Acne Fulminans

Background

Acne fulminans (AF), also known as acne maligna, was originally described as acute febrile ulcerative acne conglobata (AC). In 1958, at a meeting of the Detroit Dermatological Society, Burns and Colville presented a 16-year-old white boy with acute febrile disease and AC. Many similar cases have been reported since then. The primary features of this disease include sudden onset, severe and often ulcerating acne, fever, polyarthritis, and failure to respond to antibacterial therapy; the response to debridement in combination with steroid therapy is good. It can be the dermatologic manifestation of the synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. AF is a syndrome of fulminant, necrotizing acne associated with bone lesions, constitutional symptoms, and laboratory abnormalities.

Pathophysiology

AF is an uncommon, immunologically induced, systemic disease in which the triggering antigen is believed to be from Propionibacterium acnes. Some authors note that elevated blood levels of testosterone may play an important role in the pathogenesis of AF. High levels of testosterone and anabolic steroids cause an increase in sebum excretion and in the population density of P acnes. The increase in the amount of P acnes or related antigens may trigger the immunologic reaction in some individuals and lead to an occurrence of AF. In addition to testosterone, isotretinoin may also precipitate AF, possibly related to highly increased levels of P acnes antigens in the patient's immune system.

Another theory postulates that AF may be an autoimmune complex disease because circulating immune complexes have been demonstrated in some patients with AF. Immunologically, the reaction is a type III or IV hypersensitivity reaction.

Genetic factors may play an important role in some patients; 3 sets of identical twins who developed an identical pattern of AF have been documented.

Acne may be the only clinical sign of androgen excess in men, and one report is available about a boy with AF and androgen excess due to late-onset congenital adrenal hyperplasia.

Frequency

United States

AF is a rare disease. Over the past several years, fewer cases of this disease have occurred, possibly because of earlier and better treatment of acne.

Age

The disease predominantly affects young males with a history of acne.

Treatment

Medical Care

The recommended treatment for AF is a combination of oral steroids and isotretinoin.

• Oral steroids should be started and gradually reduced over 6 weeks to avoid adverse effects of a prolonged course of systemic steroids.
• Isotretinoin should be started at 4 weeks, initially at 0.25 mg/kg daily and gradually increased to achieve complete clearance. Isotretinoin with a minimum total dose of 120 mg/kg is recommended. Relapses are rare. If required, a repeat course of isotretinoin (150 mg/kg) may be used.
  
• Some authors suggest treating patients with spontaneous development of AF with oral steroids and supplemental intralesional therapy.
• The response to broad-spectrum antibiotic treatment is poor. Oral antibiotics are responsible for a slow response in the resolution of acne and systemic symptoms. The combination of oral isotretinoin and systemic steroids is better than the combination of oral isotretinoin and antibiotics.
• Infliximab, a recently developed monoclonal antibody against tumor necrosis factor-alpha, also may be a treatment option for patients with AF that is unresponsive to conventional therapies.

Medication

Begin treatment with oral prednisone 1 mg/kg/d and taper over 6 weeks. By the fourth week, initiate isotretinoin at 0.25 mg/kg/d. If isotretinoin cannot be used, dapsone may be substituted for the retinoid, beginning at 50 mg/d and increasing to 100-150 mg/d.

Drug Category: Corticosteroids

These agents have profound and varied metabolic effects. They possess anti-inflammatory and immunosuppressive properties.

Drug Name	Prednisone (Delta-Cortef, Econopred)
Description	Synthetic adrenocortical steroid with predominantly glucocorticoid properties. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.
Adult Dose	0.5-1 mg/kg/d PO for 6 wk; taper as condition improves Single morning dose is safer for long-term use, but divided doses have greater anti-inflammatory effects
Pediatric Dose	0.14-2 mg/kg/d initial PO divided tid/qid (4-60 mg/m2/d)
Contraindications	Documented hypersensitivity; viral, fungal, connective tissue, and tubercular skin infections; peptic ulcer disease; hepatic dysfunction; GI tract disease
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Drug Category: Retinoids

Vitamin A derivatives have many roles. They encourage cellular differentiation, are antiproliferative, and serve as immunomodulators.

Drug Name	Isotretinoin (Accutane)
Description	Oral agent that treats serious dermatologic conditions. Isotretinoin is the synthetic 13-cis isomer of the naturally occurring tretinoin (trans-retinoic acid). Both agents are structurally related to beta-carotene. 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.
Adult Dose	Initial: 0.25 mg/kg/d PO; increase gradually (usually 1 mg/kg/d) for 20 wk or a total dose of 120-150 mg/kg
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Toxicity may occur with beta carotene coadministration; pseudotumor cerebri or papilledema may occur when coadministered with tetracyclines; may reduce plasma levels of carbamazepine
Pregnancy	X - Contraindicated in pregnancy
Precautions	May decrease night vision; inflammatory bowel disease may occur; may be associated with development of hepatitis; occasionally exaggerated healing response of acne lesions (ie, excessive granulation with crusting) may occur; patients with diabetes may experience problems controlling blood glucose levels while on isotretinoin; avoid exposure to UV light or sunlight until tolerance is achieved; discontinue if rectal bleeding, abdominal pain, or severe diarrhea occurs; mood swings or depression may occur; caution in history of depression.

Drug Name	Tretinoin (Avita, Retin-A, Retin-A Micro)
Description	Structurally related to vitamin A. May be helpful for recalcitrant disease, but recurrence is common. Long-term, low-dose therapy may be suitable for selected patients. May cause skin irritation in some patients. Also, has been linked to promotion of angiogenesis; however, has not demonstrated increased telangiectasias. Also inhibits microcomedo formation and eliminates lesions. Makes keratinocytes in sebaceous follicles less adherent and easier to remove. Available as 0.025%, 0.05%, and 0.1% creams. Available also as 0.01% and 0.025% gels.
Adult Dose	Begin with lowest concentration of tretinoin formulation and increase as tolerated; apply hs or qod; lower frequency of application if irritation develops
Pediatric Dose	<12 years: Not established >12 years: Apply as in adults
Contraindications	Documented hypersensitivity
Interactions	Toxicity may occur with vitamin A coadministration; toxicity increased when coadministered with sulfur, benzoyl peroxide, resorcinol, or any product with strong drying effects; phototoxicity increased when coadministered with tetracyclines, fluoroquinolones, or thiazides
Pregnancy	C - Safety for use during pregnancy has not been established
Precautions	Photosensitivity may occur with excessive sunlight exposure; burning, stinging, peeling, pruritus, or erythema has been reported at site of application; caution with eczema (may cause severe irritation); avoid contact with mucous membranes, mouth, and angles of nose

Drug Category: Sulfone antibiotics

These agents may inhibit bacterial growth by preventing the formation of folic acid.

Drug Name	Dapsone (Avlosulfon)
Description	Bactericidal and bacteriostatic against Mycobacteria species; mechanism of action is similar to that of sulfonamides in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Anti-inflammatory mechanism of action may involve suppression of neutrophil function by inhibition of the halide-myeloperoxidase system. Excretion is primarily in urine; half-life is 28 h.
Adult Dose	50-150 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; G-6-PD deficiency
Interactions	May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists (eg, pyrimethamine); monitor for agranulocytosis during second and third mo of therapy; probenecid increases toxicity; trimethoprim with dapsone may increase toxicity of both drugs; because of increase in renal clearance, levels may decrease significantly when administered concurrently with rifampin; avoid use with zalcitabine because of increased risk of peripheral neuropathy (additive effects)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Perform weekly blood counts (first mo), then WBC counts monthly (6 mo), then semiannually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis occurs; caution in patients with methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M because of high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light