Systemic Treatment

Oral Antibiotics

Oral antibiotics are indicated for several groups of patients with inflammatory acne (table 3) [33, 38]. They include tetracyclines (tetracyclines, doxycycline, minocy-cline), erythromycin, clindamycin, and cotrimoxazole (table 4). These agents improve inflammatory acne by inhibiting the growth of P. acnes; tetracyclines and erythromy-cin have additional anti-inflammatory properties.

Tetracyclines of the first generation (tetracycline, oxy-tetracycline and tetracycline chloride) are the most commonly prescribed oral antibiotics for acne. They are used as a first-line agent because of their efficacy and low cost, although they have generated high rates of bacterial resistance. A 6-week treatment decreases the number of inflammatory lesions by approximately 50%. They are usually administered at a dose of 1 g/day (500 mg twice daily) over several months and after marked clinical improvement the dose can be reduced to 500 mg/day. Because their absorption is inhibited in the presence of food and dairy products, the drug must be taken preferably on an empty stomach one hour before meals with water for an optimal absorption.

Alternatively, tetracyclines of the second generation, namely doxycycline (initial dose of 100-200 mg/day with

Fig. 1. Mild acne papulopustulosa in a 24-year-old male patient before (left) and after a 6-month treatment with doxycycline 2 x 100 mg/day and topical tretinoin 0.1% (right).

Fig. 1. Mild acne papulopustulosa in a 24-year-old male patient before (left) and after a 6-month treatment with doxycycline 2 x 100 mg/day and topical tretinoin 0.1% (right).

Doxycycline Before And After Acne

Table 4. Oral antibiotics used in acne treatment

Antibiotic Usual dose

Comments

Tetracycline 250-500 mg x 2/day

Doxycycline 100 mg x 2/day Minocycline 50-100 mg x 2/day

Erythromycin 500 mg x 2/day

Clindamycin 300 mg x 3/day Cotrimoxazole 160/800 mg x 2/day low cost decreased absorption in presence of foods and dairy products may be taken with meals expensive may be taken with meals safety problems common emergence of resistant P. acnes strains safety problems after long-term use second-line therapy in acne

50 mg/day as maintenance dose) (fig. 1) and minocycline (usually 100 mg/day; 50 mg twice daily or 100 mg once daily) are more expensive but also more lipid soluble and better absorbed from the gastrointestinal tract. In contrast to tetracyclines of the first generation their absorption is not significantly limited by food, therefore, they can be taken with meals even though it is more effective when taken 30 min previously. Among tetracyclines, minocy-cline seems to induce more rapid clinical improvement as well as greater and more persistent reduction of inflammatory lesions and facial P. acnes counts, probably because it is the most lipophilic and may become highly concentrated in the pilosebaceous unit after its oral adminis tration [39]. Its major limitation occurs from currently observed significant safety problems (table 5) [40-43].

Erythromycin at a dosage of 1 g/day can be administered as an alternative regimen. It is equally effective with tetracycline; however, it induces higher rates of resistant P. acnes strains and may, therefore, be more often associated with treatment failures [12]. Its intolerable gastrointestinal side effects can be minimized by using intestine-soluble preparations.

Clindamycin is very effective but has disadvantages for long-term therapy because of the possible induction of pseudomembranous colitis. Cotrimoxazole (trimetho-prime/ sulfamethoxazole, 160 mg/800 mg twice daily) is effective in acne, however, it is recommended to reserve this drug for patients who responded inadequately to other antibiotics and for patients with gram-negative follicu-litis.

Bacterial resistance is not rare after systemic administration of antibiotics over several months (table 5). Gastrointestinal upset under tetracycline and doxycycline with nausea, vomiting and diarrhea and vaginal candido-sis under tetracycline are probably caused through changes in the gastrointestinal flora. Ultraviolet light sensitivity under tetracycline and doxycycline, not under minocycline, is frequent. Painful onycholysis has been occasionally observed under tetracycline treatment. Mi-nocycline may cause allergic skin reaction, reversible vestibular disturbances (e.g. dizziness, vertigo, ataxia) and a blue-grey discoloration of the skin, particularly in inflamed areas, due to a reaction with free iron. Rarely, hepatitis and reactions resembling serum sickness and lupus erythematosus have been reported in association with oral use of tetracyclines, particularly minocycline. The teeth discoloration reported in children under 10 years can rarely also occur in adults. Tetracyclines are also accused for inducing benign intracranial hypertension which is, however, a rare adverse event. Tetracyclines must not be combined with systemic retinoids because the probability for development of intracranial hypertension increases. Since tetracyclines are contraindicated in pregnancy, erythromycin has to be administered as an alternative drug. Erythromycin causes the most frequent emergence of resistant P. acnes strains. It is also responsible for intolerable gastrointestinal side effects in many patients. Clin-damycin treatment of acne is almost abandoned in several countries because of its association with pseudomembra-nous colitis due to intestinal colonization with Clostrid-ium difficile. Metronidazole is then indicated in those cases. Appearance or enhancement of a vaginal candido-sis can be observed in females, which frequently settles over the intestinal region.

Treatment with oral antibiotics should be administered for no less than 2 months but also generally not exceed 4-6 months [44]. Maximum clinical improvement is to be expected in the first 3-4 months; lack of improvement may indicate emergence of bacterial resistance [12]. Systemic antibiotics can be well combined with topical preparations, especially tretinoin, azelaic acid and ben-zoyl peroxide [45, 46].

Oral Isotretinoin

Oral isotretinoin is the most effective sebosuppressive agent and has revolutionized the treatment of severe acne

Table 5. Adverse events of systemic antibiotics

Adverse event

Bacterial resistance

Gastrointestinal discomfort Pseudomembranous colitis Postinflam. hyperpigmentation Vestibular disturbances Hypersensitivity reaction Lupus erythematosus-like syndrome Interstitial nephritis/hepatic failure/ systemic eosinophilia

Compound tetracyclines > erythromycin > cotrimoxazole > minocyclin clindamycin, tetracyclines clindamycin minocycline > tetracycline minocycline minocycline, cotrimoxazole minocycline minocycline

[28, 47-50]. It is the only drug currently available that affects all four pathogenic factors of acne. Like other retinoids, isotretinoin reduces comedogenesis. Moreover, it reduces sebaceous gland size (up to 90%) by decreasing proliferation of basal sebocytes, it suppresses sebum production in vivo and inhibits terminal sebocyte differentiation. Its stereoisomers tretinoin and alitretinoin (9-cis retinoic acid) were found inferior to isotretinoin in sebum suppression or acne treatment. Although not directly affecting P. acnes, its inhibitory effect on sebum production leads to alteration of the follicular microclimate and indirect fall of P. acnes counts reducing its ability to cause inflammation [51].

There is still debate as to the choice of dose. Some authors favor isotretinoin 0.5 mg/kg/day, others advocate higher dosage of 1 mg/kg/day. Although both regimens result to the same degree of long-term clinical improvement, relapse necessitating re-treatment occurs significantly more frequently under low-doses among patients with severe acne [52-53]. A 6-month treatment course is sufficient for 99% of the patients, but it has been documented that an initial dosage of 1 mg/kg/day for 3 months, then reduced to 0.5 and, if possible, to 0.2 mg/ kg/day for 3-9 additional months will optimize the therapeutic outcome. As a rule, after 2-4 weeks of treatment, a 50% reduction of the pustules can be expected. Improvement continues during the post-treatment period. Relapses may occur after a single 6-month course. A 22-30% relapse rate was noted in patients followed for 10 years after having received isotretinoin 1 mg/kg/day (or cumulative dose >120 mg/kg), as compared to 39-82% with lower dose schedules [48].

Today, a 6- to 12-month course isotretinoin 0.5-1 mg/ kg/day in most cases with severe acne, to reach a

Fig. 2. Severe acne papulopustulosa in a 21-year-old male patient before (left) and after a 4-month treatment with isotretinoin 0.5 mg/ kg/day (right).

Fig. 3. Acne conglobata in an 18-year-old male patient before (left) and after a 6-month treatment with isotretinoin 1 mg/kg/ day (cumulative dose 144 mg/kg) (right) [from ref. 28].

Fig. 2. Severe acne papulopustulosa in a 21-year-old male patient before (left) and after a 4-month treatment with isotretinoin 0.5 mg/ kg/day (right).

Isotretinoin Flare

> 150 mg/kg total cumulative dose is recommended [28] (fig. 2-4). Three to 4 weeks after administration of the drug, an apparent flare-up may occur with increased development of inflammatory lesions which usually do not require modification of the oral dose and improve spontaneously. Factors contributing to the need for longer treatment schedules include low dose regimens (0.1-

0.5 mg/kg/day), presence of severe acne, extra-facial involvement and prolonged history of the disease. Higher dosages are indicated particularly for severe involvement of the chest and back [54]. Individual risk factors must be taken into account for establishing the dosage. Indications for optimal use are shown in table 6.

Fig. 4. Acne tarda without hormonal disturbances in a 44-year-old female patient before (left) and after a 12-month treatment with isotretinoin 0.5 mg/kg/day combined with ethinyl estradiol 35 ^g/day - cyproterone acetate 2 mg/day (right).

Fig. 4. Acne tarda without hormonal disturbances in a 44-year-old female patient before (left) and after a 12-month treatment with isotretinoin 0.5 mg/kg/day combined with ethinyl estradiol 35 ^g/day - cyproterone acetate 2 mg/day (right).

Acne TardaYear Old With Acne

The clinical course of isotretinoin therapy shows more rapid improvement of inflammatory lesions as compared to comedones. Pustules are cleared earlier than papules or nodules, and lesions localized on the face, upper arms and legs tend to clear more rapidly than trunk lesions [55]. Non-acne patients who have received oral isotretinoin therapy for seborrhea do not usually experience relapse for months or years. However, the duration of the sebo-static effect seems to be dose-dependent. Taking good tolerance into account, a dosage of 0.1-0.3 mg/kg/day over 4 weeks is sufficient to produce a sebostatic effect for at least 8 weeks after discontinuation of treatment. Five to 10 mg/day may be sufficient as a maintenance sebosup-pressive dose over several years.

In female patients contraception is required and has to be enforced by the physician, because of the strong terato-genicity of isotretinoin [56, 57]. Isotretinoin can be well combined with a contraceptive pill which includes a hormonal anti-androgen [28, 57].

The adverse effect profile of oral isotretinoin is closely associated with hypervitaminosis A [28]. It includes a characteristic dose-dependent symptomatology with mu-cocutaneous side effects (table 7), elevation of serum lipids (approx. 20%), hyperostosis and extra-skeletal calcification (table 9). Arthralgia and myalgia may occur in up to 5% of individuals receiving high-dose isotretinoin. The major toxicity of isotretinoin results, however, from its

Table 6. Indications for optimal use of systemic isotretinoin

Severe acne (nodulocystica, conglobata, fulminans) Patients with active acne and severe acne scars or potentially possible induction of physical or psychological scars Patients with acne papulopustulosa who despite several conventional therapies, do not improve Patients with acne papulopustulosa whose acne has responded well to conventional oral treatment on two or three occasions but has relapsed quickly after interruption of oral medication Depressive and dysmorphobic patients

In combination with oral contraceptive treatment in women with acne and signs of peripheral hyperandogenism Patients with excessive seborrhea Patients with gram-negative folliculitis teratogenic potential associated with high rate of spontaneous abortions and life-threatening congenital malformations. Therefore, the preparation can only be administered in women in combination with a secure contraceptive treatment or technique. Contraception is urgently recommended from 1 month before therapy, during the entire period of treatment and up to 3 months after discontinuation of the regimen. Oral isotretinoin treatment appears today strictly contraindicated in pregnancy, the lactation period and in severe hepatic and renal dysfunction. Hyperlipidemia, diabetes mellitus and severe osteoporosis are relative contraindications. Co-medication with vitamin A (increased toxicity), tetracyclines (cranial hypertension) and high doses of aspirin (potentiation of mucosal damage) should be avoided. Liver and fat values in blood must be regularly controlled [58].

In long-term therapy (over 1-2 years), changes in the bone system with hyperostosis, periostosis, demineraliza-tion, thinning of the bones and premature calcification of epiphyses in adolescents have to be taken into consideration [59]. A radiograph and growth measurements are

Table 7. Mucocutaneous adverse events of isotretinoin (% values)

Cheilitis

75-

95

Dermatitis facialis

30-

50

Xerosis

30-

50

Dry mucosa

20-

50

Conjunctivitis

30

Epistaxis

25

Itching

25

Epidermal atrophy

15-

25

Skin fragility

15-

20

Desquamation

10-

20

Hair loss

10-

20

Retinoid dermatitis

5

Table 8. Indications for optimal use of hormonal therapy in women

Acne accompanied by mild or moderate hirsutism

Inadequate response to other acne treatments

Acne that began or worsened in adulthood

Premenstrual flares of acne

Excessive facial oilness

Inflammatory acne limited to the 'beard area'

reasonable tests before treatment of adolescents. Long-term adverse events after discontinuation of isotretinoin are rare.

Anti-Androgens

Hormonal anti-androgenic treatment can be administered in female patients to target the pilosebaceous unit and may inhibit sebum production by 12.5-65% (table 8) [25-27, 60, 61]. Once the decision has been made to initiate hormonal therapy, there are various options to choose among androgen receptor blockers and inhibitors of androgen synthesis at the levels of the ovary or the adrenal gland. Hormonal anti-androgenic treatment for acne must be continued for a sufficient period of time, at least 12 months and frequently longer. It is absolutely contraindicated in women who want to become pregnant due to the risk for sexual organ malformation in a developing fetus.

A most effective compound is cyproterone acetate, which belongs to the group of hydroxy-progresterones and blocks the binding of androgens to their receptors. There is current evidence that cyproterone acetate exhibits a dual activity by also inhibiting the synthesis of adrenal androgens because it inhibits the conversion of dehydro-epiandrosterone to androstenedione by 3P-hydroxyste-roid dehydrogenase/A5-4-isomerase, which mainly occurs in the adrenal gland, and in the skin, in the sebaceous gland. Cyproterone acetate is incorporated in a marketed hormonal contraceptive at a dose of 2 mg in combination with 35 |g ethinyl estradiol to avoid menstrual cycle problems [62-65] (fig. 5). The preparation can be used for both contraception and treatment of acne with or without signs of hyperandrogenism, even when serum androgen levels are normal. It has been shown to decrease serum gonado-tropin, testosterone and androstenedione, with control of seborrhea and acne after three months treatment. In women with abnormal androgen metabolism additional cyproterone acetate 10-20 mg/day, and in some cases up to 50 mg/day can be administered orally during the first

Table 9. Adverse events of systemic anti-acne drugs

Isotretinoin teratogenicity, skin and mucosal dryness, irritation, bone changes, increase of the blood values for neutral lipids (cholesterol, triglycerides) Hormonal contraceptives edemas, thrombosis, increased appetite, weight gain, breast tenderness, decreased libido Spironolactone breast tenderness, menstrual irregularities, increased potassium blood levels

Agent Adverse event

Fig. 5. Acne nodulocystica in a 20-year-old female patient before (left) and after a 6-month treatment with ethinyl estradiol 35 ^g/day - cyproterone acetate 2 mg/day (right).

Fig. 5. Acne nodulocystica in a 20-year-old female patient before (left) and after a 6-month treatment with ethinyl estradiol 35 ^g/day - cyproterone acetate 2 mg/day (right).

Acne Vulgaris Nodulocystica
Fig. 6. Acne tarda with increased serum dihydroepiandrosterone in a 31-year-old female patient before (left) and after a 2-month treatment with prednisolone 5 mg/ day (right).
Acne Tarda

10 days of the menstrual cycle. Alternatively, a single i.m. injection of 100-300 mg cyproterone acetate can be applied at the beginning of the cycle.

There are other hormonal blockers of androgen receptors available, such as the gestagene chlormadinone acetate (2 mg) alone or in combination with 50 ^g ethinyl estradiol or 50 ^g mestranol in a contraceptive pill [66].

Most oral contraceptives contain two agents, estrogen (generally ethinyl estradiol) and a progestin. In their early formulations, oral contraceptives included high estrogen concentrations of over 100 ^g which could directly suppress sebum production; low estrogen levels used currently act in the liver to increase the synthesis of sex hormone-binding globulin (SHBG). Circulating free testosterone levels are reduced by the increased SHBG levels, leading to a decrease in sebum production. Oral contraceptives inhibit the ovarian production of androgens by suppressing ovulation. This, in turn, decreases serum androgen levels and reduces sebum production. On the other hand, the progestins administered belong to the families of estranes and gonanes with a variety of drugs in each class. Some progestins can cross react with the androgen receptor or, like the progestins norgestrel and levonorgestrel, reduce SHBG increasing free testosterone, thus leading to increased androgenic effects and aggravating acne, hir-sutism, or androgenic alopecia [67, 68]. They can also cause changes in lipid metabolism and can increase serum glucose, leading to glucose intolerance, as well as possibly interfering with the beneficial effect of estrogen on the SHBG. Hormonal contraceptives are associated with edema, thrombosis, increased appetite, weight gain, breast tenderness and decreased libido [61].

Spironolactone, a synthetic steroid primarily acting as aldosterone antagonist, also blocks the androgen receptor exhibiting sufficient sebosuppression at doses 50-200 mg/ day, a 2 x 25 mg regimen daily or at 4-22 days of cycle being the mostly used in anti-acne therapy. It may induce, however, cycle disturbances which can be corrected by non-androgenic progestins [69]. Spironolactone may induce dose-dependent breast tenderness, menstrual irregularities and increased potassium blood levels [70].

Flutamide, a synthetic compound which has mainly been administered to hirsute females, has been also shown to be active in acne after 1-6 months of treatment at doses of 250-500 mg/day (optimum 2 x 250 mg/day over 6 months) [63]. The agent becomes active through first-pass metabolism to 2-hydroxyflutamide. It inhibits binding of 5a-dihydrotestosterone to its receptor protein and nuclear translocation of the receptor. Also, it may accelerate conversion of active androgens to inactive metabolites. Hepatic function laboratory tests should be done periodically [71].

Among nonhormonal anti-androgens, ketoconazole (cytochrome P-450 inhibitor and steroidogenesis enzyme blocker) in a dose of > 200 mg/day and cimetidine (H2-receptor antagonist) 5 x 300 mg/day exhibit weak anti-androgenic activity [70].

Gonadrotropin-releasing agonists, such as buserelin, nafarelin or leuprolide, have been used to interrupt androgen production by the adrenals and ovaries by blocking FSH and LH liberation by the pituitary gland. These drugs are efficacious in acne and hirsutism, and are available as injectable drugs or nasal spray [25, 67]. However, in addition to suppressing the production of ovarian androgens, they also suppress the production of estrogens, thereby eliminating the function of the ovary. Thus, the patient could develop menopausal symptoms and suffer from hypoestrogenism. They have variable acceptance due to the development of headaches as well as the occurrence of bone loss, due to the reduction in estrogen. They have not been registered for the treatment of acne.

Severe Inflammatory Acne and Acne fulminans

Systemic corticosteroids can become necessary in acne fulminans to suppress the excessive immunological reaction [54], in severe inflammatory forms of acne, and in order to prevent or treat a severe flare of the disease in the first 4 weeks of isotretinoin treatment. It is preferable to administer the corticosteroids for 3-4 weeks before administration of isotretinoin [72] but a combination of isotretinoin 0.5-1 mg/kg body weight/d and prednisolone 30 mg/day for 4-6 weeks (or other doses) with gradual reduction can also accelerate the conversion of fulminate disease course to common inflammatory acne [54, 73].

In contrast, oral non-steroidal anti-inflammatory agents have rarely been administered in the treatment of severe inflammatory acne forms.

Acne tarda

Systemic corticosteroids inhibit adrenal androgen liberation and, therefore, they are indicated in acne patients with adrenal hyperandrogenism and increased dihydro-piandrosterone levels, such as female patients with acne tarda [74]. This variant of acne tarda is characterized by inflammatory lesions, since increased dihydroepiandros-terone induces inflammation [75]. They are used at low prednisone, prednisolone (2.5-7.5 mg/day prednisolone) or dexamethasone doses [20] (fig. 6).

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