Section 20. Other Skin Disorders

A 20-year-old college student was seen for fatigue and an upper respiratory infection and started on amoxicillin for a sore throat. Six days later she broke out with a red rash all over her body (Figure 203-1). She went to see her family physician back home with the rash and lymphadenopathy. A monospot was drawn and found to be positive. This morbilliform rash (like measles) is typical of an amoxicillin drug eruption in a person with mononucleosis. Amoxicillin was stopped, and diphenhydramine was used for the itching.

Cutaneous drug reactions are skin manifestations of drug hypersensitivity. Drug hypersensitivity may be defined as symptoms or signs initiated by a drug exposure at a dose normally tolerated by nonhypersensitive persons.1 Drug-induced adverse reactions are often classified as type A and type B. Type A reactions are common (80%) predictable side effects caused by a pharmacologic action of the drug, and type B reactions are uncommon (10% to 15%) and considered idiosyncratic, a result of individual predisposition (e.g., an enzyme defect).2 Cutaneous drug reactions range from mild skin eruptions (e.g., exanthem, urticaria, and angioedema) to severe cutaneous drug reactions (SCARs), the latter category including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS).3

Cutaneous adverse reactions, drug reactions, medication reactions, adverse effects to drugs, hypersensitivity reactions.

• Cutaneous drug reactions are common complications of drug therapy occurring in 2% to 3% of hospitalized patients.4
• One study found that 45% of all adverse drug reactions were manifested in the skin.4
• Approximately 1 in 6 adverse drug reactions represents drug hypersensitivity, and are allergic or non-immune-mediated (pseudoallergic) reactions.2
• Maculopapular eruptions, also known as exanthematous drug eruptions, are the most frequent of all cutaneous drug reactions, representing 95% of skin reactions.5 They are often confused with viral exanthems. This occurs most commonly with β-lactams such as amoxicillin, but also with barbiturates, gentamicin, isoniazid, phenytoin, sulfonamides, thiazides, and trimethoprim-sulfamethoxazole (Figures 203-1 and 203-2).
• Urticarial drug reactions are the second most common skin eruptions, representing approximately 5% of cutaneous drug reactions.5 This reaction can result from any drug but commonly occurs with aspirin, penicillin, sulfa, angiotensin-converting enzyme (ACE) inhibitors, aminoglycosides, and blood products. Urticaria results from immunoglobulin (Ig) E reactions within minutes to hours of drug administration (Figures 203-3 and 203-4).
• Drug-induced hyperpigmentation occurs with antiarrhythmics (amiodarone), antibiotics (minocycline), NSAIDs, and chemotherapy agents (Adriamycin) (Figure 203-5).
• Warfarin-induced skin necrosis (WISN) is a rare but serious side effect predominantly seen in obese women and presents between days 3 and 6 of warfarin treatment. WISN is more common in those with thrombophilic abnormalities, given large loading doses (Figure 203-6).
• Fixed drug eruptions (FDEs) can occur with many medications, including phenolphthalein, doxycycline, ibuprofen, sulfonamide antibiotics, and barbiturates. FDEs are more commonly observed in men (Figures 203-7, 203-8, 203-9, 203-10, 203-11, 203-12, and 203-13).
• Erythema multiforme (EM) and SJS can occur secondary to drug reactions (Figures 203-14, 203-15, and 203-16). Incidence of SJS is estimated at 1.2 per 6 million people.3
• DRESS is also a severe adverse drug-induced reaction characterized by eosinophilia with liver involvement, fever, and lymphadenopathy. In a case series (N = 172), 44 drugs were associated with DRESS.6 Also called DIHS, this syndrome is estimated to occur in 1 per 1000 to 1 per 10,000 exposures to antiepileptic drugs.7
• Tables 203-1 and 203-2 list the most common medications associated with allergic cutaneous drug reactions and the rates of reactions found.8
• Table 203-3 lists the frequency of various classes of drugs associated with an eruption (in cases with <4 suspected drugs) based on a 5-year study.9

• Two mechanisms are responsible for cutaneous drug reactions—Immunologic, including all four types of hypersensitivity reactions, and, more commonly, nonimmunologic (pseudoallergic). Although the precise mechanism of immune stimulation is unknown, it may be triggered by drug-protein (hapten-carrier) complexes or through direct interaction with immune receptors (p-i concept).2 The mechanism for pseudoallergic reactions is pathogenetically poorly defined.2
• Hypersensitivity to NSAIDs is a nonimmunologic reaction that can be immediate (within hours after exposure) or delayed (more than 24 hours after administration).1
• WISN develops during the hypercoagulable state as a result of a more rapid fall in concentration of protein C compared to the other vitamin-K-dependent procoagulant factors. Thrombophilic abnormalities such as familial or acquired deficiency of protein C or S and antiphospholipid antibodies have been implicated in WISN (Figure 203-6).
• SJS/TEN is most commonly associated with penicillins and sulfonamide antibiotics but can also occur with anticonvulsants, NSAIDs, allopurinol, and corticosteroids. It is hypothesized that a specific human leukocyte antigen (HLA)-B molecule may present the drug or its metabolites to naïve CD8 cells resulting in clonal expansion of CD8 cytotoxic lymphocytes and induction of cytotoxic effector responses, resulting in apoptosis of keratinocytes.10 This pathway is not likely to be specific to SJS.

• Drug hypersensitivity reactions increase with the drug dose, duration, route of administration (topical > subcutaneous > intramuscular > oral > intravenous),11 immune activation of the individual, and immunogenetic predisposition; they are also more frequent in women.2 Multiple drug therapy may also increase risk.11
• Patients with the following HLAs are at higher risk for cutaneous drug reactions: HLA-B*1502 (confers a very high risk of carbamazepine-induced and other antiepileptic drug-induced SJS among people of southeastern Asian ethnicity); HLA-B*5801 (higher risk of allopurinol-induced severe cutaneous reactions); HLA-B*5701 (higher risk of abacavir [an antiretroviral drug] hypersensitivity reactions); HLA-B*3501, HLA-B*3505, HLA-B*1402, and HLA-Cw8 (nevirapine [an antiretroviral drug] sensitivity with rash; the latter two found in a Sardinian population); HLA-DRB1*0101 (nevirapine hypersensitivity rash with hepatitis).2,6
• Prior drug reaction may result in a faster recurrence on reexposure.11
• Concomitant illness, especially viral infections and autoimmune disorders.11

Clinical Features and Typical Distribution (The Most Common and Important Drug Eruptions)

• Maculopapular—These eruptions, red macules with papules, can occur any time after drug therapy is initiated (often 7 to 10 days) and last 1 to 2 weeks. The reaction usually starts on the upper trunk or head and neck then spreads symmetrically downward to limbs. The eruptions may become confluent in a symmetric, generalized distribution that spares the face (Figure 203-1). Mild desquamation is normal as the exanthematous eruption resolves.
• Urticaria and angioedema—Urticaria reactions present as circumscribed areas of blanching-raised erythema and edema of the superficial dermis (Figures 203-3 and 203-4). They may occur on any skin area and are usually transient, migratory, and pruritic. Angioedema represents a deeper reaction, with swelling usually around the lips and eyes (see Chapter 150, Urticaria and Angioedema).
• Hyperpigmentation—Drug-induced hyperpigmentation presents in many ways. Amiodarone causes a dusky red coloration that turns blue-gray with time in photo-exposed areas. Minocycline can cause a blue-gray color in acne lesions, on the gingiva and on the teeth. Phenytoin (Dilantin) and other hydantoins may cause melasma-like brown pigmentation on the face. Bleomycin can cause a streaking hyperpigmentation on the trunk and extremities. Adriamycin, as evident in the case above, can cause hyperpigmentation of the face and nails (Figure 203-5).
• NSAIDs—The cutaneous reactions to NSAID-associated drug hypersensitivity are urticaria, angioedema, or anaphylaxis.1 These reactions can be caused by a single NSAID or multiple NSAIDs. There is also an NSAID-exacerbated urticaria and angioedema that occurs in patients with chronic idiopathic urticaria.
• Warfarin-induced skin necrosis (WISN)—It presents with sudden onset of painful localized skin lesion that is initially erythematous and/or hemorrhagic that becomes bullous, culminating in gangrenous necrosis (Figure 203-6). It develops more often in obese women in their 50s in areas with high subcutaneous fat content such as breasts, thighs, and buttocks. This is different from a warfarin bleed secondary to too much anticoagulation (Figure 203-14).
• Fixed drug eruption (FDE)—Presents with single or multiple sharply demarcated circular, violaceous or hyperpigmented plaques that may include a central blister (Figures 203-8, 203-9, 203-10, 203-11, 203-12, and 203-13 and 203-17). The lesion(s) appear after drug exposure and reappear exactly at the same site each time the drug is taken. The site resolves, leaving an area of macular hyperpigmentation (Figure 203-8). Lesions can occur anywhere including the hands and feet, but are commonly found on the penis (Figures 203-10 and 203-11). The eruption presents 30 minutes to 8 hours after drug administration. Bullous fixed drug eruptions occur when the lesion blisters and erodes, followed by desquamation and crusting (Figures 203-7, 203-11, and 203-17).
• EM—It presents with typical target or raised edematous papules distributed acrally. Most importantly, there should be some type of epidermal disruption with bullae or erosions within the target lesions (Figures 203-14 and 203-15). Severe EM becomes and more widespread epidermal detachment may occur involving less than 10% of total body surface area (see Chapter 177, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).
• SJS—It presents with erythematous or pruritic macules, widespread blisters on the trunk and face, and erosions of one or more mucous membranes (Figure 203-16). Atypical target lesions or widespread erythema, particularly in the upper chest and back, are potential early signs of both SJS and TEN.11 Burning or painful skin can be a sign of increased severity. Epidermal detachment occurs and involves less than 30% of total body surface area.
• Toxic epidermal necrolysis (TEN)—It is on the most severe side of the SJS spectrum. EM is diagnosed when less than 10% of the body surface area is involved, SJS/TEN when 10% to 30% is involved, and toxic epidermal necrolysis when more than 30% is involved.
• Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS)—Infiltrated, palpable lesions are potential heralds of this disorder.11 Central facial edema and erythema (Figure 203-18) and a maculopapular rash are seen along with high fever, generalized lymphadenopathy, and arthralgias. Drug reaction with eosinophilia and systemic symptoms can also cause an erythroderma (Figure 203-19). Latency between starting a drug and first signs of drug reaction with eosinophilia and systemic symptoms can be up to 12 weeks.11
• Drugs most commonly known to cause SJS and TEN are sulfonamide antibiotics, allopurinol, nonsteroidal antiinflammatory agents, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine (see Chapter 177, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).12 Fifty percent of SJS/TEN cases have no identifiable cause.

Less Common Drug Reactions

• Acute generalized exanthematous pustulosis (AGEP)—is a type of drug eruption that results in clusters of small pustules along with erythematous skin (Figure 203-20). The patients are often febrile and the pustules are primarily non-follicular and sterile.
• Systemic drug-related intertriginous and flexural exanthema (SDRIFE)—is a type of drug eruption that causes erythema around the buttocks and genitalia along with intertriginous and flexural areas. If the pattern of erythema creates a red buttocks then it may also be called the baboon syndrome (Figure 203-21).

Laboratory Studies

The diagnosis of drug eruptions is usually made based on history and physical examination.

• An FDE may be diagnosed by “provoking” the appearance of the lesion with an oral rechallenge with the suspected drug; however, this can be dangerous in bullous cases.
• Severe reactions may need a complete blood count (CBC) with differential and comprehensive serum chemistry panel to look for systemic involvement and check hydration status.
• In more challenging cases, a skin biopsy may be helpful to confirm the diagnosis.
• Intradermal skin testing may be hazardous to patients, and patch tests are not useful.
• Skin biopsies are usually not required for diagnosis of WISN, but may aid in the diagnosis.
• Testing for thrombophilia (high platelet count) may also be done in WISN.
• Laboratory tests in patients with DRESS/DIHS may show atypical lymphocytes, eosinophilia, lymphocytopenia, and thrombocytopenia; liver abnormalities are often seen.

• Viral exanthems look just like generalized maculopapular drug eruptions. Sometimes when a patient is given an antibiotic for an upper respiratory infection, the rash that ensues may be the viral exanthem rather than a drug eruption. The best way to avoid this confusion is only to use antibiotics when the evidence for bacterial infection is sufficient to justify the risks of a drug reaction. (See Section 4: Viral [Chapters 123 to 134] for more information on viral exanthems.)
• Urticarial reactions present as transient migratory circumscribed areas of blanching-raised erythema and edema of the superficial dermis. Patients experience itching. Identifying urticaria is easy compared with finding the precipitating factors. If there is a temporal association with starting a new drug, it is best to stop the drug (in most cases) and see if the urticaria resolves. (See Chapter 150, Urticaria and Angioedema.)
• EM presents with sudden onset of rapidly progressive, symmetrical, and cutaneus lesions with centripetal spread. The patient may have a burning sensation in affected areas but usually has no pruritus. EM is most often caused by a reaction to an infection such as herpes simplex virus (HSV) or mycoplasma but may be caused by a drug reaction. Careful history and physical examination can help differentiate between the possible causes (see Chapter 177, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).
• SJS and TEN present with generalized cutaneous lesion with blisters, fever, malaise, arthralgias, headache, sore throat, nausea, vomiting, and diarrhea. The patient may also have difficulty in eating, drinking, or opening his or her mouth secondary to erosion of oral mucous membranes (Figure 203-16). Not all SJS or TEN is secondary to drug exposure, but it is the job of the clinician to investigate this cause and stop any suspicious medications. SJS and TEN can be life-threatening (see Chapter 177, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).
• DRESS/DIHS can be distinguished by involvement of organs other than skin including liver (hepatitis in 50% to 70%), kidney (nephritis in 10%), and, more rarely, pneumonitis, colitis, myocarditis, parotitis, meningitis, encephalitis, and pancreatitis; the pattern of organ involvement appears to depend on the drug trigger.7,13 Some of the sequelae from DRESS/DHIS are strongly related to herpes virus reactivation.7 A recurrence of symptoms at the third week is common. Diagnostic criteria have been proposed to include all of the following: maculopapular rash developing more than 3 weeks after drug exposure, prolonged clinical symptoms after drug discontinuation, fever (>38°C [100.4°F]), liver abnormalities or other organ involvement, leukocyte abnormalities (atypical lymphocytosis, leukocytosis, eosinophilia), lymphadenopathy, and human herpesvirus-6 reactivation.13
• Pityriasis rosea (PR) is a mysterious eruption of unknown etiology that could easily mimic a maculopapular drug eruption. Look and ask for the herald patch to help make the diagnosis of PR. In PR, look for the collarette scale and observe whether the eruption follows the skin lines (causing a Christmas tree pattern on the back). These features should help positively identify PR because there are no laboratory tests that are specific to PR or most drug eruptions (see Chapter 153, Pityriasis Rosea).
• Syphilis is the great imitator. Any generalized rash without a known etiology may be caused by secondary syphilis. A rapid plasma reagin (RPR) will always be positive in secondary syphilis and is easy to run (see Chapter 216, Syphilis).
• Bullous pemphigoid and pemphigus vulgaris can resemble a bullous drug eruption. Biopsies are the best way to diagnose these bullous diseases. Their clinical pictures are described in detail in Chapter 184, Bullous Pemphigoid, and Chapter 185, Pemphigus.
• Hematoma is a much more common complication of warfarin therapy and must be distinguished from WISN early to decrease permanent tissue damage; a high index of suspicion is needed and a very elevated international normalized ratio (INR) will confirm that bleeding is a result of overcoagulation (Figure 203-22).

Nonpharmacologic

• Discontinue the offending medication for all types of drug reactions whenever possible. Older patients with drug eruptions may be on multiple medications and may be very ill; however, efforts should be made to discontinue all nonessential medications.5 SOR C
• Patients with maculopapular reactions may continue to be treated with the offending agent if it is essential for treating a serious underlying condition.5
• Maculopapular drug eruptions are not a precursor to severe reactions such as TEN.5
• Hyperpigmentation—Stop the drug if possible. In the case of Adriamycin-induced skin hyperpigmentation, the Adriamycin may be continued if it is the best chemotherapy for a life-threatening malignancy (Figure 203-5).
• Local wound care, debridement, and skin grafting may need to be performed to repair resultant disfigurement from necrosis.14,15

Medications

• Maculopapular- and urticarial/angioedema-type drug reactions are treated with antihistamines. If the angioedema is causing airway compromise, epinephrine (10 mcg/kg intramuscular) and other treatments will be necessary.5,13 SOR C Usually an H1-blocker is started. In some cases of urticaria/angioedema, an H2-blocker is added on for broader antihistamine effects (see Chapter 150, Urticaria and Angioedema).
• Diphenhydramine (Benadryl)—Adult dosing is 25 to 50 mg orally every 4 to 6 hours (nonprescription).
• Hydroxyzine (Atarax)—Adults receive 25 mg orally every 6 hours. Pediatric dose 0.5 to 1.0 mg/kg per day orally 4 times daily.5
• Loratadine (Claritin)—10 to 20 mg orally 1 time daily5 (nonprescription).
• Any H2-blocker can be used by prescription or nonprescription.
• Topical steroids such as triamcinolone or desonide may be used for symptomatic relief of pruritus.5 SOR C
• Oral steroids have been used, but little benefit has been shown.5 SOR C These are used in DRESS/DHIS.13
• FDEs are treated by discontinuing the drug and applying topical corticosteroids to the affected area.4 SOR C

Referral or Hospitalization

Patients with WISN, SJS, TEN, and DRESS/DIHS are usually hospitalized.

• WISN treatment is generally supportive, including discontinuing the warfarin, admission to the hospital, and administration of vitamin K and fresh-frozen plasma.14,15
• Many clinicians recommend resuming heparin therapy if needed for the patient's underlying pathology that prompted the use of initial anticoagulation therapy.14,15
• SJS, TEN, DRESS/DIHS—Start with early diagnosis, rapid discontinuing of offending agent, intravenous fluid replacement, and placement in an intensive care unit (ICU) or burn unit (see Chapter 177, Erythema Multiforme, Steven-Johnson Syndrome, and Toxic Epidermal Necrolysis).4,5 Liver transplant has been used in patients with DRESS.13
• Most experts and studies now agree that systemic corticosteroids should not be used.4 SOR B
• Nutritional support, careful wound care, temperature control, and anticoagulation are recommended.4 SOR C
• Daily skin samples should be sent for bacterial Gram stain and culture to monitor for developing infection.4 SOR C

• In the future, prevention may occur through screening for HLA associations and drug avoidance.1
• Avoid reexposure to the drug.
• Screening for HLA-B*1502 is advised by the U.S. FDA and Health Canada for patients of southeastern Asian ethnicity before carbamazepine therapy.1

• Most cutaneous drug reactions resolve with discontinuation of the causative agent.
• Mortality, however, is high at 10% for SJS and DRESS/DHIS and 30% to 50% for TEN.5,16 In a case series of patients with possible or probably DRESS, case fatality rate was 5% (9/172).6
• Some studies show the occurrence of autoimmune diseases, including type 1 diabetes mellitus, autoimmune thyroid disease, sclerodermoid graft-versus-host disease (GVHD)-like lesions, and lupus erythematosus months to years after resolution of DIHS/DRESS.7 Because of the long symptom-free interval in some patients, this relationship is questioned.

• Follow-up is most important when the case is severe or the diagnosis is uncertain. Clear-cut mild drug reactions may not need scheduled follow-up.
• Continued surveillance for autoimmune disorders may be warranted in patients following DRESS/DHIS.

• Most patients with drug eruptions recover fully without any complications. The patient should be warned that even after the responsible medication is stopped the eruptions may clear slowly or even worsen at first; the patient should be advised that the reaction may not resolve for 1 to 2 weeks.
• The patient should also be counseled that mild desquamation is normal as the exanthematous eruption resolves. Confirming the diagnosis of an FDE, especially lesions presenting on the glans, with a drug challenge may allay the patient anxiety about the venereal origin of the disease.
• The family should be counseled as to the genetic predisposition of some drug-induced eruptions.
• The patient should be advised to enroll in a medic alert program and to wear a bracelet detailing the allergy.

Patient Resources

• MedlinePlus. Drug Allergies—http://www.nlm.nih.gov/medlineplus/ency/article/000819.htm.
• Mayo Clinic. Stevens-Johnson Syndrome—http://www.mayoclinic.com/print/stevens-johnson-syndrome/DS00940/DSECTION=all&METHOD=print.

Provider Resources

• http://www.patient.co.uk/doctor/Drug-Eruptions.htm
• http://dermnetnz.org/reactions/drug-eruptions.html
• Medscape. Drug Eruptions—http://emedicine.medscape.com/article/1049474-overview.

If the skin eruption is rare, serious, or unexpected, the drug reaction should be reported to the manufacturer and FDA.

A 64-year-old black woman presents to the office with itching keloids on her chest (Figure 204-1). The horizontal keloid started during childhood when she was scratched by a branch of a tree. The vertical keloid is the result of bypass surgery 1 year ago. The lower portion of this area could be called a hypertrophic scar as it does not advance beyond the borders of the original surgery. The patient was happy to receive intralesional steroids to decrease her symptoms. Intralesional triamcinolone did, in fact, decrease the itching and flatten the vertical keloid.

Keloids are benign dermal fibroproliferative tumors that form in scar because of altered wound healing. They form as a result of overproduction of extracellular matrix and dermal fibroblasts that have a high mitotic rate.

Cheloid

• Individuals with darker pigmentation are more likely to develop keloids. Sixteen percent of black persons reported having keloids in a random sampling.1
• Men and women are generally affected equally except that keloids are more common in young adult women—probably secondary to a higher rate of piercing the ears (Figure 204-2).2
• Highest incidence is in individuals ages 10 to 20 years.2,3

• Keloids are dermal fibrotic lesions that are a variation of the normal wound-healing process in the spectrum of fibroproliferative disorders.
• Keloids are more likely to develop in areas of the body that are subjected to high skin tension such as over the sternum (Figure 204-1).
• These can occur even up to a year after the injury and will enlarge beyond the scar margin. Burns and other injuries can heal with a keloid in just one portion of the area injured (Figure 204-3).
• Wounds subjected to prolonged inflammation (acne cysts) are more likely to develop keloids.

See reference 3.

• Darker skin pigmentation (African, Hispanic, or Asian ethnicity).
• A family history of keloids.
• Wound healing by secondary intention.
• Wounds subjected to prolonged inflammation.
• Sites of repeated trauma.
• Pregnancy.
• Body piercings (Figure 204-4).

Clinical Features

• Some keloids present with pruritic pain or a burning sensation around the scar.
• Initially manifest as erythematous lesions devoid of hair follicles or other glandular tissue.
• Papules to nodules to large tuberous lesions (Figure 204-5).
• Range in consistency from soft and doughy to rubbery and hard. Most often, the lesions are the color of normal skin but can become brownish red or bluish and then pale as they age.4
• May extend in a claw-like fashion far beyond any slight injury.
• Lesions on neck, ears, and abdomen tend to become pedunculated.

Typical Distribution

• Anterior chest, shoulders, flexor surfaces of extremities, anterior neck, earlobes, and wounds that cross skin tension lines.

Laboratory Testing

• Biopsy is rarely needed to make a diagnosis because the clinical appearance is usually distinctive and clear.

• Hypertrophic scars can appear similar to keloids but are confined to the site of original injury.
• Acne keloidalis nuchae is an inflammatory disorder around hair follicles of the posterior neck that results in keloidal scarring (Figure 204-6). Although the scarring is similar to keloids the location and pathophysiology are unique. This process can also cause alopecia (Chapter 114, Pseudofolliculitis and Acne Keloidalis Nuchae).
• Dermatofibromas are common button-like dermal nodules usually found on the legs or arms. They may umbilicate when the surrounding skin is pinched. These often have a hyperpigmented halo around them and are less elevated than keloids (Chapter 160, Dermatofibroma).
• Dermatofibrosarcoma protuberans is a malignant version of the dermatofibroma. It usually presents as an atrophic, scar-like lesion developing into an enlarging firm and irregular nodular mass. If this is suspected, a biopsy is needed (Chapter 160, Dermatofibroma).

• Patients frequently want keloids treated because of symptoms (pain and pruritus) and concerns about appearance.
• A 2006 systematic review of 396 studies and an accompanying metaanalysis of 36 articles concluded that no optimal evidence-based therapy exists and recommended choosing treatment based on cost and adverse effect profile.5

Nonpharmacologic

• Silicone gel sheeting as a treatment for hypertrophic and keloid scarring is supported by poor-quality trials susceptible to bias. There is only weak evidence of a benefit of silicone gel sheeting as prevention for abnormal scarring in high-risk individuals.6,7 SOR B

Medications

• Intralesional steroid injections—Intralesional injection of triamcinolone acetonide (10 to 40 mg/mL) may decrease pruritus, as well as decreasing size and flattening of keloids (Figure 204-7). SOR C This may be repeated monthly as needed.5,8
• Earlobe keloids can be treated with imiquimod 5% cream following tangential shave excision on both sides of the earlobe.9,10 SOR B Patients were instructed to administer imiquimod 5% cream to the excision sites the night of the surgery and daily for 6 to 8 weeks postsurgery. Imiquimod 5% cream only temporarily prevented the recurrence of presternal keloids after excision.11 SOR C
• Intralesional verapamil 2.5 mg/mL, bleomycin 1.5 IU/mL, and interferon α2b injections 1.5 million IU twice daily for 4 days are less-studied alternatives to corticosteroid treatment.3 SOR C

Complementary and Alternative Therapy

• No available evidence supports using nonprescription products such as Mederma and other creams, gels, and oils, to treat scars.7 Limited clinical trials have failed to demonstrate lasting improvement of established keloids and hypertrophic scars with onion extract topical gel (e.g., Mederma) or topical vitamin E.3 SOR B

Surgical

• Cryosurgery and intralesional triamcinolone have been used to treat smaller keloids (e.g., secondary to acne) with similar success to other therapies.3,12 SOR B
• Combined cryosurgery and intralesional triamcinolone—The lesion is initially frozen with liquid nitrogen spray and allowed to thaw. Then it is injected with triamcinolone acetate (10 to 40 mg/mL). SOR C
• Earlobe keloids can be surgically excised with a shave or excisional technique and then injected with triamcinolone acetate (10 to 40 mg/mL) after hemostasis is obtained. The triamcinolone injection can be repeated in 1 month to decrease the chance of recurrence.8 SOR B
• Keloids on the upper ear can be excised and the skin closed with sutures (Figure 204-8). SOR C
• Pulsed-dye laser treatment can be beneficial for keloids.13 Combination treatment with pulsed-dye laser plus intralesional therapy with corticosteroids and/or fluorouracil 50 mg/mL 2 to 3 times per week may be superior to either approach alone.14SOR C
• Keloids can be treated with cryosurgery alone or in combination with intralesional steroids. In one, small, controlled study, 10 patients with keloids were treated with intralesional steroid and cryosurgery vs. intralesional steroid or cryosurgery alone.15SOR B Patients were treated at least 3 times 4 weeks apart. Based upon keloid thickness, the keloids responded significantly better to combined cryosurgery and triamcinolone versus triamcinolone alone or cryotherapy alone. Pain intensity was significantly lowered with all treatment modalities. Pruritus was lowered only with the combined treatment and intralesional corticosteroid alone.15
• In another study, 20 patients with hypertrophic and keloidal scars received two 15-second cycles (total 30 seconds) of cryosurgery treatments once monthly for 12 months with intralesional injections of 10 to 40 mg/mL triamcinolone once monthly for 3 months.16 SOR B Topical application of silicone gel was added 3 times daily for 12 months. The control group included 10 patients who received treatment with silicone sheeting only. After 1 year there was improvement in all the parameters, especially in terms of symptoms, cosmetic appearance, and associated signs, compared to baseline and compared to the control group.16 SOR B
• Layton et al. reported that the intralesional injection of a steroid is helpful but cryotherapy is more effective (85% improvement in terms of flattening) for recent acne keloids located on the back.17 Treatment with intralesional triamcinolone was beneficial, but the response to cryosurgery was significantly better in early, vascular lesions.17 SOR B
• If the keloid is older and/or firmer, it may not respond to injection therapy as well as softer and newer lesions. It may help to pretreat the keloid with cryotherapy. It is not necessary to freeze a margin of normal tissue. After liquid nitrogen or another freezing modality is applied to the keloid, it is allowed to thaw and develop edema. This generally takes 1 to 2 minutes, which allows an easier introduction of intralesional steroids into the lesions. SOR C
• In one double-blind, clinical trial, 40 patients were randomized to receive intralesional triamcinolone (TAC) or a combination of TAC and 5-fluorouracil (5-FU).18 Both groups received injections at weekly intervals for 8 weeks and lesions were assessed for erythema, pruritus, pliability, height, length, and width. Both groups showed an acceptable improvement in nearly all parameters, but these were more significant in the TAC plus 5-FU group (P <0.05 for all except pruritus and percentage of itch reduction). Good-to-excellent improvement was reported by 20% of the patients receiving TAC alone and by 55% of the patients in the group receiving TAC plus 5-FU.18 SOR B
• Earlobe keloids may be excised with a shave excision and injection of the base with steroid. It is hard to get much volume of steroid into the base of these keloids, so 40 mg/mL triamcinolone is preferred as the concentration for injection. SOR C Another option is to use radiofrequency electrosurgery technique with a pure cutting setting (and using steroid in the anesthetic).
• According to one article, simple excision of earlobe keloids can result in recurrence rates approaching 80%.19 A randomized, prospective trial comparing steroid injections versus radiation therapy found that 2 of 16 keloids (12.5%) recurred after surgery and radiation therapy, whereas 4 of 12 (33%) recurred after surgery and steroid injections. These results did not produce a statistically significant difference. No alteration of skin pigmentation, wound dehiscence, or chronic dermatitis was observed in any patient in either group.19 Although radiation therapy was considered easy to obtain in this study, it is reasonable to use steroid injections in office practice.

• Avoiding trauma, including surgical trauma, whenever possible may decrease keloids in susceptible individuals.

• A 2006 systematic review of 396 studies and an accompanying metaanalysis of 36 articles concluded that any treatment gave patients an overall 70% (95% confidence interval, 49% to 91%) chance of improvement.5

• Follow-up is based on the chosen treatment. Follow-up for intra­lesional steroid injections is usually in 1 month.

• Advise patients to avoid local skin trauma, for example, ear piercing, body piercing, and tattoos, and to control inflammatory acne.

Patient Resources

• MedlinePlus. Keloids—http://www.nlm.nih.gov/medlineplus/ency/article/000849.htm.
• Skinsight. Keloid Information for Adults—http://www.skinsight.com/adult/keloid.htm.

Provider Resources

• Medscape. Keloid and Hypertrophic Scar (Dermatology)—http://emedicine.medscape.com/article/1057599.
• Medscape. Keloids (Plastic Surgery)—http://emedicine.medscape.com/article/1298013.
• Usatine R, Pfenninger J, Stulberg D, Small R. Dermatologic and Cosmetic Procedures in Office Practice. Philadelphia, PA: Elsevier; 2012. Available as a text with DVD or electronic application. Contains details, photographs and videos on how to use cryosurgery and intralesional injections to treat keloids—http://usatinemedia.com/Usatine_Media_LLC/DermProcedures_Overview.html.

A 45-year-old black man presents with greasy scale over his face and large parts of his chest and back (Figure 205-1). A previous biopsy was diagnostic for Darier disease. His mother has the same condition. His sister has the full-blown disease. His brother has similar nail findings, but his skin is affected only behind the ears (Figure 205-2). The patient has suffered with this condition for his entire life and believes that he has been ostracized from normal social life because of his appearance and bad body odor. He suffers from depression and has used various substances to treat his pain. Topical steroids provide some help for the itching and scaling, but the patient is looking for a more effective treatment. The cost of oral retinoids is currently prohibitive, but an application has been put in for patient assistance to receive acitretin.

There are more than 100 genetic syndromes with cutaneous manifestations that are referred to as genodermatoses. For example, there are disorders of pigmentation (albinism), cornification (the ichthyoses and Darier disease), vascularization (Sturge-Weber syndrome), connective tissue (Ehlers-Danlos syndrome), porphyrin metabolism, other errors of metabolism (phenylketonuria), the immune system (Wiskott-Aldrich syndrome), and DNA repair (ataxia-telangiectasia and xeroderma pigmentosa), to name a few. Some textbooks are dedicated to the topic of genodermatoses alone.1 This chapter ­introduces the topic and illustrates a couple of genodermatoses. We have chosen two disorders of cornification as an introduction to the genodermatoses: Darier disease and X-linked ichthyosis.

• Darier disease (keratosis follicularis)—1:30,000 to 1:100,000. Males and females are equally affected. Clinically becomes apparent near puberty.
• X-linked ichthyosis—1:2000 to 1:6000 males. Clinical lesions present typically during the first 1 to 2 months of life.

• Darier disease—An abnormal calcium pump in the sarco-/endoplasmic reticulum, SERCA2, results from a gene mutation in the ATP2A2 gene. It is inherited in an autosomal-dominant fashion and results in abnormal epidermal differentiation.
• X-linked ichthyosis—A deletion of the steroid sulfatase gene results in keratinocyte retention by inhibiting degradation of the desmosome. It is inherited in an X-linked recessive manner.

Darier Disease

• Clinical features—Greasy, hyperkeratotic, yellowish-brown papules in a seborrheic distribution (Figures 205-1, 205-2, and 205-3). The feet can be covered with hyperkeratotic plaques (Figure 205-4). The palms may have pits or keratotic papules, and the nails can have V-shaped nicking and alternating longitudinal red and white bands (Figure 205-5). The keratotic papules can be intensely malodorous such that it can interfere with normal social situations.
• Typical distribution—The clinical lesions involve skin in the seborrheic distribution (face, ears, scalp, upper chest, upper back, and groin) (Figures 205-1, 205-2, 205-3, and 205-4). The axilla and inframammary areas may be involved (Figure 205-6). In early, mild, or partially treated disease, only the skin behind the ears may be affected ­(Figure 205-7).2 The nails are characteristically involved.
• Laboratories—Skin biopsy reveals the characteristic histopathology. A test for the ATP2A2 gene mutation can be performed.

X-Linked Ichthyosis

• Clinical features—Firm, adherent, fish-like brown scale noted early in the life of young affected boys whose mothers were carriers of the gene on their X chromosome (Figures 205-8 and 205-9). These boys have an increased incidence of cryptorchidism and are at an increased risk of testicular cancer, independent of the risk from cryptorchidism alone.2,3 Often they are delivered by cesarian section because a placental sulfatase deficiency results in failure of labor progression. These patients can have corneal opacities on the Descemet membrane of the posterior capsule, which does not affect their vision.
• Typical distribution—Most of the body is involved, except for the typical sparing of the flexures, face, palms, and soles. The ­antecubital fossae are notably spared (Figure 205-9). There is an ­accentuation noted on the neck, giving these patients a ­characteristic “dirty neck” appearance.
• Tight skin over the fingers can be as a manifestation of X-linked ichthyosis (Figure 205-10).
• Laboratories—Increased levels of serum cholesterol sulfate levels (steroid sulfatase hydrolyses cholesterol sulfate). Steroid sulfatase activity can also be measured directly.

Darier Disease4

• Hailey-Hailey disease (aka benign familial pemphigus)—Another genodermatosis with crusted erosions and flaccid vesicles distributed in the intertriginous areas as opposed to the greasy keratotic papules in the seborrheic distribution (Figure 205-11). A 4-mm punch biopsy is adequate to make this diagnosis.
• Grover disease—This presents sporadically as many small, pruritic, erythematous to reddish-brown hyperkeratotic papules on the trunk of older adults. These typically result from conditions that cause sweating or occlusion (like lying in a hospital bed) (­Chapter 117, Folliculitis).
• Seborrheic dermatitis—Erythematous patches and thin plaques with yellow greasy scale on the scalp, central face, and chest. This is rarely as severe as Darier disease (Chapter 151, Seborrheic ­Dermatitis).

X-Linked Ichthyosis

• Ichthyosis vulgaris—A relatively common condition that is inherited in an autosomal dominant manner (approximately 1 in 250 people affected). It presents in childhood with a fine adherent scale in similar distribution to X-linked ichthyosis (Figure 205-12). These patients frequently have hyperlinear palms, keratosis pilaris, and atopic dermatitis, which are not commonly associated with X-linked ichthyosis.
• Acquired ichthyosis does not occur until adulthood. It is not inherited and may be associated with some systemic disease. The time of onset is the key to diagnosis. The legs are often are most involved and the skin appears similar to fish-scales (Figure 205-13).
• Lamellar ichthyosis—A more severe and rare disorder that has a plate-like scale, which involves most of the body, including the face and flexures (Figure 205-14). These patients are typically born as a collodion baby (they have a thin translucent membrane that surrounds the baby at birth).
• Asteatotic eczema—Dry skin that has a “dried riverbed” or “cracked porcelain” appearance, which usually involves the lower extremities. There may be erythema and serous exudate associated with the cracks. It typically presents in the winter, improves during the rest of the year, and is also known as winter itch or eczema craquelé (Chapter 145, Atopic Dermatitis).
• Xerosis—Dry scaly skin most notably on legs without significant inflammation. This is very common compared with any ichthyosis.

• Darier disease is so rare that there are no randomized controlled trials to guide treatment.
• The intense malodor that accompanies the disease, as well as the facial involvement, often adversely affects the patient's quality of life; thus, treatment is often warranted. Mild-to-moderate disease can be treated by avoiding exacerbating factors (sunlight, heat, and occlusion) and with topical medications, SOR C but severe disease is best treated with oral retinoids. SOR C
• Topical retinoids (adapalene, tretinoin, or tazarotene) are effective in some patients, but their main limitation is irritation. Adapalene use may be effective in localized variants.5 SOR C All retinoids are contraindicated in pregnancy.
• Topical corticosteroids may be of some help. Lower-potency topical corticosteroids should be used on the face, groin, and axillae to minimize side effects in these areas. SOR C
• Topical calcineurin inhibitors (pimecrolimus and tacrolimus) may also be helpful as noted in some case reports.6,7 SOR C These do not have a risk of skin atrophy like steroids, but are generally more expensive and have a controversial black box warning.
• Systemic retinoids (acitretin or isotretinoin) are the most potent treatment and treatment of choice for severe disease.8 SOR C They should only be prescribed by physicians who have experience with these medications. Patients on systemic retinoids require close monitoring and careful selection, as they are teratogenic (category X) and can cause hyperlipidemia, hypertriglyceridemia, mucous membrane dryness, alopecia, hepatotoxicity, and possible mood disturbances. Females must not get pregnant for at least 1 month after stopping isotretinoin and at least 3 years after ­stopping ­acitretin.
• Cyclosporine can be used for acute flares but should also only be prescribed by a physician who has experience with this medication. It should only be used temporarily and requires close follow-up for monitoring hypertension and nephrotoxicity. It is metabolized by the common cytochrome P450 3A4 system and has many medication interactions.
• Topical or oral antibiotics may be necessary for flares as they often are secondarily infected with bacteria. SOR C
• Laser, radiation, photodynamic, and gene therapy are newer treatment modalities that are being investigated.
• X-linked ichthyosis is rare and treatments are based on the clinical experience of experts rather than large studies.
• Frequent application of emollients, humectants, and keratinolytics are the mainstay of therapy. SOR C There are many effective nonprescription and prescription products that contain propylene glycol, urea, or lactic acid. Salicylic acid products should be used only on a limited body surface area, as systemic absorption has led to salicylate toxicity in some patients.
• Topical retinoids can be used, SOR C but systemic retinoids are rarely used.
• Refer to a urologist or ophthalmologist if testicular abnormality or corneal opacities are detected. SOR C
• Gene therapy has also been studied but has not yet become a viable treatment option.

• Darier disease—Follow-up is needed if patients are on oral retinoids to monitor patients' lipid panel and liver function tests approximately every 3 months. They should also be monitored for signs of secondary bacterial infection.
• X-linked ichthyosis—Monitoring for corneal opacities and for ­testicular cancer in men should be performed at follow-up visits.

Darier Disease

• Avoid direct sunlight, heat, occlusion, and people acutely infected with herpes simplex virus (HSV) or varicella-zoster virus.
• Watch for signs of secondary cutaneous bacterial or viral infections.

X-Linked Ichthyosis

• Use daily moisturizers, especially in dry climates and in the winter.

Patient Resources

• There are patient advocacy groups for several genetic skin conditions. A quick search online can obtain their websites and contact information.
• The American Academy of Dermatology has a summer camp that is free of charge for children with skin conditions called Camp Discovery. Information can be found at http://www.campdiscovery.org/.

Provider Resources

• A helpful free online resource for the genodermatoses, or any genetic disease for that matter, is the Online Mendelian Inheritance of Man website at http://www.omim.org.
• For information on laboratories that perform rare genetic tests and clinics that perform prenatal diagnostic testing for certain conditions, see http://www.genetests.org.
• Skin Advocate is a free application for mobile devices that is provided by the Society of Investigative Dermatology. It lists contact information for various patient advocacy groups.

A 57-year-old farm worker presents with itchy red rings on his body that have come and gone for more than 13 years (Figures 206-1 and 206-2). The erythematous annular eruption was visible on his abdomen, legs, and arms. Figure 206-2 shows the typical “trailing scale” of erythema annular centrifugum (EAC). A KOH preparation was negative for fungal elements and the patient was given the diagnosis of EAC. He recently began using paint thinner to “dry out the rash” and decrease the itching. Because topical steroids did not provide any relief for him in the past, we offered the option of using calcipotriol ointment. He chose to try the calcipotriol and stop using paint thinner.

EAC is an uncommon inflammatory skin disease characterized by slowly migrating annular or configurate erythematous lesions.

Erythema gyratum perstans, erythema exudativum perstans, erythema marginatum perstans, erythema perstans, erythema figuratum perstans, erythema microgyratum perstans, and erythema simplex gyratum.

• It may begin at any age (mean age of onset: 39.7 years), with no predilection for either sex.1
• The mean duration of skin condition is 2.8 years but may last between 4 weeks and 34 years.2

• Unknown etiology and pathogenesis, but EAC has been associated with other medical conditions, such as fungal infections (in 72% of cases),1 malignancy, and other systemic illness. Few case reports have reported the diagnosis of cancer 2 years after presentation of EAC.2
• Other infections identified as triggers for EAC include bacterial infections such as cystitis, appendicitis, and tuberculosis (TB); viral infections such as Epstein-Barr virus (EBV), molluscum contagiosum, and herpes zoster; and parasites, such as Ascaris.2
• Certain drugs, such as chloroquine, hydroxychloroquine, estrogen, cimetidine, penicillin, salicylates, piroxicam, hydrochlorothiazide, amitriptyline, lenalidomide, finasteride, and etizolam, can also trigger EAC.2-6
• Systemic diseases involving the liver, dysproteinemias, autoimmune disorders, HIV, and pregnancy are associated with EAC by various case reports.2,7,8
• Because injections of Trichophyton, Candida, tuberculin, and tumor extracts have been reported to induce EAC, a type IV hypersensitivity reaction is thought to be one possible mechanism for its development.8

Clinical Features

• Large, scaly, erythematous plaques, which begin as papules and spread peripherally with a central clearing forming a “trailing” scale. The margins are indurated and may vary in width from 4 to 6 mm1,2 (Figures 206-1, 206-2, 206-3, and 206-4).
• Pruritus is common but not always present.2
• Slowly progressing but may enlarge up to 2 to 5 mm/day.2
• Evaluation of a skin biopsy specimen by light microscopy reveals parakeratosis and spongiosis within the epidermis and a tightly cuffed lymphohistiocytic perivascular infiltrate with focal extravasation of erythrocytes in the papillary dermis.10

Typical Distribution

• Lesions typically found in lower extremities, particularly the thighs, but also can be found on trunk and face.1,2

Laboratory Studies

• No specific laboratory tests are necessary to diagnose EAC, but laboratory tests may be obtained to rule out other common conditions. Consider a KOH prep to search for tinea corporis or cutaneous candidiasis. If the patient has been in an area with Lyme disease, consider Borrelia titers to rule out Lyme disease.2,7

Biopsy

• If the diagnosis is uncertain, a punch biopsy can be performed to look for the typical histology of EAC, and a periodic acid-Schiff (PAS) stain can be performed on the specimen to look for fungal elements. Other diseases on the differential diagnosis, such as psoriasis, cutaneous lupus, and sarcoidosis, can be diagnosed with a punch biopsy.

• Pityriasis rosea has erythematous patch distributed on trunk and lower extremities, but these patches have distinctive collarette border and typically have a “herald patch” that appears first. Classically, the patches have a “Christmas tree” pattern in the back and, unlike EAC, last only 6 to 8 weeks2 (see Chapter 153, Pityriasis Rosea).
• Tinea corporis (ringworm) presents with one or multiple areas of annular plaques caused by a dermatophyte fungal infection. Tinea corporis often produces red scaling rings that resemble EAC. However, the scale in tinea corporis tends to lead with the erythema inside the ring and the scale on the outside (Figure 206-5). This is the opposite of the trailing scale seen with EAC (Figure 206-6). KOH prep shows branched hyphae with septae. Tinea corporis responds to antifungal treatment.2 Figure 206-4 shows a case of EAC that was mistaken for tinea corporis by a number of physicians (see Chapter 138, Tinea Corporis).
• Psoriatic plaques can be annular but do not have the trailing scale that is characteristic of EAC. Psoriasis will respond to steroid therapy2 (see Chapter 152, Psoriasis).
• Erythema migrans seen in Lyme disease is a large annular rash with central clearing. The red ring in erythema migrans is usually smooth without the scale seen in EAC. Patients usually have other signs of infection, positive antibodies, and may have a history of tick bite (see Chapter 218, Lyme Disease).
• Erythema gyratum repens, which is typically seen in association with malignancies, has concentric rings but trailing scale is noted.
• Cutaneous lupus could present with annular or papulosquamous plaques, with or without scales, on sun-exposed areas. Patients with lupus generally have other systemic symptoms and positive antinuclear antibodies9 (see Chapter 180, Lupus: Systemic and Cutaneous).
• Sarcoidosis may present with annular indurated papules and plaques, but they are more commonly found on the face. Patients may have other systemic manifestations of sarcoidosis. Sarcoidosis can effectively be treated with systemic corticosteroids11 (see Chapter 175, Sarcoidosis).
• Mycosis fungoides, a type of cutaneous T cell lymphoma, can mimic EAC (Chapter 176, Cutaneous T Cell lymphoma).12

• There is no proven treatment for EAC. Identifying and treating underlying medical conditions may help resolve the skin condition. Because EAC is seen in association with certain drugs, discontinuing the offending medication may resolve the problem.
• Topical corticosteroids have been traditionally used but there is little evidence to support their use. SOR C
• Case reports have reported benefits of using calcipotriol (Dovonex) daily for EAC.13 Another case report described a good outcome for a patient with EAC being treated with calcipotriol and narrow-band UVB phototherapy.14 Case reports have shown etanercept and metronidazole to be beneficial as well.15,16

The prognosis is excellent if there is no underlying disease and may resolve in an average of 11 months.17 It often resolves with effective treatment of any underlying disorder. If EAC is associated with pregnancy, it should resolve soon after delivery. If EAC is associated with a malignancy, the prognosis depends on that of the malignancy. Even if it resolves, EAC may recur repeatedly over many years.

Follow-up depends on the type of treatment provided and patient's preferences.

• EAC is not contagious or malignant.
• Although the treatment might not work and the condition may recur, it is not dangerous and is confined to the skin only.

Provider Resources

• http://emedicine.medscape.com/article/1122701-overview.
• http://www.patient.co.uk/doctor/Erythema-Annulare-Centrifugum.htm.