P. acnes and introducing adapalene or tretinoin gradually.
Staphylococcus epidermidis (24). Furthermore, The retinoid is generally applied 2 – 3 times per it does not appear to induce resistant P. acnes week initially, and increasing to nightly use over a period of about 2 months. Oral or topi- Clinically, azelaic acid 20% cream has been cal antibiotics are often combined with retinoid shown to have efficacy comparable to other therapy, due to their ability to inhibit the in- topical medications (25). It is associated with a low rate of adverse effects, the most common Tazarotene, a synthetic acetylenic retinoid, being local itching and burning sensations.
was introduced in 1997 as a gel to treat psoria-sis. After topical application, it is rapidly con- Alpha-Hydroxy Acids
verted to its active metabolite, tazarotenic acid.
Two large clinical studies found tazarotene 0.1% gel to be more effective than vehicle in hydroxy group on their second (alpha) carbon.
the treatment of acne (22), but erythema and ir- These occur naturally in sugar cane, fruits, and milk products. The most useful AHAs in der- tazarotene cream is now available as well. A matological practice are glycolic acid, lactic new method of acne treatment, called short- acid, and gluconic acid (gluconolactone).
contact tazarotene therapy, has been developed by the author. This method involves applica- AHAs facilitate desquamation of the stratum tions once or twice daily of tazarotene (0.1%) corneum (26). This finding has led to the clin- gel for 2 – 5 minutes per application, followed ical use of AHAs in the treatment of comedonal by thorough rinsing with warm water. In a pilot acne. Because these compounds are not patent- study of this method, 20 patients with facial protected drugs under strict FDA control, large acne applied open-label tazarotene 0.1% gel well-controlled trials are lacking. However, using the short-contact method. Fourteen pa- there is evidence suggesting acne improvement tients (70%) achieved at least 50% reduction in with AHAs, especially glycolic acid and glu- acne lesions within 12 weeks of therapy (see Figure. (A) A 17-year-old patient, previously untreated for acne. (B) After 7 weeks of short- contact tazarotene therapy
(23).
September/October 2001
Topical Antibiotics
ment consist mainly of 5 – 10% glycolic acid inwater-based lotions or hydroalcoholic solu- tions. Peeling agents containing 30 – 50% gly- erythromycin have been available as hydroal- colic acid may be used in the office setting coholic solutions for about two decades.
Newer formulations intended to reduce skin ir- ritation include hydrophilic gels and lotions.
their therapeutic usefulness in part due to the The 1990s have seen an increase in the popu- lower likelihood of causing skin irritation.
larity of the pledget application system, which is often more convenient than the traditional found their way into the treatment of mild acne, particularly in pre-adolescents and colonization of P. acnes, and they may also pos-sess direct anti-inflammatory effects via sup- Inflammatory Acne
pression of neutrophil chemotaxis (36, 37).
A clinical study showed that two different topical solutions, one containing 1.5% ery- acne is the comedo, a majority of acne patients thromycin and the other containing 1% clin- can benefit by using keratolytic agents. In ad- damycin, were therapeutically equivalent for dition, when the predominant lesion type is the acne (37). Further, in a double-blind clinical inflammatory papule or pustule, the traditional trial, therapy with clindamycin 1% solution was mainstays of treatment are topical and systemic found to be as effective as oral tetracycline 250 “Combination therapy” for acne is gener- Two fixed combination gels, the first con- ally defined as ongoing treatment with two or taining erythromycin 3% with benzoyl peroxide more agents applied at different times. Com- 5% and the second containing clindamycin 1% monly, a topical antibiotic is applied in the with benzoyl peroxide 5%, have been found to morning and a keratolytic agent is applied at be superior to their individual components for bedtime. Because antibiotic-resistant P. acnes acne treatment (32, 39, 40). An added advan- and staphylococci are well documented (29, tage of these combinations may be a reduction 30), a better regimen might be twice-daily an- in drug-resistant P. acnes (29). Erythromycin is tibiotic followed by a keratolytic agent at bed- also available as a 2% solution with zinc, a sup- time. If two agents are applied at the same pressor of inflammation. A recent study sug- time, care must be taken to ensure that the two gests that zinc may act mainly as an inhibitor to are compatible and that they are not thereby di- penetration, leaving the antibiotic on the skin luted to ineffective strengths. For example, surface longer (41). The clinical correlate of tretinoin is inactivated by benzoyl peroxide, while adapalene and tazarotene are not.
Other topical antibiotics that are useful in acne treatment include metronidazole, elemen- Benzoyl Peroxide
tal sulfur and sulfur compounds. These may actmainly as direct inhibitors of inflammation; Benzoyl peroxide is a potent bactericidal they are generally considered to be more useful agent that is widely available in prescription in treating acne rosacea, a condition with early and non-prescription acne products, including inflammation, than true acne, which starts with gels, lotions and cleansers. In concentrations of 2.5 – 10%, it effectively reduces P. acnes andfree fatty acids in sebum (31). There is evi- Systemic Antibiotics
dence that it reduces comedones (14, 32), in ad-dition to improving inflammatory acne (33).
There has been little change in systemic an- tibiotic therapy for acne in recent years. Oral and bleaching of the skin and fabrics. Occa- drugs are indicated for moderate-to-severe sionally, true contact allergy occurs. Recent forms of acne, particularly those with a poten- concerns that benzoyl peroxide enhances car- cinogenesis in laboratory animals (34) are Effective systemic therapies for acne in- thought to be of little relevance to humans by clude: tetracycline and its relatives minocycline and doxycycline; erythromycin; azithromycin; Vol. 68 Nos. 4 & 5
and trimethoprim alone or in combination with nation has low intrinsic androgenicity and min- sulfamethoxazole (42). Traditionally, systemic antibiotic treatment has been initiated in the modest-to-low-dose range, which is then ta- during treatment with norgestimate/ethinyl estra- pered over a period of weeks to months. It may diol might take 3 – 4 months to become apparent be time to reconsider this strategy, in recogni- (49). The principal adverse effect noted in this tion of the increase in antibiotic-resistant bacte- study was nausea. As expected, OC treatment ria, which occurs not only in acne patients, but was protective against pregnancy and appeared also in their household contacts (29). A sug- to alleviate dysmenorrhea, which was more com- gested alternative is full-dose antibiotic treat- mon in the control group. The chief limitation of ment for 2 – 3 weeks, given at several-month in- anti-androgen therapy for acne is the obvious one: it cannot be used with male patients.
An alternative drug for treating hormonal fects, the most notable in this category being: acne in women is spironolactone (51), which phototoxicity from the tetracycline group, espe- can be combined with OC therapy. Other anti- cially doxycycline; vertigo-like dizziness from androgenic therapies that may prove useful in minocycline; gastrointestinal distress from ery- the future include cyproterone acetate, flu- tamide, finasteride, and gonadotropin-releasing Stephens-Johnson syndrome, from trimetho- prim-sulfamethoxazole. In addition, all oral an-tibiotics predispose to Candida infections, par- Nodulocystic Acne
A recent study of the safety of the tetracy- All of the treatments mentioned previously cline-related antibiotics showed minocycline to can be used with some success in severe, nodu- have a greater tendency than tetracycline and locystic acne. Particularly useful are oral an- doxycycline to cause rare adverse effects, in- tibiotics combined with topical keratolytic cluding hypersensitivity reactions, serum-sick- agents, as well as hormonal therapy in women.
ness-like reactions, drug-induced lupus, and While oral and intralesional corticosteroids are single organ failure (43). While minocycline is useful as temporary measures to help control generally considered safe for long-term use severe outbreaks (54), chronic corticosteroid (44), these rare but serious reactions, as well as its higher cost, must be taken into account.
Isotretinoin
Hormonal Therapy
Numerous studies have shown a direct cor- isotretinoin (13-cis-retinoic acid) remains the relation between serum androgen levels and treatment of choice for recalcitrant nodulocystic acne (45, 46). Androgens increase sebaceous acne and the more severe variant, acne conglo- gland activity and may also cause hyperkerato- bata (55). Isotretinoin causes de-differentiation sis of the pilosebaceous gland (47). It has also of the sebaceous gland, suppressing sebum pro- been hypothesized that sebaceous glands of duction to pre-adolescent levels (56). As with acne-prone individuals are hyperresponsive to other retinoids, it also promotes shedding of keratinocytes. In addition, colonization with P. acnes subsides, due to disappearance of sebum.
successfully in acne treatment for decades, this Isotretinoin’s clinical effect on acne is dra- mode of therapy for female patients made a re- matic, often reducing lesion counts by 90% or cent breakthrough. For the first time, in 1997, more within three months. Its results are pro- the FDA approved a triphasic, combination oral longed, with one 20-week course producing sig- contraceptive (OC), which contains norgesti- nificant improvement for 3 years or longer in mate 0.215 mg and ethinyl estradiol 0.035 mg, to be used specifically for acne treatment. This The usual dosage range of isotretinoin is decision followed a large, multicenter study 0.5 – 2.0 mg/kg/day. Studies have shown doses which showed that this OC reduced acne lesion as low as 0.1 mg/kg/day to be effective, but counts by more than 50% in female subjects, acne relapse rates are high, approaching 50%, compared with lesion reductions of about 26% at this dose (58). As a predictor of the final out- in controls (49). The progestin in this combi- come, researchers have observed that the 20- September/October 2001
week cumulative dose is more important than Patients on isotretinoin may experience a the daily dose. In 1997, a consensus regarding temporary flare-up of acne after 2 – 4 weeks of isotretinoin dosage was reached among interna- therapy. As is the case with topical retinoids, tional acne experts (59). Their guidelines rec- gradual introduction of the drug, along with pa- ommend a cumulative dose of 120 mg per kilo- tience, usually leads to a favorable outcome. A gram of body weight over a single 20-week rare but troubling event that may occur during course of therapy, using the original oral formu- isotretinoin therapy is the onset of acne fulmi- lation of isotretinoin. Currently, an ultrami- nans (65). This condition is a painful, severe cronized form of oral isotretinoin is being intro- exacerbation of cystic acne with exuberant duced for the purpose of more efficient absorp- granulation tissue and scarring. Acne fulmi- tion of the active ingredient. It is unclear how nans can be managed with variable success by this new product may impact dosing guidelines.
temporarily decreasing the isotretinoin dose Because isotretinoin has a half-life of 10 – 20 and treating concurrently with a short course of hours, 24-hour dosing intervals are adequate, but systemic corticosteroid (66). Dapsone may also twice-daily dosing may reduce side effects.
Tetracycline derivatives and vitamin prepa- course of isotretinoin, practitioners who follow rations containing vitamin A should be avoided cumulative dosing guidelines may choose to vary during isotretinoin therapy, since these medica- the length of treatment slightly. FDA guidelines, tions may increase the risk of pseudotumor however, still include an 8-week drug-free period cerebri (44), a rare side effect of isotretinoin.
isotretinoin are its teratogenicity and its effect sense supports the concept of “pulse-dosing” on serum lipids. The former cannot be overem- with isotretinoin. It is likely that the risk of ter- phasized: the risk of birth defects mandates atogenicity, isotretinoin’s most serious side ef- careful patient selection, contraceptive counsel- fect (60), would increase when drug treatment ing, and strict monitoring of women who may is prolonged, interrupted or inadequately moni- become pregnant. Isotretinoin is not muta- tored. In a recent study of intermittent dosing genic, and federal guidelines suggest that preg- with isotretinoin for one week each month over nancy is safe one month after drug cessation.
6 months, resolution of acne was impressive, about 90%, but the 12-month relapse rate was isotretinoin therapy due to its teratogenic po- tential. Two negative pregnancy tests are now Adverse effects from isotretinoin are seen required prior to initiation of isotretinoin ther- in virtually 100% of its users but generally sub- apy, and monthly testing is mandatory for sexu- side one to three weeks after cessation of ther- ally active females during treatment.
Serum lipid and lipoprotein alterations are branes, and chapped lips (retinoid cheilitis) are common, with elevation of triglycerides being universal at therapeutic doses. Patches of reported most frequently (67). Mean triglyc- eczema (retinoid dermatitis) occur commonly, eride levels have been shown to increase by typically on the dorsal hand and forearm.
about 50% within 2 – 3 months on the drug, and These complaints are managed with moisturiz- cholesterol by about 15%. Overweight patients ers, greasy topical corticosteroids, and dosage have an increased risk of isotretinoin-induced adjustment, if necessary. Skin fragility and sus- hypertriglyceridemia. Blood work, including ceptibility to sunburn are frequently reported.
fasting triglyceride and cholesterol levels, Dry eyes, nosebleeds, hair shedding, myalgias should be performed at baseline and at 2 – 4 week intervals during isotretinoin therapy (56).
Recently, several cases of psychological de- Isotretinoin has been linked with premature pression and even suicide have been reported closure of the epiphyses of long bones in labo- among patients taking isotretinoin (62). Para- ratory animals (63). For this reason, some doxically, previous studies had shown an im- physicians prefer to reserve its use for patients provement in well-being and self-esteem (63).
past their growth spurt. A baseline serum alka- Whether isotretinoin plays a causal role with re- line phosphatase level is often helpful to assess gard to these symptoms is unclear, as a recent the level of adolescent bone growth.
large, population-based study failed to show an increased risk of depression in isotretinoin isotretinoin treatment occurs in a significant users compared with other acne patients (64).
Vol. 68 Nos. 4 & 5
within three years (57). Patients at particular References
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Discussion and Summary
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September/October 2001
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