Selasa, 20 November 2007

Acne Vulgaris

Background

Acne vulgaris is a common skin disease that affects 85-100% of people at some time during their lives. It is characterized by noninflammatory follicular papules or comedones and by inflammatory papules, pustules, and nodules in its more severe forms. Acne vulgaris affects the areas of skin with the densest population of sebaceous follicles; these areas include the face, the upper part of the chest, and the back.

Pathophysiology

The pathogenesis of acne vulgaris is multifactorial. Four key factors are responsible for the development of an acne lesion. These factors are follicular epidermal hyperproliferation with subsequent plugging of the follicle, excess sebum, the presence and activity of Propionibacterium acnes, and inflammation.

Follicular epidermal hyperproliferation is the first recognized event in the development of acne. The exact underlying cause of this hyperproliferation is not known. Currently, the 3 leading hypotheses have been proposed to explain why the follicular epithelium is hyperproliferative in individuals with acne.

First, androgen hormones have been implicated as the initial trigger. Comedones, the clinical lesion that results from follicular plugging, begin to appear around adrenarche in persons with acne. Furthermore, the degree of comedonal acne in prepubertal girls correlates with circulating levels of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S). Additionally, androgen hormone receptors are present in the portion of the follicle where the comedone forms; individuals with malfunctioning androgen receptors do not develop acne.

Second, changes in lipid composition have been implicated in the development of acne vulgaris. Persons with acne frequently have excess sebum production and oily skin. This excess sebum may dilute the normal epidermal lipids and result in a change in the relative concentrations of the various lipids. Diminished concentrations of linoleic acid have been demonstrated in individuals with acne and, interestingly, these levels normalize after successful treatment with isotretinoin. This relative decrease in linoleic acid may be what initiates comedone formation.

Inflammation is the third hypothesized factor incriminated in comedone formation. Interleukin (IL)–1–alpha is a proinflammatory cytokine. It has been used in a tissue model to induce follicular epidermal hyperproliferation and comedone formation. Although inflammation is not apparent microscopically or clinically in early lesions of acne, it may still play a pivotal role in the development of acne vulgaris and the comedones.

Excess sebum is another key factor in the development of acne vulgaris. Sebum production and excretion are regulated by a number of different hormones and mediators. Androgen hormones, in particular, promote sebum production and release. Still, most men and women with acne have normal circulating levels of androgen hormones. An end-organ hyperresponsiveness to androgen hormones has been hypothesized. Androgen hormones are not the only regulators of the human sebaceous gland. Numerous other agents, including growth hormone and insulinlike growth factor, also regulate the sebaceous gland and may contribute to the development of acne.

P acnes is a microaerophilic organism present in many acne lesions. Although, it has not been shown to be present in the earliest lesions of acne, the microcomedo, its presence in later lesions is almost certain. The presence of P acnes promotes inflammation through a variety of mechanisms. P acnes stimulates inflammation by producing proinflammatory mediators that diffuse through the follicle wall. Recent studies have shown that P acnes activates the toll-like receptor 2 on monocytes and neutrophils. Activation of the toll-like receptor 2 then leads to the production of multiple proinflammatory cytokines, including IL-12, IL-8, and tumor necrosis factor. Hypersensitivity to P acnes may also explain why some individuals develop inflammatory acne vulgaris while others do not.

Inflammation may be a primary phenomenon or a secondary phenomenon. Most of the evidence to date suggests a secondary inflammatory response to P acnes as mentioned above. However, IL-1-alpha expression has been identified in the microcomedone, and it may play a role in the development of acne.

Frequency

United States

Acne vulgaris affects 85-100% of people at some time during their lives.

Mortality/Morbidity

  • Acne can cause physical pain and psychosocial suffering.
  • Acne can lead to scarring.
  • A severe inflammatory variant of acne, acne fulminans, can be associated with fever, arthritis, and other systemic symptoms.

Race

  • The prevalence of acne in North Americans of African ancestry and whites is similar.

Sex

  • Acne vulgaris is more common in males than in females during adolescence.
  • It is more common in women than in men during adulthood.

Age

  • Acne vulgaris may be present in the first few weeks and months of life when a newborn is still under the influence of maternal hormones and when the androgen-producing portion of the adrenal gland is disproportionately large. This neonatal acne resolves spontaneously.
  • Adolescent acne usually begins prior to the onset of puberty, when the adrenal gland begins to produce and release more androgen hormone.
  • Acne is not limited to adolescence. Twelve percent of women and 5% of men at age 25 years have acne. By age 45 years, 5% of both men and women still have acne.
Treatment

Background

Acne vulgaris is a common skin disease that affects 85-100% of people at some time during their lives. It is characterized by noninflammatory follicular papules or comedones and by inflammatory papules, pustules, and nodules in its more severe forms. Acne vulgaris affects the areas of skin with the densest population of sebaceous follicles; these areas include the face, the upper part of the chest, and the back.

Pathophysiology

The pathogenesis of acne vulgaris is multifactorial. Four key factors are responsible for the development of an acne lesion. These factors are follicular epidermal hyperproliferation with subsequent plugging of the follicle, excess sebum, the presence and activity of Propionibacterium acnes, and inflammation.

Follicular epidermal hyperproliferation is the first recognized event in the development of acne. The exact underlying cause of this hyperproliferation is not known. Currently, the 3 leading hypotheses have been proposed to explain why the follicular epithelium is hyperproliferative in individuals with acne.

First, androgen hormones have been implicated as the initial trigger. Comedones, the clinical lesion that results from follicular plugging, begin to appear around adrenarche in persons with acne. Furthermore, the degree of comedonal acne in prepubertal girls correlates with circulating levels of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S). Additionally, androgen hormone receptors are present in the portion of the follicle where the comedone forms; individuals with malfunctioning androgen receptors do not develop acne.

Second, changes in lipid composition have been implicated in the development of acne vulgaris. Persons with acne frequently have excess sebum production and oily skin. This excess sebum may dilute the normal epidermal lipids and result in a change in the relative concentrations of the various lipids. Diminished concentrations of linoleic acid have been demonstrated in individuals with acne and, interestingly, these levels normalize after successful treatment with isotretinoin. This relative decrease in linoleic acid may be what initiates comedone formation.

Inflammation is the third hypothesized factor incriminated in comedone formation. Interleukin (IL)–1–alpha is a proinflammatory cytokine. It has been used in a tissue model to induce follicular epidermal hyperproliferation and comedone formation. Although inflammation is not apparent microscopically or clinically in early lesions of acne, it may still play a pivotal role in the development of acne vulgaris and the comedones.

Excess sebum is another key factor in the development of acne vulgaris. Sebum production and excretion are regulated by a number of different hormones and mediators. Androgen hormones, in particular, promote sebum production and release. Still, most men and women with acne have normal circulating levels of androgen hormones. An end-organ hyperresponsiveness to androgen hormones has been hypothesized. Androgen hormones are not the only regulators of the human sebaceous gland. Numerous other agents, including growth hormone and insulinlike growth factor, also regulate the sebaceous gland and may contribute to the development of acne.

P acnes is a microaerophilic organism present in many acne lesions. Although, it has not been shown to be present in the earliest lesions of acne, the microcomedo, its presence in later lesions is almost certain. The presence of P acnes promotes inflammation through a variety of mechanisms. P acnes stimulates inflammation by producing proinflammatory mediators that diffuse through the follicle wall. Recent studies have shown that P acnes activates the toll-like receptor 2 on monocytes and neutrophils. Activation of the toll-like receptor 2 then leads to the production of multiple proinflammatory cytokines, including IL-12, IL-8, and tumor necrosis factor. Hypersensitivity to P acnes may also explain why some individuals develop inflammatory acne vulgaris while others do not.

Inflammation may be a primary phenomenon or a secondary phenomenon. Most of the evidence to date suggests a secondary inflammatory response to P acnes as mentioned above. However, IL-1-alpha expression has been identified in the microcomedone, and it may play a role in the development of acne.

Frequency

United States

Acne vulgaris affects 85-100% of people at some time during their lives.

Mortality/Morbidity

  • Acne can cause physical pain and psychosocial suffering.
  • Acne can lead to scarring.
  • A severe inflammatory variant of acne, acne fulminans, can be associated with fever, arthritis, and other systemic symptoms.

Race

  • The prevalence of acne in North Americans of African ancestry and whites is similar.

Sex

  • Acne vulgaris is more common in males than in females during adolescence.
  • It is more common in women than in men during adulthood.

Age

  • Acne vulgaris may be present in the first few weeks and months of life when a newborn is still under the influence of maternal hormones and when the androgen-producing portion of the adrenal gland is disproportionately large. This neonatal acne resolves spontaneously.
  • Adolescent acne usually begins prior to the onset of puberty, when the adrenal gland begins to produce and release more androgen hormone.
  • Acne is not limited to adolescence. Twelve percent of women and 5% of men at age 25 years have acne. By age 45 years, 5% of both men and women still have acne.
Medication

The goal of pharmacotherapy is to reduce morbidity and to prevent complications.

Drug Category: Retinoids

These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes, and they may reduce the potential for malignant degeneration. They also modulate keratinocyte differentiation.

Drug NameIsotretinoin (Accutane)
DescriptionMost effective oral medication. Oral agent that treats serious dermatologic conditions. Isotretinoin is synthetic 13-cis isomer of naturally occurring tretinoin (trans-retinoic acid). Both agents are structurally related to vitamin A. Decreases sebaceous gland size and sebum production. May inhibit sebaceous gland differentiation and abnormal keratinization.
Effective March 1, 2006 the FDA requires that prescribers of isotretinoin, patients who take isotretinoin, and pharmacists who dispense isotretinoin all must register with the iPLEDGE system.
Female patients must sign an informed consent that they will use contraceptives during the treatment course and for 30 d after discontinuing therapy.
Adult DoseTotal cumulative dose of 120-150 mg/kg recommended; starting dose should be <0.5>
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsToxicity may occur with vitamin A coadministration; pseudotumor cerebri or papilledema may occur when coadministered with tetracyclines; may reduce plasma levels of carbamazepine
PregnancyX - Contraindicated in pregnancy
PrecautionsObtain 2 negative pregnancy test results in patients of childbearing potential prior to initiating therapy; pregnancy must be avoided during and for 1 mo after treatment, and monthly pregnancy test results must be documented; hyperlipidemia may develop; pseudotumor cerebri, vision impairment, headaches, myalgias, arthralgias, and depression have been reported; dry skin and cheilitis are nearly universal adverse effects

Drug NameTretinoin (Retin-A, Retin-A Micro, Avita)
DescriptionInhibits microcomedo formation. Normalizes follicular epidermal differentiation and exhibits anti-inflammatory properties. Available as 0.025%, 0.05%, and 0.1% creams. Also available as 0.01% and 0.025% gels.
Adult DoseBegin with lowest tretinoin formulation and increase as tolerated; apply hs or qod; lower the frequency of application if irritation develops
Pediatric Dose<12 years: Not established
>12 years: Apply as in adults
ContraindicationsDocumented hypersensitivity
InteractionsCoadministration with benzoyl peroxide may lessen effectiveness
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsPhotosensitivity may occur with excessive sunlight exposure; erythema and peeling may occur (most prominent within first few wk of treatment)

Drug NameAdapalene (Differin)
DescriptionA naphthoic acid derivative that binds the retinoic acid receptor. Normalizes follicular epidermal differentiation and exhibits anti-inflammatory properties. Available in cream, gel, solution, and pledget formulations.
Adult DoseApply a small amount to involved skin qd
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsErythema and peeling may occur in some individuals; avoid contact with mucous membranes, eyes, mouth, and nostrils; avoid exposure to sunlight and sunlamps; dryness of skin, scaling, erythema, burning, and pruritus may occur

Drug NameTazarotene (Tazorac, AVAGE)
DescriptionRetinoid prodrug whose active metabolite modulates differentiation and proliferation of epithelial tissue; may also have anti-inflammatory and immunomodulatory properties. Available in 0.05% and 0.1% cream and gel formulations.
Adult DoseApply sparingly to affected area qd
Pediatric DoseChildren: Not established
Adolescents: Administer as in adults
ContraindicationsDocumented hypersensitivity
InteractionsDo not use concomitantly with dermatologic drugs or cosmetics that have a strong drying effect on the skin (eg, salicylic acid, benzoyl peroxide, astringents)
PregnancyX - Contraindicated in pregnancy
PrecautionsErythema and peeling may occur at application site

Drug Category: Antibiotics

Topical and systemic antibiotics used in the treatment of acne vulgaris are directed at P acnes. They also have anti-inflammatory properties.

Drug NameMinocycline (Dynacin, Minocin)
DescriptionTreats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible chlamydial, rickettsial, and mycoplasmal organisms. Available in 50-, 75-, and 100-mg preparations.
Adult Dose50-100 mg PO bid
Pediatric Dose<8 years: Not recommended
>8 years: 4 mg/kg PO initially, followed with 2 mg/kg q12h
ContraindicationsDocumented hypersensitivity; severe hepatic dysfunction
InteractionsBioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
PregnancyD - Unsafe in pregnancy
PrecautionsPhotosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines; hepatitis or lupuslike syndromes may occur

Drug NameDoxycycline (Bio-Tab, Doryx, Vibramycin)
DescriptionAntibacterial agent effective against gram-positive and gram-negative organisms. Available in 20-, 50-, and 100-mg preparations.
Adult Dose100 mg PO bid
Pediatric Dose<8 years: Not recommended
>8 years: 2-5 mg/kg/d PO/IV in 1-2 divided doses; not to exceed 200 mg/d
ContraindicationsDocumented hypersensitivity; severe hepatic dysfunction
InteractionsBioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
PregnancyD - Unsafe in pregnancy
PrecautionsPhotosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug NameTetracycline (Sumycin)
DescriptionAntibacterial agent effective against gram-positive and gram-negative organisms.
Adult Dose250-500 mg PO q6h
Mild-to-moderate infections: 500 mg PO bid or 250 mg PO qid for 7-14 d
Pediatric Dose<8 years: Not recommended
>8 years: 25-50 mg/kg/d (10-20 mg/lb) PO divided qid
ContraindicationsDocumented hypersensitivity
InteractionsBioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
PregnancyD - Unsafe in pregnancy
PrecautionsPhotosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug NameTrimethoprim/sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)
DescriptionAntibiotic with activity against many gram-positive and gram-negative organisms. Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Available as 80 mg trimethoprim and 400 mg sulfamethoxazole or as 160 mg trimethoprim and 800 mg sulfamethoxazole (double strength).
Adult Dose160 mg TMP/800 mg SMZ PO q12h
Pediatric Dose8 mg/kg/d TMP/40 mg/kg/d SMZ PO/IV divided q12h
ContraindicationsDocumented hypersensitivity; megaloblastic anemia due to folate deficiency
InteractionsMay increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly persons; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsFor adults, adjust dosage accordingly: CrCl (mL/min) 80-50, IV dose q18h recommended; CrCl 50-10, IV dose qd recommended; CrCl <10, not recommended; HD, 4-5 mg/kg after HD; and during peritoneal dialysis, 0.16-0.8 g q48h
Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, persons with chronic alcoholism, elderly persons, those receiving anticonvulsant therapy, those with malabsorption syndrome); hemolysis may occur in individuals with G-6-PD deficiency; in patients with AIDS, TMP-SMZ may not be tolerated or cause a response; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation