Acne vulgaris, Acne conglobata & Acne fulminans

Are You Confident of the Diagnosis?

Acne is an exceptionally common disorder in adolescents, affecting up to 85% of 12-24–year olds. In fact, most patients can accurately diagnose themselves. The presence of inflammatory papules and pustules along with comedones, involving the face, chest, shoulders and back, are hallmarks of acne vulgaris. Nodules and nodulocystic lesions are seen in more severe disease. Secondary changes, such as scarring and post-inflammatory hyperpigmentation or erythema are common and should be documented, as they impact both management and disease outcomes.

Characteristic findings on physical examination

Lesions of acne include open and closed comedones. Open comedones, or “blackheads,” are small, approximately 1 mm papules with a dilated follicular outlet that is black (Figure 1). The black color is thought to result from melanin deposition and lipid oxidation of keratin debris within the follicle. Closed comedones are similarly sized papules without an apparent follicular opening (Figure 2). Importantly, both open and closed comedones lack any associated erythema. Deep comedones can often be quite large and may have no follicular outlet. Stretching the skin makes these more apparent

The clinically inflammatory lesions seen in acne vary from papules and pustules to more severe nodules and nodulocystic lesions (Figure 3). Papules are less than 0.5cm in size. Pustules are similarly sized and filled with thick, white, purulent fluid. The presence of nodules often correlates with greater acne severity. Nodules are greater than 0.5cm and can be indurated and very tender. At times, nodules can combine; forming large suppurative plaques that can result in persistent scarred sinus tracts.

Algorithm I.n

Acne Treatment Algorithm

Additionally, it is important to note the presence of secondary changes of acne. Scarring most often results from more severe inflammatory acne lesions but can occur with milder forms as well. Keloids may form in at-risk individuals. They usually arise in cases of severe nodular acne, but can occur in fairly mild cases as well. In darker skinned patients, post-inflammatory hyperpigmentation is often present and can last for several months after resolution of inflammatory acne, and in rare instances may be permanent. Lighter skinned patients may show postinflammatory erythema that also can take many months to improve.

Acne Variants

Acne fulminans is a severe, eruptive form of acne that primarily occurs in teenaged boys, ages 13-16. The acne appears abruptly over the face and upper body with uniform papules and friable nodules that can coalesce, suppurate and bleed. Scarring, often severe and keloidal, is inevitable. Systemic symptoms often accompany acne fulminans. These include: fever, arthralgias, myalgias and heptosplenomegaly. Osteolytic bone lesions, affecting the clavicle or sternum most commonly, may be associated. Eythema nodosum has been reported with acne fulminans as well.

Laboratory studies are nonspecific but reflect the degree of inflammation. Abnormalities include leukocytosis, anemia, elevated erythrocyte sedimentation rate and proteinuria. Treatment of acne fulminans is aimed at controlling the inflammation quickly while preventing an isotretinon-associated flare (see treatment).Typically oral corticosteroids are started with a gradual introduction of isotretinoin.

Acne conglobata is another form of severe, nodulocystic acne. Numerous nodules melt together into suppurative plaques. This form is notoriously difficult to treat and residual scarring is quite severe. Isotretinoin is the most effective treatment, but recurrences may occur. Acne conglobata is included in the follicular occlusion tetrad along with hidradenitis suppurativa, dissecting cellulitis of the scalp and pilonidal cysts.

Neonatal acne (acne occurring from birth to about 3 months) affects about 20% of healthy newborns and typically presents as small inflamed papules and pustules on the cheeks and nasal bridge. Comedones are not present. It generally resolves spontaneously. Yeast, including Malessezia species, are thought to play a pathogenic role. Neonatal cephalic pustulosis is an alternate term used to describe this benign neonatal eruption.

Infantile acne generally occurs between 3 and 6 months of age, lasting throughout the first and into the second year of life. Comedones are present, along with variable inflammatory lesions. Acne in this age group is due to elevated androgen levels, including DHEAS resulting from an immature adrenal gland. Boys may also have increased testosterone production. Treatment is indicated, as scarring commonly occurs in this age group.

Mid-childhood acne presents after 1 year to 7 years. The presence of acne in this age group warrants evaluation for hyperandrogen states including: Cushing syndrome, congenital adrenal hyperplasia (CAH), premature adrenarche, gonadal or adrenal tumors, and precocious puberty. A full physical exam looking for secondary sexual characteristics, review of growth charts, and a bone age should be performed. Laboratory studies should include TSH, LH/FSH, prolactin, 17-hydroxyprogesterone, serum DHEAS, and total and free testosterone. Additional evaluation includes ultrasound and MRI as indicated. A pediatric endocrinologist should be consulted to evaluate the child if any abnormal parameters are found.

Preadolescent acne occurs with the normal onset of adrenarche, usually about 7-8 years of age. Comedonal acne predominates with a midline distribution of lesions. Early, severe comedonal acne is associated with more severe adolescent acne, thus warranting long-term follow-up.

Differential Diagnosis

The differential diagnosis for acne (Table I) is relatively large but can be appropriately narrowed based on the age of the patient as well as the morphology and distribution of the lesions.

Table I.

Acne Vulgraris – Comedonal	Acne Vulgaris- Inflammatory	Neonatal/ Infantile Acne
Milia	Rosacea	Sebaceous hyperplasia
Contact acne	Lupus miliaris disseminata faciei	Miliaria
Steroid acne	Steroid acne	Milia
Angiofibromas	Drug-induced acne	Infantile eosinophilic pustulosis
Trichodiscomas	EGFR inhibitor acneiform eruption	Idiopathic facial aseptic granuloma
Trichoepitheliomas	Perioral dermatitis	Neonatal cephalic pustulosis
Fibrofolliculomas	Keratosis pilaris
Trichostasis spinulosa	Pseudofolliculitis
Sebaceous hyperplasia	Staphylococcal folliculitis
Dilated pore of Winer	Eosinophilic folliculitis
Favre-Racouchot	Gram-negative folliculitis
Nevus comedonicus	Acne keloidalis nuchae
Familial juvenile colloid milium	Furuncle /carbuncle
Steatocystoma multiplex	Neurotic excoriations/ facticial
Eruptive vellus hair cysts

In adolescents and adults the differential diagnosis is extensive and includes:

1. Keratosis pilaris (small,dry, “goosebump-like” follicular papules particularly on the extensor surface of the arms, but can also be present on the face, especially in children)

2. Perioral dermatitis/periorificial dermatitis (small, grouped, erythematous papules in a periorificial distribution (mouth, nose, eye, and groin) with sparing of the skin around the vermilion border of the lip)

3. Folliculitis including staphylococcal folliculitis, gram-negative folliculitis and eosinophilic folliculitis (erythematous papules and pustules that can be differentiated from acne by their monomorphous nature and lack of comedones)

4. Sebaceous hyperplasia (lobulated papules that are yellow in color and typically present on the forehead and cheeks of adults, erythema, and comedones are not present)

5. Papulopustular rosacea (background erythema, papules and pustules in a central facial distribution, can be separated from acne by the presence of telangectasias and the absence of comedones)

6. Pseudofolliculitis barbae/acne keloidalis nuchae (inflammatory papules and pustules that occur in the beard and nuchal area).

Additionally, true acne vulgaris should be differentiated from acneiform eruptions. These include:

1. Drug-induced acne (monomorphous papular eruption, unlike acne vulgaris which is polymorphous; can be caused by several medications, most notably systemic corticosteroids)

2. Tropical acne (follicular acneiform eruption that results from exposure to extreme heat, typically occurs in the trunk and buttock area, history of exposure to tropical climate or sweltering occupational environment such as furnace worker can be elicited)

3. Radiation acne (comedo-like papules that occur in sites of previous radiation exposure, tend to appear as the acute phase of radiation dermatitis is resolving)

4. Acne cosmetica (papules and pustules with or without accompanying comedones that most commonly affects adult women. Inquire about recent use of new cosmetics)

5. Acne mechanica (acne that occurs in a linear or geometric distribution. Inquire about use of chin straps, helmets or other causes of repeated mechanical friction to the skin)

6. Occupational acne (results from exposure to follicle-occluding substances. Ask about exposure to cutting oils, chlorinated aromated hydrocarbons, or coal tar derivatives)

7. Epidermal growth factor receptor inhibitor- (EGFR) induced eruption. (EGFR inhibitors are drugs used in the treatment of solid tumors and a subsequent acneiform eruption commonly occurs in treated patients; the papules and pustules are monomorphous and follicular in appearance, additionally comedones are noticeably absent.)

In neonates, the following differential diagnosis should be considered:

1. Sebaceous hyperplasia (transient yellow papules on cheeks, nasal bridge, and forehead can be differentiated from acne by their yellowish color and non-inflammatory nature)

2. Mila (small, white, noninflammatory papules on the cheeks and nose that spontaneously resolve)

3. Milaria rubra (small red papules on a background of erythema caused by temporary obstruction of eccrine ducts from overheating and bundling. They are more uniform in nature than neonatal acne and resolve spontaneously when the source for excess sweating is removed.)

Who is at Risk for Developing Acne Vulgaris?

Acne is a common disorder in adolescents, affecting up to 85% of 12-24 year olds. Adult acne is much more prevalent than originally thought.The reported prevalence of acne in women aged 30-39 years is 35%. Adolescent acne appears to show a slightly more male predominance while, while post-adolescent acne predominantly affects women. Genetic influences and ethnicity also impact risk. A patient with severe acne is more likely to report a family history of severe acne. Women with hormonal abnormalities as well as diseases of insulin resistance such as polycystic ovarian syndrome (PCOS), are at risk for development of acne. Other groups with an increased risk for development of acne include those with hyperandrogenism, hypercortisolism, precocious puberty and those with the XYY genotype. Additionally, these groups tend to have acne that is more severe and less responsive to traditional therapy.

What is the Cause of Acne Vulgaris?

Etiology
Pathophysiology

The pathophysiology of acne vulgaris centers on the pilosebaceous unit and is multifactorial. There are four primary factors identified, which are all intertwined and not sequential in occurrence:

Increased sebum production. At puberty, increased sebum production occurs in conjunction with enlarging sebaceous glands. This provides a lipid rich environment ideal for Propinobacterium acnes (P. acnes), a resident anaerobic diptherioid. Increasing androgen levels, particularly DHEA and DHEAS are thought to hormonally drive acne in part through increased sebum production (though most patients with acne do not have grossly elevated androgen levels, they do trend higher than their unaffected counterparts).
Follicular hyperkeratinization. Hyperkeratinization of the follicle results in the formation of a hyperkeratotic plug or microcomedo. This results in impaired sebum excretion and induces local inflammatory mediators, including IL-1.
Increased colonization of P. acnes. P. acnes are gram-negative, nonmotile rods that normally colonize the skin. They are proinflammatory, releasing lipases and other enzymes. They have been shown to activate inflammasomes (NLRP3) and caspase-1 resulting in secretion of IL-β. Recent studies have shown increased IL-17(through Th17+ lymphocytes) as well. They also induce innate immunity inflammatory cascades, through toll-like receptor 2 and metalloproteinases.
Inflammation. This is caused by a variety of factors, including: the proliferation of P. acnes, the proinflammatory cascades it promotes, and hyperkeratinization, all resulting in the eventual rupture of the follicle and attraction of cellular inflammatory infiltrate to the area.

A high glycemic diet has been stipulated as a potential aggravator of acne, but a strong link between diet and acne remains to be proven. Dairy, particularly skim milk, has also been implicated as a possible aggravating factor in acne. However, these data need to be corroborated by clinical trials before recommendations to patients can be made. Additionally, while patients often report that their acne flares during periods of high stress, a strong causal association has not been shown. Genetic influences can influence the severity of disease.

Systemic Implications and Complications

There are several complex syndromes where acne or acneiform eruptions may be the common presenting feature. Warning signs to suggest that acne may be part of an underlying medical syndrome include acne that is very severe, treatment resistant, diffuse in presentation or sudden in onset.To accurately diagnose these syndromes, a detailed medical history must be obtained. Patients should be asked about the presence of hair loss, hirsutism, irregular menses, and arthritis, which are commonly associated features of these syndromes.

Polycystic Ovarian Syndrome (PCOS) – The most common syndrome associated with acne is PCOS, an endocrine disorder characterized by polycystic ovaries, oligo and/or anovulation, and biochemical and/or clinical signs of hyperandrogenism. Five to 20 percent of women are thought to suffer from this disorder. PCOS is also strongly associated with insulin resistance.

Women with PCOS frequently also suffer from acne, central obesity, hirsutism, alopecia and infertility. Acne is present in 23-35% of women with PCOS. PCOS should be suspected in women whose acne is severe, persistent and resistant to conventional therapies. Biochemical markers of hyperandrogenism include elevated serum testosterone (from 150 to 200 ng/dl) and an increased LH/FSH ratio greater than 2–3:1. Treatment consists of weight loss, insulin sensitizers such as metformin, and oral contraceptives.

SAHA – The association of seborrhea and acne with hirsutism and/or androgenic alopecia characterizes SAHA syndrome. It is thought to result either from elevated circulating androgen levels or increased sensitivity of the pilosebaceous unit to androgens. The full clinical spectrum rarely occurs (20% of patients exhibit all four symptoms); however, seborrhea is always present. Acne occurs in a minority (10%) of patients. Treatment consists of lifestyle modification (weight loss), oral contraceptives, insulin sensitizing agents, and antiandrogens.

This disorder affects approximately 1% of the general population, is marked by signs of hyperandrogenism: childhood or adolescent acne, hirsutism and androgenic alopecia. Additional signs in females include unrecognized genital structural defects, abnormal menstrual cycles or infertility. This form is due to partial defects in 21-hydroxylase and the severity of presentation is highly variable.

The clinical signs of non-classical CAH result from impaired aldosterone and/or cortisol mediated negative feedback control of ACTH secretion.Treatment of CAH therefore consists of substituting cortisol (oral glucocorticoids) and/ or aldosterone (fludrocortisone) daily. Similarly the treatment of acne in non-classical CAH, which is often severe, cystic and refractory to antibiotics and isotretinoin, consists of low dose oral glucocorticoids which counteract adrenal androgen production, specifically, low dose oral prednisolone (2.5-–5 mg per day) or dexamethasone (0.25–0.75 mg nightly).

Apert syndrome – This congenital disorder is also known as acrocephalosyndactyly and results from mutations in FGFR2, which encodes fibroblast growth factor receptor. This autosomal dominant disorder is also defined by disfiguring synostoses of the bones of the hands and feet, vertebral bodies, and cranium. Patients with Apert syndrome present with widespread acneiform papules, including the entire extensor aspects of the arms, buttocks and thighs. Unfortunately, the acneiform lesions of Apert syndrome are highly resistant to topical therapies; however, isotretinoin has been beneficial in severe cases.

PAPA – The triad of sterile pyogenic arthritis, pyoderma gangrenosum, and acne conglobata characterizes PAPA syndrome.It results from mutations in the gene that encodes proline–serine–threonine phosphatase interacting protein 1 (PSTPIP1; also known as CD2 antigen-binding protein 1 [CD2BP1]) and is part of a related group of inflammatory disorders that includes inflammatory bowel disease, uveitis, and psoriasis. Treatment involves oral glucocorticoids, which concomitantly helps treat the arthritis, pyoderma gangrenosum and acne conglobata. Disease modifying agents, biologic therapies and dapsone have also been shown to be efficacious.

SAPHO – This syndrome is a rare disorder (occurring in 1/10,000) that is characterized by chronic recurrent osteomyeltis, acute sterile arthritis, or sterile osteitis with associated skin manifestations such as pustular psoriasis, palmoplantar pustulosis or severe acne. The clinical presentation of acne can be variable but is typically more consisting of acne conglobata or acne fulminans. Treatment of SAPHO is difficult, and many different classes of drugs have been tried in the past with conflicting results. Nonsteroidal anti-inflammatory agents and disease modifying agents, such as methotrexate, are typically used. Recently, TNF-alpha blockers such as infliximab have emerged as a promising new treatment.

Treatment Options

Treatment options are summarized in (Table II.

Table II.

Topical Treatment Options

Retinoid	Brand	Formulation	Size	Comments
	Generic	tretinoin cream 0.025%,0.05%, 0.1%tretinoin 0.01%, 0.025% gel	20g, 45g15g, 45g	Caution patients on waxing while on topical retinoidsUse with BPO may inactivate tretinoin
	Retin-A®	tretinoin cream 0.025%,0.05%, 0.1%tretinoin 0.01%, 0.025% gel	20g, 45g15g, 45g	Microsphere gel
	Retin-A Micro®	tretinoin 0.04%, 0.1% gel	20g, 45g, 50g
	Avita®	tretinoin 0.025% cream tretinoin 0.025% gel	20g, 45g	Gel contains 83% ethanol
	Tretin-X™	tretinoin 0.025%, 0.05%, 0.1% creamtretinoin 0.0375% creamtretinoin 0.01% 0.025% gel	35g kit35g35g	Kit includes cleanser and moisturizergel contains 90% alcohol
	Atralin™	0.05% gel	45g	Contains fish collagen
	Refissa™	0.05% cream	40g
	Ziana™	tretinoin 0.025% + clindamycin 1.2% gel	30g, 60g
	Veltin™	tretinoin 0.025% + clindamycin 1.2% gel	30g, 60g
	Generic	adapalene 0.1% gel adapalene 0.1% cream	45g
	Differin®	adapalene 0.1%, 0.3% gel adaplaene 0.1% creamadapalene 0.1% lotion	45g	Alcohol free gel
	Epiduo®	adapalene 0.1%+ benzoyl peroxide 2.5% gel	45g
	Tazorac®	tazarotene 0.1% cream tazarotene 0.1% gel	30g, 100g
Benzoyl Peroxide	Numerous OTC/ RX preparations	benzoyl peroxide 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.3%, 5.5%, 7%, 8%, 8.5%,10%bar, cloth, cream, foam, gel, liquid, lotion, pad, soap, wash	varies	Bleaching agent. Warn patients to protect linens and clothing. May apply to back/ chest if patient wears a white T shirt at night.
Benzoyl Peroxide + Erythromycin	Generic	benzoyl peroxide 50 mg/g + erythromycin 30mg	23g, 47g
	Benzamycin®	benzoyl peroxide 50 mg/g + erythromycin 30mg	47g	Contains 20% alcohol
	Benzamycin® Pak	benzoyl peroxide 50 mg/g + erythromycin 30mg per 0.8g packet	60s
Benzoyl Peroxide + Clindamycin	Generic	benzoyl peroxide 5% + clindamycin 1%	50g
	BenzaClin®	benzoyl peroxide 5% + clindamycin 1%	25g50g pump
	Duac® CS	benzoyl peroxide 5% + clindamycin 1%	1 kit	Kit with cleanser
	Acanya®	benzoyl peroxide 2.5% + clindamycin 1%	50g
Erythromycin	Generic	erythyromycin 2% gelerythromycin 2% solution	30g, 60g60ml
	Akne-mycin®	erythromycin 2% ointment	25g
	Ery®	erythromycin 2% pledget	60s
Clindamycin	Generic	clindamycin 1% gelclindamycin 1% lotionclindamycin 1% pledgetclindamycin 1% solution	30g, 60g60ml60s,30ml, 60ml	Pledget contains 50% isopropyl alcohol
	Cleocin T®	clindamycin 1% gelclindamycin 1% lotionclindamycin 1% pledgetclindamycin 1% solution	30g, 60g60s30ml, 60ml	Pledget contains 50% isopropyl alcohol
	Clindgel®	clindamycin 1% gel	40ml, 75ml
	Clindamax®	clindamycin 1% gelclindamycin 1% lotion	30g, 60g60ml
	Evoclin®	clindamycin 1% foam	50g,100g	Contains 58% ethanol
	ClindaReach®	clindamycin 1% pledget	120s	Pledget contains 50% isopropyl alcohol
Azelaic acid	Azelex®	azelaic acid 20% cream	30g, 50g
Dapsone	Aczone®	daspone 5% gel	30g, 60g	May cause reddish-orange staining when used with BPOSafe in G6PD deficient patientsSafe in those that are sulfa allergic
Salicylic acid	Numerous OTC preparations	salicylic acid 0.5%, 2%bar, cloth, cream, gel, foam, liquid, lotion, ointment, wash	varies

Oral Treatment Options

Antibiotics	Brand	Formulation	Dose (Range)	Comments
	Generic	Tetracycline250mg, 500mgcapsule	500mg bid(250mg to 500mg once or twice daly)	Must take on an empty stomach.
	Generic	Doxycycline50mg,100mgcapsule or tablet	100 mg bid(50 to 100 mg po once or twice daily)	Generally taken with food to decrease GI upset.Warn about photosensitivity
	Adoxa®:	Doxycycline75mg, 150mg capsule	75mg or 150mg daily	Once daily dosing
	Monodox®	Doxycycline50mg, 75mg,100mg capsule	50 mg, 75mg or 100 mg dialy to twice daily
	Doryx®	Doxycyline extended release75mg, 100mg, 150mgtablet	75mg to 150mg daily	Once daily dosing
	Vibramycin®	Doxycycline syrup50 mg/5 mL	100 mg bid(50 to 100 mg po once to twice daily)	Raspberry-apple flavor
	Generic	Minocycline50 mg, 75 mg, 100 mgcapules/ tablets	100mg twice daily(50mg to 100mg daily to twice daily)	May take with food. Counsel patients on risk of pseudotumor cerebri, blue hyperpigmentation, autoimmune hepatitis and drug induced lupus. may decrease efficacy of oral contraceptive therapy.
	Minocin®Minocin® PAC	Minocycline50 mg, 100 mgcapsule	100mg twice daily(50mg to 100mg daily to twice a day)
	Dynacin®	Minocycline50 mg, 75mg, 100 mgcapsule	50 mg, 75mg or 100 mg daily to twice daily
	Solodyn®	Minocycline extended release	45-54 kg: 45 mg daily55-77 kg: 65 mg daily78-102 kg: 90 mg daily103-125 kg: 115 mg daily126-136 kg: 135 mg daily	Once daily dosing

Retinoids	Brand	Formulation	Dose	Comments
	Branded Generics: Amnesteem® Claravis™ Sotret®	Isotretinoin10 mg, 20 mg, 30 mg, 40 mg capsule	0.5mg to 1mg/kg/day ÷ bid	Must comply with iPledge risk management programTake with food for better absorptionWarn female (and male) patients not to wax hair while on isotretinoin
Intralesional Treatment Options

Corticosteroids	Brand	Formulation	Dose	Comments
	Generic	triamcinolone acetonide	2.5mg to 5 mg/ ml injection	Inject into larger, resistant nodules. Risk of atrophic scarring and hypopigmentation in darker skin types.

Optimal Therapeutic Approach for this Disease

General History and Physical Examination

The first step is to complete a thorough history and physical examination. This will help you organize an appropriate and effective treatment plan.Specifically ask about all prescription and over-the-counter medications used for acne or other conditions. Note the clinical responsiveness and tolerability to any prior treatments. In female patients, a menstrual and oral contraceptive history is important in determining hormonal influences on acne.

Female patients may report a worsening prior to their menses. Stress is also often associated with flares, and it is common for students to report that their acne appears to worsen around exam time or finals. Patients may also report an exacerbation with certain foods (eg. dairy, high fat foods, and chocolate) although a clear association between any particular food and acne has not been proven. Also ask use of about cleansers, toners, and moisturizers, as harsher products may affect tolerability. It is also important to speak frankly with the patient and determine what effect the acne is having on their quality of life.

Negative psychological outcomes such as anxiety, depression, and social withdrawal, are widely reported among individuals with acne and acne scars. If the patient complains of significant anxiety or depression, this should be noted and an appropriate referral to a psychologist or psychiatrist may be necessary if severe.

A detailed medication history should always be taken, including the use of vitamin, protein/muscle building supplements. Several medications are known to cause acne or acneiform eruptions, particularly: corticosteroids, phenytoin, lithium, and isoniazid as well as vitamins B2, B6 and B12. It is important to ask about use of topical cosmetics and hair products, as some oils within these products may worsen acne. Additionally, it is useful to ask about patients’ occupational history, including their hobbies, as these may result in aggravation of acne. For example, it may be important to ask about the use of anabolic steroids in athletic young men.

On physical examination, carefully note the lesion morphology, including the presence of comedones, inflammatory lesions, and nodules. Also look for secondary changes such as scarring and postinflammatory pigmentary changes, as these are important clinical findings that may alter your treatment strategy. Note the patient’s skin type; this may affect the chosen formulation for topical medications.

Labwork is rarely necessary in the diagnosis of acne, especially in the adolescent population, but may be warranted if acne is very abrupt in onset or accompanied by other signs of hormonal or metabolic imbalance such as hirsutism, hair loss, or other signs of virilization. Onset of acne in mid-childhood always warrants a complete evaluation for causes of androgen excess.

Treatment Algorithms

The algorithms below provide a treatment overview followed by specific algorithms for treatment of mild, moderate, and severe acne.

Acne Treatment Algorithm 1

Algorithm I.

Initial treatment	2nd line	3rd line
Topical retinoid +/- BPOor BPO aloneor BPO/ antibiotic * may be given singly or in manufactured combination form	Add retinoid or BPO or BPO/ antibiotic (if not already in combination)	See moderate acne
	Change retinoid or BPO formulation
	Azelaic acid or salicylic acid or topical dapsone

Algorithm 2

Algorithm II.

Initial treatment	2nd line	3rd line
Topical retinoid+ BPO* or BPO/ antibiotic +Oral antibiotic (in some cases) may be given singly or in manufactured combination form	Add retinoid or BPO or BPO/ antibiotic (if not already in combination regimen)Change retinoid or BPO formulation	See severe acne
	Add or change oral antibiotic
	Add azelaic acid or salicylic acid or topical dapsone
	In females: Consider hormonal therapy (oral contraceptive pill or spironolactone)

Algorithm 3

Algorithm III.

Initial treatment	2nd line	3rd line
Topical retinoid+BPO* or BPO/ antibiotic +Oral antibiotic may be given singly or in manufactured combination form	Isotretinoin	Oral dapsone
Isotretinoin (in severe, nodular acne)	Change retinoid or BPO or BPO/ antibiotic formulationChange oral antibiotic
	Add azelaic acid or salicylic acid or topical dapsone
	In females: Consider hormonal therapy (oral contraceptive pill or spironolactone)

Topical Retinoids

Retinoids are anticomedogenic (through normalization of follicular keratinization), comedolytic, have significant direct and indirect anti-inflammatory effects, and prevent the formation of new microcomedos. This is particularly important, as the microcomedo is the precursor to all acne lesions, both comedones and papules/pustules.

The most commonly utilized topical retinoids include: tretinoin, adapalene, and tazarotene. Tretinoin was the first topical comedolytic agent developed for the treatment of acne. Adapalene is a synthetic retinoid that specifically binds the retinoic acid receptor Ɣ (RARƔ). Unlike tretinoin, adapalene is light-stable and resistant to oxidation by benzoyl peroxide. Tazarotene is also a synthetic receptor specific retinoid that is converted to its active metabolite, tazarotenic acid, when applied to the skin.

As previously mentioned, enhanced efficacy of topical retinoids is achieved when used in combination with benzoyl peroxide or other topical antibiotics. This is because topical retinoids normalize desquamation and enhance the penetration of coadministered medication into the sebaceous follicle. Additionally, antimicrobial agents also induce mild keratolytic effects by mechanisms that are different from those of retinoids.

Patients should be advised that local erythema, dryness, and itching commonly occur within the first weeks of usage but these effects decrease with continued use. Additionally, a pustular flare of acne during the initial 3–4 weeks of treatment may occur, however it resolves spontaneously with continued usage. With continued use of topical retinoids, irritation and thinning of the stratum corneum may increase the user’s susceptibility to sunburn. Therefore, the use of sunscreens is advised.

Patients should be instructed to apply a pea-sized amount of retinoid all over their face, not just active areas. If tretinoin is being used it must be applied at night to prevent early degradation as it is photolabile. If BPO is also being used, patients should be advised to use this in the morning, as tretinoin is susceptible to oxidation by BPO. Unlike tretinoin, adapalene is light-stable and resistant to oxidation by BPO. It is also less drying and has a milder side effect profile.

To minimize excessive dryness and irritation, patients should be started on a lower-concentration retinoid with gradual increase in the strength and frequency as necessary. For example, alternate-night to every-third-night application may be necessary initially; frequency can be increased in stepwise 3-4 week increments as tolerated. As retinoids are known teratogens, the use of topical retinoids, particularly tazarotene during pregnancy is discouraged.

Benzoyl Peroxide and Topical Antibiotics

Benzoyl peroxide (BPO) is a potent bacteriocidal agent that primarily works by reducing P. acnes within the follicle. As previously mentioned, it is effective when used alone or when combined with topical retinoids. In contrast to topical antibiotics, microbial resistance to BPO has not been reported. It is therefore preferable to topical antibiotics for long-term use and maintenance therapy.

Many preparations of BPO are available in both over-the-counter and prescription formulations. These include bar soaps, washes, gels and lotions that are available in concentrations of 2.5%, 5% and 10%. Higher concentrations of BPO may be more irritating and not necessarily more efficacious than lower concentrations. The formulation is also an important cofactor in the product’s irritancy.

Patients should be advised that benzoyl peroxide is a bleaching agent and whitening of clothing, towels, and bedding can occur. Bleach resistant bedding is available at some major national retailers. Also, development of contact dermatitis to benzoyl peroxide is possible, and should be suspected in patients who develop marked erythema with its use.

Other commonly used antimicrobials include topical antibiotics such as clindamycin and erythromycin. They are available in various formulations from creams and gels to solutions and pledgets. Because of the risk of antibiotic resistance, it is preferable that topical antibiotics alone be avoided as monotherapy and should be paired with BPO.

Manufactured Combination Products

Fixed-dose combination products with a topical retinoid and an antimicrobial are available. By nature they provide improved patient convenience, which may translate to improved adherence. Currently, adapalene is the only topical retinoid to be formulated with BPO.

Combined adapalene and BPO has greater efficacy than monotherapy with either product alone with a cutaneous tolerability that is comparable to adapalene monotherapy.

Both clindamycin and erythromycin are available in topical combination formulations both with BPO which all had comparable efficacy and significantly reduced acne lesions. Topical BPO/erythromcyin should be refrigerated, which could impact adherence. Tretinoin/clindamycin is also available as a fixed dose combination product.

Dapsone gel

Topical dapsone is used for its anti-inflammatory properties in the treatment of acne vulgaris. It has greater efficacy in treating inflammatory acne lesions than comedones. Use with BPO can cause a yellow-orange staining of skin and hair. Topical use is safe in G6PD deficient patients and in those that are sulfa allergic.

Salicylic acid

Salicylic acid is a comedolytic and mild anti-inflammatory agent. It is also a mild chemical irritant that works in part by drying up active lesions.

Salicylic acid is available in numerous over-the-counter concentrations of up to 2% in a variety of delivery formulations, including gels, creams, lotions, foams and solutions. Side effects of topical salicylic acid are mild and include erythema and scaling

Azelaic acid

Azelaic acid is a naturally occurring dicarboxylic acid found in cereal grains. It is available as a topical cream. It inhibits the growth of P. acnes and improves both comedonal and particularly inflammatory acne. Azelaic acid is applied twice daily and its use is reported to have fewer local side effects than topical retinoids. Additionally, it can help lighten post-inflammatory hyperpigmentation.

Sodium sulfacetamide

Sodium sulfacetamide is an alternative well-tolerated topical antibiotic that is thought to restrict the growth of P. acnes through competitive inhibition of the condensation of para-aminobenzoic acid with pteridine precursors. It is available in a 10% lotion, either alone or in combination with 5% sulfur.

Oral Antibiotics: Tetracyclines

(Minocycline, Doxycycline, Tetracycline)

All tetracyclines can cause photosensitivity (particularly doxycycline) and can cause staining of the teeth. They should also be avoided during pregnancy as they can negatively affect bone and cartilage growth of the fetus. Other side effects to counsel patients on include gastrointestinal upset, most commonly experienced with doxycycline. Pseudotumor cerebri is a rare side effect seen with the tetracyclines as well. Rare hypersensitivity reactions including serum sickness-like reaction and DRESS syndrome have been reported. Minocycline is associated with blue pigmentation of the skin or gums, lupus-like reaction, and autoimmune hepatitis.

Tetracycline absorption is affected by elemental ions including calcium, aluminum, iron, and zinc and therefore should not be ingested with meals particularly those involving dairy products or antacids. Minocycline and doxycycline are less influenced by foods and generally can be taken with food. Reconsider if patient is not responding to the oral antibiotic therapy as expected, as individual absorption rates and influences can vary widely.

As with topical antibiotics, bacterial resistance is of concern with oral antibiotics. High rates of resistance have been correlated with high outpatient use of antibiotics and selection pressure can affect other more pathogenic bacteria in addition to P. acnes. Additionally, the tetracyclines, particularly doxycycline, have been implicated as a possible risk factor for inflammatory bowel disease (Note: further studies are needed.) For this reason the duration of antibiotic use should be limited to 3 months if possible and the clinical response and need for continuation frequently assessed. Additionally, antibiotic monotherapy either for acute treatment or maintenance therapy should be avoided.

Systemic Treatments: Other

Several other oral antibiotics have been used for the treatment of acne. These include trimethoprim-sulfamethexazole, amoxicillin and other penicillins, cephalosporins, and azithromycin. Data on their efficacy and safety is not well established and their use in the treatment of acne is generally discouraged.

Oral dapsone can be used as a 3rd line treatment for severe acne in patients who cannot take or have failed oral tetracycline and isotretinoin therapy. Patients should be checked for G6PD deficiency prior to starting and monitored for hemolysis.

Other agents used for their anti-inflammatory properties include nicotinomide, both topically and orally, and zinc. Their use and efficacy in the treatment of acne is not fully established.

The use of several other systemic agents has been reported in generally in complicated cases of severe, refractory acne. These include anti TNF alpha agents, entanercept and infliximab, and anti-androgens, such as flutamide.

Isotretinoin

Isotretinoin works by normalizing epidermal differentiation, markedly decreasing sebum production, reducing the presence of P. acnes and exerting anti-inflammatory effects. It has been FDA-approved for patients with severe, nodulocystic acne and is commonly used in any significant acne unresponsive to therapy (including oral antibiotics) that results in significant physical or emotional scarring, as well as Gram-negative folliculitis, pyoderma faciale, and acne fulminans. Therapy is generally initiated at a dose of 0.5 mg/kg/d for 4 weeks, then increased to 1.0 mg/kg/day as tolerated and continued until a cumulative dose of 120-150 mg/kg is achieved.

In general, isotretinoin tends to provide outstanding results; however, there are several identified subsets of patients who are less likely to respond to isotretinoin or require more than one course of treatment. Patients under 16 years of age with nodulocystic acne are likely to need a second or third course of isotretinoin therapy within 2–4 years. Patients with endocrine abnormalities contributing to the pathogenesis of their acne typically do not achieve the same satisfactory results, nor do adult females with less severe acne. Additionally, scarred nodules and sinus tracts, sequelae from previously active nodular acne, are not isotretinoin-responsive and surgical techniques are required to improve these lesions.

In cases of severe acne such as acne fulminans, it may be prudent to co-administer the medication with oral corticosteroids at the onset of therapy to avoid an initial worsening of acne that can sometimes occur with initiation of therapy.

Mild side effects are often seen with isotretinoin use including: chelitis, generalized xerosis, and dryness of the oral and nasal mucosa.

Several serious side effects of isotretinoin therapy exist including acne fulminans, formation of excessive granulation tissue, and an increased risk of cutaneous infections (especially Staphylococcus aureus). Additionally, isotretinoin is a potent teratogen, therefore strict adherence to the FDA mandated risk management program iPledge is vital. In women of childbearing age, two negative pregnancy test results are required before therapy can be started. Contraception counseling should also be seriously discussed and two effective forms of birth control should be used in women who are sexually active.

Baseline laboratory testing before isotretinoin therapy is also recommended and generally includes cholesterol and triglyceride assessment and hepatic transaminase levels. These values should be rechecked once the patient is at a steady dosing. Monthly pregnancy tests must be continued during the entire course of treatment.

Data regarding a possible association between depression and an increased risk of suicide during treatment with isotretinoin is unclear. A true causal relationship between the two has not been proven. Still, patients must sign a consent form acknowledging they are aware of this potentially life-threatening risk and physicians should monitor for signs and symptoms of depression throughout the course of treatment.

Similar controversies surround isotretinoin and the risk of inflammatory bowel disease. Again the available data does not suggest a causal association but patients should be counseled appropriately on the possible risk.

Options for Female Patients:

Combined Oral Contraceptive Pills

Hormonal therapy is an established second-line treatment for female patients with acne.Common side effects from combined oral contraceptive pills (COCs) include nausea, vomiting, abnormal menses, weight gain, and breast tenderness. Rare but more serious complications include thrombophlebitis, pulmonary embolism, and hypertension. Oral contraceptives should be used cautiously in patients that smoke, have a history of hypercoagulable states, or breast cancer.

Hormonal therapies have demonstrated efficacy in adult women with persistent inflammatory papules and nodules that commonly involve the lower face and neck. These women also commonly report that their acne flares prior to their menstrual periods and consists of a few tender deep-seated inflammatory papules and nodules. These patients often note little improvement in their acne despite multiple courses of various antibiotics. In such patients, oral antibiotics can be discontinued and hormonal therapy with oral contraceptives initiated, because the latter block both ovarian and adrenal production of androgens.

Current COC formulations combine an estrogen with a progestin in order to minimize the risk of endometrial cancer that is known to occur with unopposed estrogens. Because progestins have intrinsic androgenic activity, oral contraceptive formulations with low-androgenic progestins such as drosperinone, norethindrone and levonorgestrel are preferred. Patients should be advised that clinical response to OCPs generally requires at least 3 months before one is able to determine efficacy.

Currently three different OCPs have been FDA approved for acne. These include Estrostep (ethinyl estradiol 20, 30, 35/norethindrone 1000), Ortho Tri-Cyclen (ethinyl estradiol 35/norgestimate 180, 215, 250), and Yaz (ethinyl estradiol 20/drospirenone 3000).

Additionally, clinical evidence supports the use of the following OCPs for acne: Alesse (ethinyl estradiol 20/levonorgestrel 100), Diane-35 (ethinyl estradiol 35/cyproterone acetate 2000 – not available in the US), and Yasmin (ethinyl estradiol 30/drospirenone 3000).

Spironolactone

The androgen receptor blocker spironolactone is another second line option for females with inflammatory acne. It works by inhibiting 5ɑ-reductase and at doses of 50–100 mg twice daily, it has been shown to improve acne (primarily by decreasing sebum production).

Side effects are dose-related and include potential hyperkalemia (however hyperkalemia is rare in young healthy patients), irregular menstrual periods, breast tenderness, headache, and fatigue.

Because it is an anti-androgen, there is a risk of feminization of a male fetus if a pregnant woman takes this medication. This potential risk can be minimized by combining spironolactone with an oral contraceptive, and has the added benefit of combating potential symptoms of irregular menstrual bleeding, the most common side effect of spironolactone.

Spironolactone side effects are dose-dependent and can also be minimized if therapy is initiated with a low dose (25–50 mg/day) and then gradually built up as necessary. Effective maintenance doses are in the range of 25 to 200 mg/day. Similar to COCs, clinical response may take up to 3 months.

Some patients noted health benefits beyond improved in acne such as decreased facial oiliness, decreased hirsutism, improvement of premenstrual syndrome symptoms, decreased metrorrhagia, reduced endometriosis pain, and increased libido.

Surgical Options

Comedo extraction can improve the cosmetic appearance and aid in therapeutic responsiveness to prescribed comedolytic agents.

The contents of open comedones can be expressed by use of a comedo extractor and the Schamberg, Unna and Saalfield types of comedo expressers are most commonly used. Additionally, nicking the surface of a closed comedo with an 18-gauge needle or a no. 11 blade will allow easier expression.

Deep, inspissated, and persistent comedones are unlikely to respond to topical therapy alone and are likely to respond well to comedo extraction Comedo extraction works best when used in conjunction with a topical retinoid or other comedolytic treatment and should not be performed on inflamed comedones or pustules, as this increases the risk of scarring

Light electrocautery and electrofulguration have also been reported as effective treatments for comedones and electrofulguration has the added benefit of not requiring the prior use of a topical anesthetic.

Cryotherapy represents another surgical option for the treatment of comedonal acne.

Chemical peels are used both in the treatment of comedonal acne and acne scarring. A variety of preparations in varying concentrations including glycolic acid, alpha and beta hydroxy acids and salicylic acid, have all been used.

For deep and inflamed cystic lesions, intralesional injection of corticosteroid can quickly improve both the appearance and the tenderness of these lesions. Larger nodulocystic lesions may require incision and drainage prior to steroid injection.

Triamcinolone acetonide (2-5 mg/ml) is injected into selected cystic lesions using a 30-gauge needle. The maximal amount of corticosteroid used per lesion should not exceed 0.1 ml. The risks of corticosteroid injections include hypopigmentation (particularly in darkly pigmented skin), atrophy, telangiectasias and needle tract scarring.

Light-based treatments:

There are many surgical treatments available for treatment of acne including various lasers, such as pulsed dye lasers (PDL), 1064 Nd:YAG laser, 1450-nm diode laser, as well as photodynamic therapy. Light-based treatments work by reducing P. acnes levels and/or disrupting sebaceous gland function. Additionally, light may also have endogenous antiinflammatory properties via action on inflammatory cytokines. They can also be used for scar revision once the acne is under control.

Light decreases P. acnes levels by interfering with its normal metabolism. For instance, P. acnes contains light-sensitive porphyrin compounds, which absorb visible light at several wavelengths, particularly between 400 and 700 nm. Absorption of light excites the porphyrin compound, causing formation of reactive free radicals, which damage lipids in the cell wall of P. acnes, resulting in destruction of the organism. Many lasers and light sources emit at this desired wavelength, including intensed pulse light (IPL) devices (broadband light), PDLs (585-595 nm), KTP lasers (532 nm), orange/red light lasers or light sources (610-635 nm).

Unfortunately, evidence in the form of randomized control trials to prove the clear effectiveness of these therapies is lacking. In addition there are no studies that actually compared light-based treatments with the current standard of care–combination therapy with a topical retinoid plus one or more antimicrobial agents. There is also little standardized information available about the long-term effects of such therapies or the optimal device settings, or frequency of administration in active acne.

As the mechanism of action of many current light treatments and lasers is by suppression of P. acnes activity, treatment is generally only effective when used chronically and relapse has been shown to occur shortly after cessation, these are currently unlikely to be cost-effective options for most patients. Additionally, as they do not affect the formation of both comedones and the microcomedo, therapy needs to be combined with retinoids to prevent future acne. However, it may be a good adjuvant therapy for some patients.

Patient Management

Follow up

The patient follow-up will depend on acne severity. Mild to moderate cases can be followed up at 3-4 month intervals once treatment is initiated. Severe cases should be followed up more closely, at 2-3 month intervals.It should be stressed that significant improvement may not occur until the 8-week mark or longer. Interim visits can be useful to establish tolerability and compliance. If a patient does not appear to have adequately responded to the treatment you have initiated after 2-3 months of diligent use, an alternative treatment strategy should be considered. Patients on isotretinoin are followed monthly for the duration of their treatment in compliance with the iPledge system.

Compliance

Before changing treatment strategies it should be clearly ascertained that the patient was adequately using the prescribed medication consistently and correctly. Poor adherence to acne treatment plans is a common cause of inadequate therapeutic response. Giving realistic treatment expectations up front, more frequent visits, and simplifying treatment routines are strategies used to increase adherence. Also discussion with the patient about what they do not like about a certain product and substituting accordingly may help as well.

Cosmetics

Use of cosmetics can be very beneficial in covering up active acne and improving patient quality of life. The use of make-up has not been shown to adversely affect a patient’s response to acne treatment. Patients should be instructed to look on the label for a water-based, non-comedogenic formulation. Additionally, it is important to counsel patients to discard any liquid make-up that is expired (generally older than 6 months).

Sunscreen

When recommending a sunscreen for patients with acne consider the oiliness, sensitivity and phototype of the patient. As with cosmetics, many sunscreens are labelled as non-oily or non-comedogenic. Use of sunscreen in patients on medications that can cause photosensitivity, such as retinoids or doxycycline, is a must and their use should be advocated with each visit. Also, patients with acne should be discouraged from using tanning as a treatment for acne. While the tan may mask the acne, the short-term benefit is outweighed by the long-term photodamage and increased risk of skin cancer.

Diet

In most patients with acne, specific changes to diet are not recommended. The data on the effects of diet on acne is still too unclear to make specific recommendations to patients. That said, if a patient notes the ingestion of a certain food exacerbates their acne, that food can be avoided in that individual. Food avoidance should not be a substitute for standard acne treatment, however.

Unusual Clinical Scenarios to Consider in Patient Management

Vigilance for the possibility of hyperandrogenism should allow the clinician to consider PCOS, HAIR-AN, SAHA, and CAH syndromes. If there are arthritic complaints, one should entertain the possibility of PAPA and SAPHO syndromes.

What is the Evidence?

Eichenfield, LF, Krakowski, AC, Piggott, C, DelRosso, J. “American Acne and Rosacea Society. Evidence-based recommendations for the diagnosis and treatment of pediatric acne”. Pediatrics. vol. 131. 2013 May. pp. S163-86. (This report provides comprehensive guidelines on the diagnosis and management of acne in pediatric patients.)

Dr譯, B, Thiboutot, D, Layton, AM, Berson, D, Perez, M, Kang, S. “Global Alliance to Improve Outcomes in Acne. Large-scale international study enhances understanding of an emerging acne population: adult females. “. J Eur Acad Dermatol Venereol. vol. 29. 2015 Jun. pp. 1096-106. (An observational, international study evaluating the clinical characteristics and lifestyle correlates of acne in adult females.)

Fried, RG, Webster, GF, Eichenfield, LF, Friedlander, SF, Fowler, JF, Levy, ML. “Medical and psychosocial impact of acne”. Semin Cutan Med Surg. vol. 29. 2010 Jun. pp. 9-12. (This is a good review of the data highlighting the negative psychological impact that having acne can have on patients, as well the permanent physical sequelae.)

Mallon, E, Newton, JN, Klassen, A, Stewart-Brown, SL, Ryan, TJ, Finlay, AY. “The quality of life in acne: a comparison with general medical conditions using generic questionnaires”. Br J Dermatol. vol. 140. 1999. pp. 672-6. (This is a landmark study showing the impact that acne can have on the psychological well being of those affected by it.)

Thiboutot, D, Gollnick, H, Bettoli, V, Dréno, B, Kang, S, Leyden, JJ. “New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acnegroup”. J Am Acad Dermatol. vol. 60. 2009 May. pp. S1-50. (This comprehensive article gives up to date consensus treatment guidelines from a large, international group of acne experts.)

Seukeran, DC, Cunliffe, WJ. “The treatment of acne fulminans: a review of 25 cases”. Br J Dermatol. vol. 141. 1999 Aug. pp. 307-9. (This review of 25 patients with acne fulminans provides data on treatment options, responses and outcomes.)

Chen, W, Obermayer-Pietsch, B, Hong, JB, Melnik, B, Yamasaki, O, Dessinioti, C. “Acne-associated syndromes: models for better understanding of acne pathogenesis”. J Eur Acad Dermatol Venereol. vol. 25. 2011. pp. 637-46. (This article provides an excellent review of the genetic causes, diagnosis and treatment of acne-associated syndromes.)

Marqueling, AL, Zane, LT. “Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review”. Semin Cutan Med Surg. vol. 26. 2007. pp. 210-20. (A comprehensive review of the available data regarding the association of isotretinoin use and the risk of depression.)

Kaminsky, A. “Less common methods to treat acne”. Dermatology. vol. 206. 2003. pp. 68-73. (A good review of alternate treatment options for acne.)

Herane, MI, Ando, I. “Acne in infancy and acne genetics”. Dermatology. vol. 206. 2003. pp. 24-8. (This study highlights the strong influence that genetics play in the risk of acne severity.)

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