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The treatment of acne involves skillful use of medications, avoidance of provoking factors, physical evacuation of cysts and comedones, and in some cases intense emotional support. Therapy must be tailored to each case and must be adjusted regularly as condi-

Figure 4: Macrodistribution of acne vulgaris.

tions change. In general, grade I and mild grade II acne can be treated with topical regimens. Moderate to severe grade II and grade III disease usually requires systemic agents combined with topical medication.

General Measures

From the specific history, the treating practitioner should point out to patients any extrinsic factors that may be provoking their disease so that these can be modified or avoided.

Cosmetics: Patients should be advised to avoid greasy, oil-based cosmetics and should receive specific advice on what is allowed. We ask our patients to use a foundation that is labeled "oil-free" and recommend a loose or pressed-powder blush, but allow complete latitude in the choice of lipsticks and eye cosmetics. Recommended sunscreens are clear gel-based products with an SPF of at least 30. Caution patients to avoid face masks, toners, and astringents, as these products may interfere with the treatment regimen. It is best to warn patients that disease flaring within a few months of initiating a new cosmetic makes that product a suspected aggravating factor.

Cleansing should be done gently two or three times daily, and we emphasize that although good hygiene is important, excessive hygiene can have a negative effect. For oily-skinned patients, a mild glycerin-based acne bar, warm (not hot) water, and gentle cleansing without undue pressure in the morning and evening are effective. For patients with dry or sensitive skin, a lipid-free lotion cleanser (such as Cetaphil Cleansing Lotion®) used in the same gentle fashion is more satisfactory. Abradant cleansers are harsh and encourage scrubbing with excess pressure that can precipitate deeper, more scarring acne. These are to be avoided. Steam packs aggravate the disease.

Picking and manipulation of acne lesions should be discouraged. This subject can be a touchy area and must be approached cautiously after patient and practitioner have developed rapport. Some patients are aware of their habit, while others completely deny doing it. These latter patients often have deep-seated emotional reasons for the habit and may find direct discussion quite threatening.

Diet has no clearly demonstrable effect on acne. For patients who insist on dietary advice, simply recommend avoidance of any food the patient feels has a repeated adverse effect.

Regular rest ("beauty rest") is important. Patients who are "burning the candle at both ends" usually experience flare-ups that resolve without other measures when a normal schedule is resumed.

Acne Surgery

Manual removal of whiteheads and blackheads, and the gentle evacuation of inflammatory papules, pustules, and cysts is an established and integral part of acne treatment. Properly done on a regular schedule, this procedure speeds recovery and prevents scarring. Although there are occasional patients without demonstrable comedo formation, most patients need active removal to achieve a satisfactory result. Several styles of comedo extractors are available. This procedure should be done only by a skilled operator, preferably the treating practitioner. Allowing patients or family members to perform this procedure usually leads to increased scarring or less than optimal improvement.

Ultraviolet Light

Modest amounts of natural sunlight or artificial UVB therapy are beneficial in most cases. The benefit is mainly due to removal of comedones. Because of the long-term aging and carcinogenic effects, use of this modality should be limited and it should be reserved as an adjunct to the primary treatment program.

Intralesional Steroids

Deep nodules and cysts can be rapidly improved with intralesional injection of small amounts of triamcinolone acetonide diluted to a concentration of 2.5 to 5.0 mg/cc in physiologic saline. Injection is best done using a control syringe with a 30-gage needle. Care should be taken to keep the solution within the lesion to prevent atrophy of the adjacent skin. Used appropriately, these injections will rapidly resolve painful nodules and cysts and minimize permanent scarring. By limiting the total dose to 10 mg or less in any

1-month period, and restricting usage to times of absolute need, the risk of systemic side effects is negligible.

Topical Therapy

Topical antibiotics: During the past several decades, the safety and value of topical antibiotic therapy in mild, minimally inflammatory acne have been well established. These are seldom used as monotherapy, but are combined with a retinoid or a benzoyl peroxide preparation. Products that contain erythromycin or clindamycin are available in an array of solutions, lotions, pledgets, and gel bases in concentrations of 1 to 2%. The choice of base depends on the patient's degree of oiliness and acceptance. Gel bases and high-alcohol vehicles seem to suit oily-skinned patients. Patients with dry or sensitive skin prefer vehicles with some degree of lubrication and lower alcohol content. The feel of the product can greatly affect compliance. Combination products, with erythromycin or clindamycin and benzoyl peroxide all in one, are also available. Some of these require refrigeration, which diminishes their shelf life and patient compliance. Teenagers dislike having to run to the refrigerator to apply an ice-cold medication. Newer combination products avoid this problem.

A topical antibiotic preparation should be used for 6 to 8 weeks before judging its effectiveness. Instruct patients to apply these products once daily in the morning. They may be worn under makeup, and should be reapplied after showering, swimming, and the like. Antibiotics are applied alone at a different time than other topicals, such as retinoids or benzoyl peroxides, that are used at bedtime. Side effects and allergic reactions have been rare. If these products are applied to wet skin immediately after cleansing, transient stinging and irritation may occur. This can be avoided by simply waiting 5 to 10 minutes.

Rare reports of allergic sensitization to erythromycin and clindamycin are recorded, and there have been rare reports of pseudomembranous colitis with topical clindamycin. Some practitioners use systemic and topical antibiotics concurrently. This is a wasteful practice and with the demonstrated antagonism between erythromycin and clindamycin, it could be self-defeating. Topical antibiotics are less effective in the deeper, more inflammatory types of acne. Occasionally, however, topicals can be very beneficial in patients who, for one reason or another, refuse systemic treatment.

Azelaic acid in a 15% gel or 20% cream preparation is also available as an alternative to traditional topical antibiotics. This agent has an antibacterial effect, modest comedo-lytic activity, and may also speed the resolution of postinflammatory hyperpigmentation. It has more potential for irritation than traditional topical antimicrobials.

Topical benzoyl peroxide preparations: These products are commonly available in concentrations ranging from 2.5 to 10% in a variety of lotion, pledget, gel, and hydrogel bases. Benzoyl peroxide loosens comedones, has a separate antibacterial effect, and suppresses excessive oil secretion. Hydrogel preparations tend to be less irritating. Irritation, dryness, and visible peeling are not essential to achieve the beneficial effects. Initiate this type of topical as a night lotion in conjunction with systemic antibiotics or the morning application of a topical antibiotic. The strength and vehicle are chosen based on the patient's visible oiliness, history, and reactivity to any previously used topicals. For patients with large amounts of comedonal acne, add a topical retinoid later, instructing the patient to use the two products on alternate evenings.

Benzoyl peroxide will bleach clothing and bed linens if used in cavalier fashion. It is important to warn the patient about this. Also instruct the patient to wait 5 to 10 minutes after washing before application. Otherwise, stinging and burning may occur and irritancy may be increased. Contact allergy to benzoyl peroxide is fairly common and, once present, eliminates this medication from the armamentarium. If a reaction occurs, document whether the reaction is true hypersensitivity or just irritation so that this important topical is not needlessly lost. Many generic benzoyl peroxide products are available. If a generic product is prescribed, make certain the pharmacy is consistent with one generic. The efficacy and irritancy of these generic products varies markedly with the composition of the vehicle, and can produce inconsistent treatment results. Although there is little evidence that higher concentrations of benzoyl peroxide have increased theraputic effect, the more concentrated preparations help to supress the excessive oiliness that some acne victims find very distressing. It is for this reason these more concentrated preparations remain on the market.

Topical retinoids: Tretinoin (also known as trans-retinoic acid or vitamin A acid) has become a mainstay of topical acne treatment. Use of tretinoin requires skill and close monitoring. It is manufactured in four strengths and is available in three vehicles: (1) 0.025%generic cream, (2) 0.025% gel, and (3) Retin A Micro® which comes in 0.04 and 0.1% concentrations in an optimized, microsphere gel base, which greatly reduces irritating side effects while maintaining efficacy.

Skin irritation manifested by dryness, redness, and peeling is a common side effect, and the drug must be started carefully after proper patient instruction. Failure to do this or to properly monitor the early side effects will result in low patient compliance. After a period of use, the epidermis "hardens" to the medication and stronger concentrations and more frequent applications are tolerated. The microsphere gels are the least irritating, followed by the cream and then the gel vehicles.

A second problem with tretinoin is its tendency to rapidly release comedones to the surface, causing an apparent flare of more inflammatory acne. This is particularly discouraging in the early stages of treatment, when the patient is seeking signs of remission and has yet to establish a trusting relationship with the practitioner. Proper instruction, reassurance, and careful selection as to the timing of entry of this medication into the regimen will lead to better results and a more satisfied and compliant patient. A simple explanation that the flaring is a prelude to long-term improvement is reassuring, and tells the patient that the practitioner understands the medication.

Tretinoin is particularly useful in the treatment of comedonal (grade I) acne and papu-lopustular (grade II) disease. In cases that are essentially comedonal, introduce tretinoin into the initial regimen by using it on an alternate-evening basis with a benzoyl peroxide hydrogel. The benzoyl peroxide hydrogel helps to control excessive oiliness and the inflammatory flare that can occasionally follow introduction of tretinoin. Try to use the tretinoin microsphere gel vehicle because of the lower irritancy and greater choice of concentrations. Start low and increase the concentration of the product as hardening occurs.

In papulopustular (grade II) disease, tretinoin must be introduced more cautiously or significant inflammatory flaring can occur. Start these patients on a regimen of a systemic or topical antimicrobial combined with bedtime applications of a benzoyl peroxide hydro-gel. Once the inflammatory component of the acne settles, carefully introduce tretinoin, using a microsphere gel vehicle at what appears to be an appropriate strength. Alternate the tretinoin with the benzoyl peroxide product, or use it every third night in very sensitive cases. Concentration and frequency of application may then be gradually increased.

Tretinoin is generally ineffective in nodulocystic (grade III) acne unless there is a significant comedonal component. Even when comedones are present, the deep inflammatory component predominates and may be aggravated by tretinoin. Usage in nodulocystic disease should be very cautious and only after control of inflammation is achieved.

Adapalene is a topical retinoid introduced as an alternative to topical tretinoin. It is used and introduced in a similar fashion, but appears less irritating and less prone to cause early treatment flares than tretinoin. Adapalene is supplied as a 0.1% cream, gel, or solution. The cream is the least irritating and the solution the most. Unlike tretinoin, adapa-lene is not photosensitizing. Head-to-head comparative studies with tretinoin preparations are needed.

A third topical retinoid is tazarotene, which is marketed as a 0.05 and 0.1% cream or gel. This preparation tends to be more irritating than the other retinoids and carries a category X pregnancy warning. It is approved for mild to moderate acne.

Retinoids are teratogenic and fetotoxic in lower animals. Although there are no documented reports of problems to date, use during pregnancy and breastfeeding is not recommended. Tretinoin is also photosensitizing and has been reported to increase the tumerogenic effects of ultraviolet light in lower animals. For these reasons, patients should be instructed to wash the medication off before outdoor activities, avoid intense sun exposure, and wear a sunscreen with an SPF of 30 or greater on a daily basis. The generic tretinoin gel vehicle has been reported to be flammable. Warn patients about use around any open flame.

Other topicals: There also exists an extensive array of alternative proprietary and prescription topicals for acne. There are three in particular that may be useful.

In patients allergic to benzoyl peroxide or where heavy perspiration seems to be a factor, a prescription lotion of 6.25% aluminum chloride hexahydrate in 96% anhydrous ethyl alcohol (Xerac A-C®) can be quite effective. It is used as a night lotion, and comes with an applicator-topped bottle.

Extensive nodulocystic acne on the back and shoulders, and patients allergic to ben-zoyl peroxide, benefit from a lotion that contains 0.5% salicylic acid and 5% resorcin in a vehicle of 70% isopropanol. This inexpensive preparation can be easily compounded by the pharmacist and is simple and convenient to use.

Also effective as adjunctive therapy or monotherapy in mild cases is a clear prescription lotion of 10% sodium sulfacetamide (Klaron Lotion®). This may also be used in patients allergic to benzoyl peroxide, but must be avoided in patients with sulfonamide and sulfite sensitivity.

Systemic Therapy

Antibiotics: Tetracycline has been used since the mid-1950s for the treatment of inflammatory acne, and its efficacy and safety are well-established. Treatment is usually initiated at a dose of 250 mg QID and is tapered once adequate control is achieved. The main drawback to this medication is the frequency of dosing and adverse effect on its absorption by food, especially dairy products and iron. Single doses of 500 mg or daily dosing above 1 g/day have a high incidence of GI side effects. Photosensitivity can be a problem in sunny climates; however, this is uncommon and usually occurs only at maximal doses. Effectiveness of tetracycline or other antimicrobials should not be judged until 6 to 8 weeks after the start of treatment.

Erythromycin is also effective, and is usually administered in a divided starting dose of 500 to 1000 mg/day. It is more compatible with food, but has a greater potential for interaction with other medications (such as theophylline and some nonsedating antihista-mines). Erythromycin is not photosensitizing. It seems to cause about the same amount of GI intolerance as tetracycline. Like tetracycline, it has an established safety record with chronic administration. The starting dose depends on the quality and extent of the inflammatory component. Both drugs are inexpensive.

A third inexpensive oral agent, frequently overlooked but often effective, is ampicillin. This antimicrobial is usually well tolerated by patients who experience GI intolerance to tetracycline and erythromycin. Dosing should start at 500 to 1000 mg/day in a divided dose depending on inflammatory activity. Amoxicillin may be used in a similar fashion.

The three antibiotic agents described above are usually used for initial treatment of mild to moderate grade II acne and mild grade III disease. Severe grade II and moderate to severe grade III acne are best treated with either doxycycline or minocycline.

Doxycycline is moderately priced, has a convenient BID dosing schedule, and can be quite effective. Drawbacks include occasional GI distress and a fairly high incidence of photosensitivity. Efficacy seems to fall between tetracycline and minocycline. Initial dose is usually 100 mg BID. It is indicated in moderate to severe grade II acne.

Minocycline is distinctly more rapid in onset and more effective in severe grade II and grade III acne. Minocycline is also helpful in patients who are prone to vaginal moniliasis. In severe acne disease, it is initiated at a dose of 100 mg BID. In less severe cases, 100 mg/day is often effective and is an appropriate maintenance dose once control is achieved. Because of high cost, appropriate dosing is essential. In severe cases, however, the drug can be very cost-effective by reducing the frequency of follow-up and by minimizing the long-term sequelae of the disease. Photosensitivity can occur, but is quite rare. An annoying idiosyncratic side effect is vertigo, which may occur many months after the start of treatment. This rapidly reverses upon withdrawal of the medication, but recurs with readministration. Another rare side effect is reversible liver toxicity. Minocycline can be administered with food but should not be taken at the same time as iron or iron-containing vitamin preparations. GI intolerance is rare. An additional rare side effect is the precipitation of connective tissue disease (lupus and rheumatoid arthritis) in a small number of patients.

Other antimicrobials used for resistant acne include trimethoprim/sulfamethoxazole and amoxicillin/clavulanic acid preparations. These resistant cases should be referred for dermatologic follow-up.

For patients with extensive mild to moderate inflammatory acne who are prone to vaginal yeast infections or are otherwise concerned about long-term use of antibiotics, a subantimicrobial regimen has been reported effective consisting of doxycycline 20 mg BID. This dose does not appear to alter skin, oral, bowel, or vaginal flora.

Female patients of childbearing age should be warned to stop systemic treatment in the event of a pregnancy or when breast-feeding.

Isotretinoin (13-cis retinoic acid): Because of the high cost, the significant potential for side effects, the risk of severe developmental defects if used during pregnancy, and the temporary but annoying side effects during usage, the decision to use isotretinoin should be based on proper indications that are well established. In addition, it should be administered only to a committed and reliable patient. Isotretinoin is indicated in cases of severe nodulocystic acne that are unresponsive to conventional therapy. Treatment should be initiated at a dose of 1.0 mg/kg of body weight or slightly higher. Lower dosing schedules will produce an initial response, but have a much higher incidence of relapse. In general, the incidence of side effects is dose-related. Treatment should continue for 16 to 20 weeks. It is important to complete at least a 4-month course. Treatment failures are higher in patients who fail to achieve a cumulative dose of 120 mg/kg of body weight. Many cases clear during the treatment period; however, some cases continue to improve after the regimen is complete. If disease activity persists, a second course may be initiated after a 2-month hiatus.Many patients will have a total remission, while others will convert to acne that is readily responsive to more conventional measures. As more experience is gained with isotretinoin, it is apparent that late recurrences several years posttreatment may occur. Even these are usually mild compared to the original disease.

Other factors besides isotretinoin dosage that are associated with a high recurrence rate include the following:

1. Papulopustular (grade II acne) without nodules or cysts.

2. Female patients with microcystic acne and signs of endocrine disease (such as irregular or absent menses, obesity, or hirsutism).

3. Predominantly truncal acne of any type.

4. Female patients greater than 25 years of age.

When these factors are present, conventional therapy may be more effective, safer and more cost-effective. The most serious side effects include photosensitivity, alopecia (both temporary and permanent), severe birth defects, hyperglycemia and aggravation of existing diabetes, reversible episodes of inflammatory bowel disease, xerophthalmia and reduced night visual acuity that may be permanent, pseudotumor cerebri, muscle injury with enzyme elevations usually triggered by sustained vigorous physical strain, reversible chemical hepatitis, and cases of acute pancreatitis (with triglyceride elevations).

A great controversy has arisen regarding possible linkage of this drug to suicidal depression. At the present time available evidence favors no connection, but the press coverage and legislative hearings have created a charged atmosphere. Patients should be screened for a history of depression and use in those with a positive history is not recommended.

When initiating systemic isotretinoin, all other systemic acne medicines should be suspended (especially tetracycline derivatives and vitamin products containing vitamin A). Patients should be warned to expect dry skin, fissured lips, increased sun sensitivity, and occasional muscle cramps. Existing deep acne may exacerbate during the first 4 to 6 weeks of treatment. Emollient skin lotions and lip pomades should be encouraged. Regular use of a sunscreen with an SPF of at least 30 is recommended, and even with the sunscreen, caution should be exercised when in the sun. CBC, liver functions, and lipid levels should be monitored every 2 weeks for the first 6 weeks of therapy and compared to a baseline study.

Isotretinoin treatment should be avoided in patients who plan periods of sustained vigorous physical exercise.

Female patients should be warned about the high risk and severity of possible birth defects, and should practice an effective form of pregnancy prevention for at least 1 month before and after treatment. Practitioners who use isotretinoin should be familiar with and follow the manufacturer's stringent guidelines in regard to pregnancy prevention. A pregnancy test prior to beginning treatment is essential.

Patients on isotretinoin should be warned to promptly report the following symptoms: visual changes, abdominal pain, rectal bleeding, and diarrhea. Diabetics should report any consistent change in blood sugar levels. Contact lens users should suspend or limit the use of those appliances. Blood donors should not donate during and for 1 month after completing treatment.

Isotretinoin is a marvelous medication for a group of acne victims for whom we once had little to offer. Use of this drug involves an in-depth familiarity with the disease process and the medication. The decision to proceed carries a heavy burden of responsibility for both physician and patient.

Systemic steroids: Occasionally patients present with nodulocystic acne that is so severe and extensive that isotretinoin is initially contraindicated. These cases must be initially handled with a combination of traditional treatment and moderate to high doses of oral prednisone. These patients should be promptly referred to a dermatologic consultant.

Emotional Support

Emotional support may be a major factor in the successful treatment of acne, and is especially important in the early stages when significant clearing is not yet evident. Patients who pick or manipulate their lesions need constant gentle prodding and support. The severity of the physical disease is not a measure of the emotional impact on the victim.

Scarring

Once the disease process comes under control, the patient's attention turns to the injury that has occurred. Most patients are anxious and prematurely pessimistic in this regard. Advise them that absolute control is the first essential step. Reassure them that much of what they see will soften or disappear, and that this process will continue for up to a year after good control has been achieved. If significant scarring remains at that point, a dermatologic consultation is indicated.

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