Acne and acneiform eruptions

Acne vulgaris is the most common dermatologic disorder, affecting between 40 and 50 million individuals of all ages in the United States. Eighty-five percent of people between the ages of 12 and 24 years will have some acne. Direct costs related to acne, including factors such as loss of productivity and related depression, exceed $2.2 billion annually in the United States.

Bhambri S, Del Rosso JQ, Bhambri A: Pathogenesis of acne vulgaris: recent advances, J Drug Dermatol 8:615–617, 2009.

White GM: Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris, Arch Dermatol 39:S34–S37, 1998.

The pilosebaceous unit, made up of a follicle (pore), sebaceous gland, and a vellus hair, is the target organ affected in acne. The face, chest, and back are areas with the greatest concentration of pilosebaceous follicles, corresponding to the areas most commonly affected by acne lesions. The primary lesion of acne is the microcomedo. This is the result of obstruction of the sebaceous follicles by sebum and abnormally differentiated and desquamated keratinocytes that may produce large comedones (Fig. 21-1). The four main pathophysiologic factors in acne vulgaris are:

Acne presents in many forms and variations. The most common form is acne vulgaris, which is classified according to the predominant lesion type as comodonal, papular, pustular, nodular, or cystic. It can be graded as mild, moderate, or severe (Fig. 21-2). Other clinical subtypes of acneiform skin lesions include:

The major constituent of sebaceous lipid is triglyceride, which makes up over 50% of the lipid; wax esters account for 25%, squalene 15%, and there are small amounts of cholesterol esters and free cholesterol. Increased sebum production is characteristic of patients with acne, but the seborrhea itself is not sufficient to produce acne. Desaturation of the fatty acids in sebum may lead to the development of acne lesions. Lipoperoxidases characterize the sebum of acne patients, and this, along with other qualitative changes in the sebum lipids, induce alteration of keratinocyte differentiation and induce interleukin-1 (IL-1) secretion, leading to follicular hyperkeratinization.

Kurokawa I, Danby FW, Ju Q, et al: New developments in our understanding of acne pathogenesis and treatment, Exp Dermatol 18:821–832, 2009.

Downing DT, Stewart ME, Wertz PW, et al: Essential fatty acids and acne, J Am Acad Dermatol 14:221–225, 1986.

Yes, it seems to. Many patients report that emotional stress makes their acne worse. In one survey of 4576 consecutive patients with various dermatologic problems, 55% of those with acne reported that episodes of emotional stress were closely related to exacerbation of their acne. A prospective cohort study, published in 2003, of 22 university students with acne during exams showed increased acne severity that was significantly associated with increased stress levels. Another study in high school students also found that increased stress correlated with increased acne severity. There did not seem to be an increase in sebum production during times of stress in this study. New data regarding the physiology of sebaceous glands indicate that these skin organs have receptors for numerous neuropeptides (NPs), and these receptors modulate inflammation, proliferation, and sebum production and composition, as well as androgen metabolism in human sebocytes. Further elucidation of these neural skin connections may help our understanding of the connection between stress and acne.

Chiu A, Chon SY, Kimball AB: The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress, Arch Dermatol 139:897–900, 2003.

Koo, JYM, Smith LL: Psychologic aspects of acne, Pediatr Dermatol 8:185–188, 1991.

Yosipovitch G, Tang, M, Dawn AG, et al: Study of psychological stress, sebum production and acne vulgaris in adolescents, Acta Derm Vereneol 87:35–39, 2007.

Minimally. Association between diet and acne has long been postulated. Arguments for such an association include the observations that acne prevalence is low in rural, nonindustrialized societies and increases with the adoption of a Western diet. A study published in 1971 rechallenged patients with large amounts of foods that reportedly exacerbated their acne without showing any significant change in acne severity. In another study, 1925 patients kept food diaries and found milk to be most commonly associated with their acne flares. A study showing no association between chocolate bar consumption and acne has been criticized for several reasons most recently, because the chocolate bars given to subjects during the study did not contain milk, in contrast to the average chocolate bar of the time. To further examine the role of diet and acne, especially dairy consumption, a recent study examined data from the Nurses Health Study (NHS) II to see if there was a positive association between milk in the teenage diet and acne. Intake of milk during adolescence was associated with a history of teenage acne. The association was more marked for skim than whole milk. Interestingly, soda, French fries, chocolate candy, and pizza were not significantly associated with acne. The authors hypothesized that the hormonal content, not the fat in milk, may be responsible for the acne. Two other large studies have reported a similar positive association between milk intake and acne. Smith, Mann, Braue, et al. enrolled 43 men with moderate acne, ages 15 to 25, in a trial randomized to a low glycemic index diet or a high glycemic–index diet. The men on the low glycemic–index diet lost significantly more weight and had significantly improved acne over the other group. The relative contribution of the high glycemic–load diet on acne pathogenesis versus the improvement in insulin and hormone levels with weight loss is unknown.

Adebamowo CA, Spiegelman D, Danby FW, et al: High school dietary intake and teenage acne, J Am Acad Dermatol 52:207–214, 2005.

Smith RN, Man NJ, Braue A, et al: The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: a randomized, investigator-masked controlled trial. J Am Acad Dermatol 57: 247–256, 2007.

Spencer, EH, Ferdowsian HR, Barnard ND: Diet and acne: a review of the evidence, Int J Dermatol 48:339–347, 2009.

Acne affects approximately 8% of adults aged 25 to 34, and 3% aged 35 to 44. Most teenage boys can anticipate clearing of their acne between 20 and 25 years of age. For women, the news is not so good. The majority of patients with adult acne, including adult-onset acne, are women. This can last up to and beyond age 40.

Goulden V, Stables GI, Cunliffe WJ: Prevalence of facial acne in adults, J Am Acad Dermatol 41:577–580, 1999.

The single most important topical medications used to treat acne are retinoids. We now have numerous topical preparations to choose from that are less irritating and decrease the most common complaint associated with class of acne therapy. These include adapalene (Differin), tazarotene (Tazorac), and tretinoin (Avita, Retin-A, Retin-A Micro). Twelve weeks of use is required for maximum benefit. Retinoids are the only drugs that normalize keratinization within the follicular infundibulum and prevent comodone formation. Propironibacterium acnes, the anaerobic bacterium associated with acne pathogenesis, stimulates the innate immune response via Toll-like receptors (TLRs). This sets off an inflammatory cascade of cytokines. Retinoids are known to downregulate TLRs and inhibit downstream inflammatory transcription factors. Recent recommendations from a global alliance to improve outcomes in acne recommended that retinoid-based combination therapy (retinoid plus antimicrobial or benzoyl peroxide) be the first-line treatment for most forms of acne vulgaris. Retinoids have been shown to maintain improvement achieved with this initial combination therapy.

Other topical treatments include benzoyl peroxide (BPo), topical antibiotics (erythromycin, clindamycin, and sodium sulfacetamide), α-hydroxy acids, salicylic acid, and azelaic acid. Antibiotic resistance of P. acnes has become more common. More than half of patients undergoing therapy with a topical antibiotic will develop resistance. No bacterial resistance has been reported with topical benzoyl peroxide. The following are recommendations for preventing bacterial resistance in the treatment of acne: combining antimicrobials with a retinoid and BPo, limiting the duration of antimicrobial therapy, not using antimicrobials as monotherapy, and avoiding concurrent use of oral and topical antibiotics, especially if chemically different.

Theboutot D, Gollnick, H, Bettoli V, et al: New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne Group, J Am Acad Dermatol 60:S1–S50, 2009.

Antibiotics are indicated in patients with inflammatory lesions (red papules, pustules, or nodules) of moderate to severe grade. Antibiotics appropriate for use in acne are the tetracyclines and the macrolides, with trimethoprim/sulfamethoxasole as a distant alternative. Antibiotics reduce the numbers of P. acnes in the follicles and also have numerous antiinflammatory effects.

Antibiotics should never be used as monotherapy in acne. There is a significant problem with antibiotic resistance, and only two of the four main pathophysiologic mechanisms of disease are being addressed. Oral antibiotics should be combined with a keratolytic such as a topical retinoid and topical benzoyl peroxide. Oral therapy will take 4 to 8 weeks to show significant improvement. After adequate clinical response in 3 to 6 months, the dose should be tapered in an attempt to provide maintenance with topical medications.

Espersen F: Resistance to antibiotics used in dermatological practice, Br J Dermatol 139:4–8, 1998.

OCs most often used today to treat acne are a combination of ethinyl estradiol and a progestin. The only OCs officially approved by the Food and Drug Administration (FDA) for use in acne are Ortho-TriCyclen (Ortho-McNeil Pharmaceutical, Raritan, NJ), Estrostep (Parke-Davis, Detroit, MI), and, most recently, YAZ (Bayer Healthcare Pharmaceuticals, Montville, NJ). The second- and the third-generation progestins combined with an estrogen are the most appropriate choices for the treatment of acne because they have the lowest androgenic activity (Table 21-1). Multiple studies suggest that OCs are significantly better than placebo in the treatment of mild to moderate acne. The trials comparing different OCs are somewhat conflicting. OCs work by suppressing the endogenous production of androgens, reducing free testosterone, and increasing sex hormone–binding globulin. Patients should be screened for risk factors associated with OCs prior to beginning this therapy (see Table 21-1). The World Health Organization and the American College of Obstetricians and Gynecologists no longer require pelvic exam before initiating OC therapy in most healthy female patients of childbearing age.

Arowojulo AO, Gallo MF, Lopez LM, et al: Combined oral contraceptive pills for treatment of acne, Cochrane Database Syst Rev 8;(3):CD004425, 2009.

Frangos JE, Alvaian CN, Kimball AB: Acne and oral contraceptives: update on women’s health screening guidelines, J Am Acad Dermatol 58:781–786, 2008.

Sawaya ME: Antiandrogens and androgen inhibitors, In Wolverton SE, editor: Comprehensive dermatologic drug therapy, ed 2, Philadelphia, 2007, Saunders, pp 430–432.

Isotretinoin is the mainstay of therapy for severe acne. It is indicated for patients with severe, scarring, nodulocystic acne and those with moderate to severe acne who have failed an adequate trial (3 to 6 months) of conventional therapy (retinoid and/or benzoyl peroxide [BP] plus an oral antibiotic). Isotretinoin is also beneficial for patients with severe hidradenitis suppurativa, acne rosacea, and gram-negative acne who are unresponsive to conventional therapy. However, it is not as effective in these diseases as it is in severe acne vulgaris, and relapses are more frequent. The recommended dose is 1.0 mg/kg/day for 20 to 24 weeks. Isotretinoin should be used as monotherapy for acne vulgaris.

Goldsmith LA, Bolognia JL, Callen JP, et al: American Academy of Dermatology Consensus Conference on the Safe and Optimal Use of Isotretinoin: summary and recommendations, J Am Acad Dermatol 50:900–906, 2004.

Isotretinoin is a potent teratogen. Of the pregnancies that have occurred in patients taking isotretinoin, one third have resulted in spontaneous abortion, one third ended in therapeutic abortion, and of the one third that continued to term, 20% showed a major fetal malformation, including those of the brain, heart, and ears. Many of these patients, who had a pregnancy while taking isotretinoin, were pregnant when the drug was started. When considering treatment with isotretinoin in females of childbearing age, the FDA requires documentation of two negative pregnancy tests. Contraceptive counseling must be done and documented on the patient’s chart, and two forms of birth control are recommended for the duration of therapy plus 6 weeks posttherapy. Therapy should be started on the third day of the menstrual cycle with a negative pregnancy test to ensure that the patient is not pregnant when therapy is initiated. Beginning in March 2006, the FDA requires all patients, prescribers, and dispensers of isotretinoin to be registered with the internet-based iPLEDGE program (www.iPLEDGEprogram.com).

Other side effects of isotretinoin include dry skin, lips, and eyes, dry mucous membranes with nosebleeds, headache (including rare instances of pseudotumor cerebri), muscle and backaches, hypertriglyceridemia, increased liver function tests, and depression (see next question). These should be discussed in detail with the patient prior to starting therapy and documentation of the discussion made in the chart. There are also several case reports of inflammatory bowel disease (IBD) being triggered by isotretinoin use. A review of adverse events reported to the United States FDA Medwatch scheme over a 5-year period (1997 to 2002) revealed 85 cases of IBD, of which the causal association with isotretinoin was considered probable or highly probable in 73% of cases.

Reddy D, Siegel CA, Sands BE, et al: Possible association between isotretinoin and inflammatory bowel disease, Am J Gastroenterol 101:1569–1573, 2006.

A number of case reports and case series appear in the literature that link depression, suicide, and suicidal ideation to isotretinoin use. In several of these cases, cessation of the drug resulted in improvement of the depressive symptoms and rechallenge caused recurrence of depression. Between 1982 and 2000, the FDA received reports of 394 cases of depression and 37 suicides occurring in patients exposed to isotretinoin. However, depression is more common in the age group affected by acne than in the general population. To complicate matters further, there is evidence that acne itself has significant psychological effects, and there are case reports of improvement in depression scores of acne patients during and after treatment with isotretinoin. Epidemiologic studies to date have not shown a causal relationship between isotretinoin and depression and suicide. Because depression and suicide are serious matters, careful monitoring of patients undergoing therapy with isotretinoin for signs/symptoms of depression and suicidal ideation is advisable.

Magin P, Pond D, Smith W: Isotretinoin, depression, and suicide: a review of the evidence, Br J Gen Pract 55:134–138, 2005.

One of the important pathogenic mechanisms of acne is Propionibacterium acnes growth in the follicle. P. acnes produces porphyrins, which can be activated by visible light, inducing a photodynamic reaction that kills the bacteria. Several studies have shown improvement in acne utilizing visible light, especially in the blue light spectrum (400 to 420 nm) where these porphyrins are most strongly activated. Blue and red (660 nm) light combined has also been used, as well as light in the yellow and green spectrum (500 to 600 nm). Several studies have shown improvement in acne lesions with relatively few side effects. However, clearing seems to be variable among patients and relapse rates are high.

Photodynamic therapy utilizes a lower-power visible light source in which the effectiveness is amplified by the use of a topical photosensitizing agent, most often aminolevulinic acid (ALA). Photodynamic therapy tends to have more side effects, such as burning at the sites of treatment and postinflammatory hyperpigmentation. Existing studies suggest promise for this therapy, with sustained improvement in acne for up to 20 weeks after several treatments.

Several laser devices have been employed and studied in the treatment of acne. There are a few small studies evaluating the 1450-nm diode laser was used to target and destroy sebaceous glands. Due to differences in treatment regimen and other allowed acne treatment, no comparisons can be made between studies.

Elman M, Lebzelter J: Light therapy in the treatment of acne vulgaris, Dermatol Surg 30:139–146, 2004.

Theboutot D, Gollnick, H, Bettoli V, et al: New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne Group, J Am Acad Dermatol 60:S1–S50, 2009.

This syndrome combines synovitis, acne, pustulosis, hyperostosis, and osteitis. It is a disorder characterized by noninfectious osteoarticular inflammatory lesions and a variety of skin abnormalities demonstrating aseptic, neutrophil-rich pseudoabscesses. In adults, chronic multifocal osteomyelitis is a classic manifestation. Skin findings include palmoplantar or other forms of pustulosis, severe acne, or psoriasis. The acne associated with this syndrome is most often acne conglobata, with highly inflammatory comedones, nodules, abscesses, and draining sinuses located primarily on the trunk, which often heal with significant scarring.

Magrey M, Kahn MA: New insights into synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome, Curr Rheumatol Rep 11:329–333, 2009.

Yes. Neonatal acne occurs in up to 20% of newborns; it usually develops during weeks 2 to 4 of life (Fig. 21-3). It is more common in males, is relatively mild, and regresses spontaneously in most infants by age 6 months. It is thought to be due to maternal androgens and is not associated with significant scarring or an increased incidence of acne in later life. Infantile acne usually begins between the third and sixth months of life and may persist to age 5 and rarely longer. It is uncommon and occurs more often in males. It can be severe, with nodules, cysts, and significant residual scarring. Endocrine abnormalities and virilizing tumors can be associated. Some studies show an increased incidence of severe acne in later life.

A wide range of drugs have been reported to cause or aggravate acne, although many of these associations are isolated case reports (Table 21-2).

This is an acute, ferocious skin disease of women aged 15 to 40. It strikes like a hurricane, often in patients with no previous history of acne. It most commonly involves the central face but may affect the upper trunk. It is characterized by severe pustules, nodules, cysts, and draining sinus tracts (Fig. 21-4). Many of the patients have a history of flushing, and some authors regard it as a severe variant of acne rosacea. It has been reported in some patients during pregnancy or immediately postpartum.

This is one of the few times that oral steroids should be used to treat acne. Prednisone in a dose of 40 to 60 mg daily tapered over 3 to 4 weeks is indicated. Isotretinoin should be started in a dose of 1 mg/kg/day in conjunction with the prednisone and continued for 4 to 6 months. Once the disease has been brought under control, it rarely, if ever, recurs.

Table 21-2. Drugs That Cause or Aggravate Acne

Steroid hormones Topical corticosteroids Systemic corticosteroids Anabolic steroids Some progestins Testosterone Antidepressants Lithium Amineptine Antiepileptic drugs Phenytoin Trimethadione

Halogens Iodides Bromides Halogenated hydrocarbons Antituberculous drugs Isoniazid Miscellaneous drugs Thiourea Thiouracil PUVA

PUVA, Psoralen plus ultraviolet light, type A.

Plewig G, Jansen T, Kligman AM: Pyoderma faciale, Arch Dermatol 128:1611–1617, 1992.

This rare systemic disease is seen predominately in young men. Its clinical features include fever, polyarthritis, leukocytosis, malaise, weight loss, anorexia, and severe, acute cystic and often ulcerative acne lesions. It occurs primarily on the upper trunk, but lesions may also be seen on the buttocks, proximal extremities, neck, and face (Fig. 21-5). The etiology is unknown, but it is thought to be immunologically mediated. It has been described in young men, particularly soldiers, who are introduced into a tropical environment where they are exposed to high humidity, temperature, and the friction of wearing a backpack. Like pyoderma faciale, it usually responds well to treatment with isotretinoin and oral prednisone.

Hidradenitis is a chronic, suppurative, recurring inflammatory disease that affects apocrine gland–bearing sites. The axilla and groin are most frequently involved, but the disease is also seen on the perineum, buttocks, neck, and scalp (Fig. 21-6). It is more common in females and begins after puberty. It is characterized by inflammatory nodules, abscess formation, scarring, and sinus tract formation.

This frustrating chronic disease is treated by measures that reduce friction and moisture. Weight reduction, loose undergarments, topical antiseptic soaps, and topical aluminum chloride are helpful in some patients.

Acne rosacea is a chronic skin disease that most commonly occurs between the ages of 30 and 50 years, although it can be seen in adolescents and elderly patients. The course is typically chronic with remissions and relapses. It is characterized by flushing, telangiectasia, papules, and pustules, and in severe late-stage disease, patients may develop chronic facial lymphedema and rhinophyma. It is usually symmetrical and is most commonly seen on the convex areas of the face, including the nose, cheeks, forehead, and chin (Fig. 21-7). Blepharitis, conjunctivitis, and keratitis are common associations.

The etiology of rosacea is unknown. Genetic factors seem to play a role in that the disease is more common in persons of Celtic ancestry and less common in blacks. Factors that stimulate flushing, such as hot beverages, alcohol, ultraviolet light exposure, and emotional factors, frequently exacerbate the disease. A rosacea-like eruption can be induced by the topical application of fluorinated corticosteroids and tacrolimus ointment to the face.

Powell FC: Rosacea, N Engl J Med 352:793–803, 2005.

Trigger factors that produce flushing should be avoided. These triggers vary greatly from patient to patient. Both oral and topical metronidazole are effective. Topical erythromycin, azelaic acid cream, and sodium sulfacetamide have also been shown to be effective treatments. Tetracycline, doxycycline, minocycline erythromycin are effective systemic therapies for rosacea. Subantimicrobial doses of doxycycline (40 mg extended release tablet) have been shown to decrease papulopustules in rosacea via antiinflammatory effects. Combined with topical azelaic acid or metronidazole there seems to be a synergistic effect.

Oral isotretinoin is helpful for severe resistant cases, but the drug is not as effective as when used for severe cystic acne, and relapses are more common. Oral antibiotics have little effect on flushing, telangiectasia, lymphedema, or rhinophyma. Isotretinoin may provide some benefit for early rhinophyma, but severe rhinophyma is best treated by surgical paring or electrosurgery. Persistent telangiectasia can be treated by a tunable dye vascular laser with good cosmetic results.

Fowler JF Jr: Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, USP monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea, J Drugs Dermatol 6: 641–645, 2007.