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Stockings providing less compression, such as antiembolism hose, are poor substitutes. Use of emollients and/or mid-potency topical glucocorticoids and avoidance of irritants are also helpful in treating stasis dermatitis. Protection of the legs from injury, including scratching, and control of chronic edema are essential to prevent ulcers. Diuretics may be required to adequately control chronic edema. Stasis ulcers are difficult to treat, and resolution is slow. It is extremely important to elevate the affected limb as much as possible. The ulcer should be kept clear of necrotic material by gentle debridement and covered with a semipermeable dressing and a compression dressing or compression stocking. Glucocorticoids Figure 71-2 Dyshidrotic eczema. This example is characterized by deep-seated vesicles and scaling on palms and lateral fingers, and the disease is often associated with an atopic diathesis. Figure 71-3 Stasis dermatitis. An example of stasis dermatitis showing erythematous, scaly, and oozing patches over the lower leg. Several stasis ulcers are also seen in this patient. 347 CHAPTER 71 Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders should not be applied to ulcers, because they may retard healing; however, they may be applied to the surrounding skin to control itching, scratching, and additional trauma. Secondarily infected lesions should be treated with appropriate oral antibiotics, but it should be noted that all ulcers will become colonized with bacteria, and the purpose of antibiotic therapy should not be to clear all bacterial growth. Care must be taken to exclude treatable causes of leg ulcers (hypercoagulation, vasculitis) before beginning the chronic management outlined above. SEBORRHEIC DERMATITIS Seborrheic dermatitis is a common, chronic disorder characterized by greasy scales overlying erythematous patches or plaques. Induration and scale are generally less prominent than in psoriasis, but clinical overlap exists between these diseases (“sebopsoriasis”). The most common location is in the scalp, where it may be recognized as severe dandruff. On the face, seborrheic dermatitis affects the eyebrows, eyelids, glabella, and nasolabial folds (Fig. 71-4). Scaling of the external auditory canal is common in seborrheic dermatitis. In addition, the postauricular areas often become macerated and tender. Seborrheic dermatitis may also develop in the central chest, axilla, groin, submammary folds, and gluteal cleft. Rarely, it may cause widespread generalized dermatitis. Pruritus is variable. Seborrheic dermatitis may be evident within the first few weeks of life, and within this context it typically occurs in the scalp (“cradle cap”), face, or groin. It is rarely seen in children beyond infancy but becomes evident again during adult life. Although it is frequently seen in patients with Parkinson’s disease, in those who have had cerebrovascular accidents, and in those with HIV infection, the overwhelming majority of individuals with seborrheic dermatitis have no underlying disorder. Figure 71-4 Seborrheic dermatitis. Central facial erythema with overlying greasy, yellowish scale is seen in this patient. (Courtesy of Jean Bolognia, MD; with permission.) Table 71-2 Papulosquamous Disorders Clinical Features Other Notable Features Histologic Features Psoriasis Sharply demarcated, erythematous plaques with mica-like scale; predominantly on elbows, knees, and scalp; atypical forms may localize to intertriginous areas; eruptive forms may be associated with infection May be aggravated by certain drugs, infection; severe forms seen in association with HIV Acanthosis, vascular proliferation Lichen planus Purple polygonal papules marked by severe pruritus; lacy white markings, especially associated with mucous membrane lesions Certain drugs may induce: thiazides, antimalarial drugs Interface dermatitis Pityriasis rosea Rash often preceded by herald patch; oval to round plaques with trailing scale; most often affects trunk; eruption lines up in skinfolds giving a “fir tree–like” appearance; generally spares palms and soles Variable pruritus; self-limited, resolving in 2–8 weeks; may be imitated by secondary syphilis Pathologic features often nonspecific Dermatophytosis Polymorphous appearance depending on dermatophyte, body site, and host response; sharply defined to ill-demarcated scaly plaques with or without inflammation; may be associated with hair loss KOH preparation may show branching hyphae; culture helpful Hyphae and neutrophils in stratum corneum TREATMENT Seborrheic Derma titis Treatment with low-potency topical glucocorticoids in conjunction with a topical antifungal agent, such as ketoconazole cream or ciclopirox cream, is often effective. The scalp and beard areas may benefit from antidandruff shampoos, which should be left in place 3–5 min before rinsing. High-potency topical glucocorticoid solutions (betamethasone or clobetasol) are effective for control of severe scalp involvement. High-potency glucocorticoids should not be used on the face because this treatment is often associated with steroid-induced rosacea or atrophy. PAPULOSQUAMOUS DISORDERS (Table 71-2) PSORIASIS Psoriasis is one of the most common dermatologic diseases, affecting up to 2% of the world’s population. It is an immune-mediated disease clinically characterized by erythematous, sharply demarcated papules and rounded plaques covered by silvery micaceous scale. The skin lesions of psoriasis are variably pruritic. Traumatized areas often develop lesions of psoriasis (the Koebner or isomorphic phenomenon). In addition, other external factors may exacerbate psoriasis, including infections, stress, and medications (lithium, beta blockers, and antimalarial drugs). The most common variety of psoriasis is called plaque-type. Patients with plaque-type psoriasis have stable, slowly enlarging plaques, which remain basically unchanged for long periods of time. The most commonly involved areas are the elbows, knees, gluteal cleft, and scalp. Involvement tends to be symmetric. Plaque psoriasis generally develops slowly and runs an indolent course. It rarely remits spontaneously. Inverse psoriasis affects the intertriginous regions, including the axilla, groin, submammary region, and navel; it also tends to affect the scalp, palms, and soles. The individual lesions are sharply demarcated plaques (see Fig. 70-7), but they may be moist and without scale due to their locations. Guttate psoriasis (eruptive psoriasis) is most common in children and young adults. It develops acutely in individuals without psoriasis or in those with chronic plaque psoriasis. Patients present with many small erythematous, scaling papules, frequently after upper respiratory tract infection with β-hemolytic streptococci. The differential diagnosis should include pityriasis rosea and secondary syphilis. In pustular psoriasis, patients may have disease localized to the palms and soles, or the disease may be generalized. Regardless of the extent of disease, the skin is erythematous, with pustules and variable scale. Localized to the palms and soles, it is easily confused with eczema. When it is generalized, episodes are characterized by fever (39°–40°C [102.2°–104.0°F]) lasting several days, an accompanying generalized eruption of sterile pustules, and a background of intense erythema; patients may become erythrodermic. Episodes of fever and pustules are recurrent. Local irritants, pregnancy, medications, infections, and systemic glucocorticoid withdrawal can precipitate this form of psoriasis. Oral retinoids are the treatment of choice in nonpregnant patients. 348 PART 2 Cardinal Manifestations and Presentation of Diseases Fingernail involvement, appearing as punctate pitting, onycholysis, nail thickening, or subungual hyperkeratosis, may be a clue to the diagnosis of psoriasis when the clinical presentation is not classic. According to the National Psoriasis Foundation, up to 30% of patients with psoriasis have psoriatic arthritis (PsA). There are five subtypes of PsA: symmetric, asymmetric, distal interphalangeal predominant (DIP), spondylitis, and arthritis mutilans. Symmetric arthritis resembles rheumatoid arthritis, but is usually milder. Asymmetric arthritis can involve any joint and may present as “sausage digits.” DIP is the classic form, but occurs in only about 5% of patients with PsA. It may involve fingers and toes. Spondylitis also occurs in about 5% of patients with PsA. Arthritis mutilans is severe and deforming. It affects primarily the small joints of the hands and feet. It accounts for fewer than 5% of PsA cases. An increased risk of metabolic syndrome, including increased morbidity and mortality from cardiovascular events, has been demonstrated in psoriasis patients. Appropriate screening tests should be performed. The etiology of psoriasis is still poorly understood, but there is clearly a genetic component to the disease. In various studies, 30–50% of patients with psoriasis report a positive family history. Psoriatic lesions contain infiltrates of activated T cells that are thought to elaborate cytokines responsible for keratinocyte hyperproliferation, which results in the characteristic clinical findings. Agents inhibiting T cell activation, clonal expansion, or release of proinflammatory cytokines are often effective for the treatment of severe psoriasis (see below). TREATMENT Psoriasis Treatment of psoriasis depends on the type, location, and extent of disease. All patients should be instructed to avoid excess drying or irritation of their skin and to maintain adequate cutaneous hydration. Most cases of localized, plaque-type psoriasis can be managed with mid-potency topical glucocorticoids, although their long-term use is often accompanied by loss of effectiveness (tachyphylaxis) and atrophy of the skin. A topical vitamin D analogue (calcipotriene) and a retinoid (tazarotene) are also efficacious in the treatment of limited psoriasis and have largely replaced other topical agents such as coal tar, salicylic acid, and anthralin. Ultraviolet (UV) light, natural or artificial, is an effective therapy for many patients with widespread psoriasis. Ultraviolet B (UVB), narrowband UVB, and ultraviolet A (UVA) light with either oral or topical psoralens (PUVA) is used clinically. UV light’s immunosuppressive properties are thought to be responsible for its therapeutic activity in psoriasis. It is also mutagenic, potentially leading to an increased incidence of nonmelanoma and melanoma skin cancer. UV-light therapy is contraindicated in patients receiving cyclosporine and should be used with great care in all immunocompromised patients due to the increased risk of skin cancer. Various systemic agents can be used for severe, widespread psoriatic disease (Table 71-3). Oral glucocorticoids should not be used for the treatment of psoriasis due to the potential for development of life-threatening pustular psoriasis when therapy is discontinued. Methotrexate is an effective agent, especially in patients with psoriatic arthritis. The synthetic retinoid acitretin is useful, especially when immunosuppression must be avoided; however, teratogenicity limits its use. The evidence implicating psoriasis as a T cell–mediated disorder has directed therapeutic efforts to immunoregulation. Cyclosporine and other immunosuppressive agents can be very effective in the treatment of psoriasis, and much attention is currently directed toward the development of biologic agents with more selective immunosuppressive properties and better safety profiles (Table 71-4). Experience with these biologic agents is limited, and information regarding combination therapy and adverse events continues to emerge. Use of tumor necrosis factor (TNF-α) inhibitors may worsen congestive heart failure (CHF), and they should be used with caution in patients at risk for or known to have CHF. Further, none of the immunosuppressive agents used in the treatment of psoriasis should be initiated if the patient has a severe infection; patients on such therapy should be routinely screened for tuberculosis. There have been reports of progressive multifocal leukoencephalopathy in association with treatment with the TNF-α inhibitors. Malignancies, including a risk or history of certain malignancies, may limit the use of these systemic agents. Table 71-4 Biologics Approved for Psoriasis or Psoriat ic Arthr itis Administration Agent Mechanism of Action Indication Route Frequency Warnings Etanercept Anti-TNF-α Ps, PsA SC Once or twice weekly Serious infections, hepatotoxicity, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies Adalimumab Anti-TNF-α Ps, PsA SC Every other week Serious infections, hepatotoxicity, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies Infliximab Anti-TNF-α Ps, PsA IV Initial infusion followed by infusions at weeks 2 and 6, then every 8 weeks Serious infections, hepatotoxicity, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies Golimumab Anti-TNF-α PsA SC Monthly Serious infections, hepatotoxicity, CHF, hypersensitivity reactions, neurologic events, potential for increased malignancies Ustekinumab Anti-IL-12 and anti-IL-23 Ps SC 2 doses 4 weeks apart, then every 12 weeks Serious infections, neurologic events, potential for increased malignancies Abbreviations: CHF, congestive heart failure; IL, interleukin; IM, intramuscular; Ps, psoriasis; PsA, psoriatic arthritis; SC, subcutaneous; TNF, tumor necrosis factor. Table 71-3 FDA-Approved Systemic Therapy for Psoriasis Administration Agent Medication Class Route Frequency Adverse Events (Selected) Methotrexate Antimetabolite Oral Weekly Hepatotoxicity, pulmonary toxicity, pancytopenia, potential for increased malignancies, ulcerative stomatitis, nausea, diarrhea, teratogenicity Acitretin Retinoid Oral Daily Teratogenicity, hepatotoxicity, hyperostosis, hyperlipidemia/pancreatitis, depression, ophthalmologic effects, pseudotumor cerebri Cyclosporine Calcineurin inhibitor Oral Twice daily Renal dysfunction, hypertension, hyperkalemia, hyperuricemia, hypomagnesemia, hyperlipidemia, increased risk of malignancies 349 CHAPTER 71 Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders LICHEN PLANUS Lichen planus (LP) is a papulosquamous disorder that may affect the skin, scalp, nails, and mucous membranes. The primary cutaneous lesions are pruritic, polygonal, flat-topped, violaceous papules. Close examination of the surface of these papules often reveals a network of gray lines (Wickham’s striae). The skin lesions may occur anywhere but have a predilection for the wrists, shins, lower back, and genitalia (Fig. 71-5). Involvement of the scalp (lichen planopilaris) may lead to scarring alopecia, and nail involvement may lead to permanent deformity or loss of fingernails and toenails. LP commonly involves mucous membranes, particularly the buccal mucosa, where it can present on a spectrum ranging from a mild, white, reticulate eruption of the mucosa to a severe, erosive stomatitis. Erosive stomatitis may persist for years and may be linked to an increased risk of oral squamous cell carcinoma. Cutaneous eruptions clinically resembling LP have been observed after administration of numerous drugs, including thiazide diuretics, gold, antimalarial agents, penicillamine, and phenothiazines, and in patients with skin lesions of chronic graft-versus-host disease. In addition, LP may be associated with hepatitis C infection. The course of LP is variable, but most patients have spontaneous remissions 6 months to 2 years after the onset of disease. Topical glucocorticoids are the mainstay of therapy. PITYRIASIS ROSEA Pityriasis rosea (PR) is a papulosquamous eruption of unknown etiology occurring more commonly in the spring and fall. Its first manifestation is the development of a 2- to 6-cm annular lesion (the herald patch). This is followed in a few days to a few weeks by the appearance of many smaller annular or papular lesions with a predilection to occur on the trunk (Fig. 71-6). The lesions are generally oval, with their long axis parallel to the skinfold lines. Individual lesions may range in color from red to brown and have a trailing scale. PR shares many clinical features with the eruption of secondary syphilis, but palm and sole lesions are extremely rare in PR and common in secondary syphilis. The eruption tends to be moderately pruritic and lasts 3–8 weeks. Treatment is directed at alleviating pruritus and consists of oral antihistamines; mid-potency topical glucocorticoids; and, in some cases, UVB phototherapy. CUTANEOUS INFECTIONS (Table 71-5) IMPETIGO, ECTHYMA, AND FURUNCULOSIS Impetigo is a common superficial bacterial infection of skin caused most often by S. aureus (Chap. 172) and in some cases by group A β-hemolytic streptococci (Chap. 173). The primary lesion is a superficial pustule that ruptures and forms a characteristic yellow-brown Figure 71-5 Lichen planus. An example of lichen planus showing multiple flat-topped, violaceous papules and plaques. Nail dystrophy, as seen in this patient’s thumbnail, may also be a feature. (Courtesy of Robert Swerlick, MD; with permission.) Figure 71-6 Pityriasis rosea. In this patient with pityriasis rosea, multiple round to oval erythematous patches with fine central scale are distributed along the skin tension lines on the trunk. honey-colored crust (see Fig. 173-3). Lesions may occur on normal skin (primary infection) or in areas already affected by another skin disease (secondary infection). Lesions caused by staphylococci may be tense, clear bullae, and this less common form of the disease is called bullous impetigo. Blisters are caused by the production of exfoliative toxin by S. aureus phage type II. This is the same toxin responsible for staphylococcal scalded-skin syndrome, often resulting in dramatic loss of the superficial epidermis due to blistering. The latter syndrome is much more common in children than in adults; however, it should be considered along with toxic epidermal necrolysis and severe drug eruptions in patients with widespread blistering of the skin. Ecthyma is a deep non-bullous variant of impetigo that causes punched-out ulcerative lesions. It is more often caused by a primary or secondary infection with Streptococcus pyogenes. Ecthyma is a deeper infection than typical impetigo and resolves with scars. Treatment of both ecthyma and impetigo involves gentle debridement of adherent crusts, which is facilitated by the use of soaks and topical antibiotics in conjunction with appropriate oral antibiotics. Furunculosis is also caused by S. aureus, and this disorder has gained prominence in the last decade because of CA-MRSA. A furuncle, or boil, is a painful, erythematous nodule that can occur on any cutaneous surface. The lesions may be solitary but are most often multiple. Patients frequently believe they have been bitten by spiders or insects. Family members or close contacts may also be affected. Furuncles can rupture and drain spontaneously or may need incision and drainage, which may be adequate therapy for small solitary furuncles without cellulitis or systemic symptoms. Whenever possible, lesional material should be sent for culture. Current recommendations for methicillinsensitive infections are β-lactam antibiotics. Therapy for CA-MRSA was discussed previously (see “Atopic Dermatitis”). Warm compresses and nasal mupirocin are helpful therapeutic additions. Severe infections may require IV antibiotics. ERYSIPELAS AND CELLULITIS See Chap. 156. DERMATOPHYTOSIS Dermatophytes are fungi that infect skin, hair, and nails and include members of the genera Trichophyton, Microsporum, and Epidermophyton (Chap. 243). Tinea corporis, or infection of the relatively hairless skin of the body (glabrous skin), may have a variable appearance depending on the extent of the associated inflammatory reaction. Typical infections consist of erythematous, scaly plaques, with an annular appearance that accounts for the common name “ringworm.” Deep inflammatory nodules or granulomas occur in 350 PART 2 Cardinal Manifestations and Presentation of Diseases some infections, most often those inappropriately treated with mid- to high-potency topical glucocorticoids. Involvement of the groin (tinea cruris) is more common in males than in females. It presents as a scaling, erythematous eruption sparing the scrotum. Infection of the foot (tinea pedis) is the most common dermatophyte infection and is often chronic; it is characterized by variable erythema, edema, scaling, pruritus, and occasionally vesiculation. The infection may be widespread or localized but generally involves the web space between the fourth and fifth toes. Infection of the nails (tinea unguium or onychomycosis) occurs in many patients with tinea pedis and is characterized by opacified, thickened nails and subungual debris. The distal-lateral variant is most common. Proximal subungual onychomycosis may be a marker for HIV infection or other immunocompromised states. Dermatophyte infection of the scalp (tinea capitis) continues to be common, particularly affecting inner-city children but also affecting adults. The predominant organism is Trichophyton tonsurans, which can produce a relatively noninflammatory infection with mild scale and hair loss that is diffuse or localized. T. tonsurans can also cause a markedly inflammatory dermatosis with edema and nodules. This latter presentation is a kerion. The diagnosis of tinea can be made from skin scrapings, nail scrapings, or hair by culture or direct microscopic examination with potassium hydroxide (KOH). Nail clippings may be sent for histologic examination with periodic acid–Schiff (PAS) stain. TREATMENT Derma tophytosis Both topical and systemic therapies may be used in dermatophyte infections. Treatment depends on the site involved and the type of infection. Topical therapy is generally effective for uncomplicated tinea corporis, tinea cruris, and limited tinea pedis. Topical agents are not effective as monotherapy for tinea capitis or onychomycosis (see below). Topical imidazoles, triazoles, and allylamines may be effective therapies for dermatophyte infections, but nystatin is not active against dermatophytes. Topicals are generally applied twice daily, and treatment should continue for 1 week beyond clinical resolution of the infection. Tinea pedis often requires longer treatment courses and frequently relapses. Oral antifungal agents may be required for recalcitrant tinea pedis or tinea corporis. Oral antifungal agents are required for dermatophyte infections involving the hair and nails and for other infections unresponsive to topical therapy. A fungal etiology should be confirmed by direct microscopic examination or by culture before oral antifungal agents are prescribed. All of the oral agents may cause hepatotoxicity. They should not be used in women who are pregnant or breast-feeding. Griseofulvin is approved in the United States for dermatophyte infections involving the skin, hair, or nails. When griseofulvin is used, a daily dose of 500 mg microsized or 375 mg ultramicrosized, administered with a fatty meal, is adequate for most dermatophyte infections. Higher doses are required for some cases of tinea pedis and tinea capitis. Markedly inflammatory tinea capitis may result in scarring and hair loss, and systemic or topical glucocorticoids may be helpful in preventing these sequelae. The duration of griseofulvin therapy may be 2 weeks for uncomplicated tinea corporis, 8–12 weeks for tinea capitis, or as long as 6–18 months for nail infections. Due to high relapse rates, griseofulvin is seldom used for nail infections. Common side effects of griseofulvin include gastrointestinal distress, headache, and urticaria. Oral itraconazole is approved for onychomycosis. Itraconazole is given with food as either continuous daily therapy (200 mg/d) or pulses (200 mg bid for 1 week per month). Fingernails require 2 months of continuous therapy or two pulses. Toenails require 3 months of continuous therapy or three pulses. Itraconazole has the potential for serious interactions with other drugs requiring the P450 enzyme system for metabolism. Itraconazole should not be administered to patients with evidence of ventricular dysfunction or patients with known CHF. Terbinafine (250 mg/d) is also effective for onychomycosis, and the granule version is approved for treatment of tinea capitis. Therapy with terbinafine is continued for 6 weeks for fingernail and scalp infections and 12 weeks for toenail infections. Terbinafine has fewer interactions with other drugs than itraconazole, but caution should be used with patients who are on multiple medications. The risk/benefit ratio should be considered when an asymptomatic toenail infection is treated with systemic agents. TINEA VERSICOLOR Tinea versicolor is caused by a nondermatophytic, dimorphic fungus, Malassezia furfur, a normal inhabitant of the skin. The expression of infection is promoted by heat and humidity. The typical lesions consist of oval scaly macules, papules, and patches concentrated on the chest, shoulders, and back but only rarely on the face or distal extremities. On dark skin the lesions often appear as hypopigmented areas, while on light skin they are slightly erythematous or hyperpigmented. A KOH preparation from scaling lesions will demonstrate a confluence of short hyphae and round spores (“spaghetti and meatballs”). Lotions or shampoos containing sulfur, salicylic acid, or selenium sulfide will clear the infection if used daily for 1–2 weeks and then weekly thereafter. These preparations are irritating if left on the skin for >10 min; thus, they should be washed off completely. Treatment with some oral antifungal agents is also effective, but they do not provide lasting results and are not FDA approved for this indication. A very short course of ketoconazole has been used, as have itraconazole and fluconazole. The patient must sweat after taking the medication if it is to be effective. Griseofulvin is not effective and terbinafine is not reliably effective for tinea versicolor. CANDIDIASIS Candidiasis is a fungal infection caused by a related group of yeasts whose manifestations may be localized to the skin and mucous membranes or, rarely, may be systemic and life-threatening (Chap. 240). The causative organism is usually Candida albicans. These organisms are normal saprophytic inhabitants of the gastrointestinal tract but may overgrow due to broad-spectrum antibiotic therapy, diabetes mellitus, or immunosuppression and cause disease. Candidiasis is a Table 71-5 Common Skin Infect ions Clinical Features Etiologic Agent Treatment Impetigo Honey-colored crusted papules, plaques, or bullae Group A Streptococcus and Staphylococcus aureus Systemic or topical antistaphylococcal and antistreptoccal antibiotics Dermatophytosis Inflammatory or noninflammatory annular scaly plaques; may involve hair loss; groin involvement spares scrotum; hyphae on KOH preparation Trichophyton, Epidermophyton, or Microsporum spp. Topical azoles, systemic griseofulvin, terbinafine, or azoles Candidiasis Inflammatory papules and plaques with satellite pustules, frequently in intertriginous areas; may involve scrotum; pseudohyphae on KOH preparation Candida albicans and other Candida spp. Topical nystatin or azoles; systemic azoles for resistant disease Tinea versicolor Hyper- or hypopigmented scaly patches on trunk; characteristic mixture of hyphae and spores (“spaghetti and meatballs”) on KOH preparation Malassezia furfur Topical selenium sulfide lotion or azoles 351 CHAPTER 71 Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders very common infection in HIV-infected individuals (Chap. 226). The oral cavity is commonly involved. Lesions may occur on the tongue or buccal mucosa (thrush) and appear as white plaques. Fissured, macerated lesions at the corners of the mouth (perléche) are often seen in individuals with poorly fitting dentures and may also be associated with candidal infection. In addition, candidal infections have an affinity for sites that are chronically wet and macerated, including the skin around nails (onycholysis and paronychia), and in intertriginous areas. Intertriginous lesions are characteristically edematous, erythematous, and scaly, with scattered “satellite pustules.” In males, there is often involvement of the penis and scrotum as well as the inner aspect of the thighs. In contrast to dermatophyte infections, candidal infections are frequently painful and accompanied by a marked inflammatory response. Diagnosis of candidal infection is based upon the clinical pattern and demonstration of yeast on KOH preparation or culture. TREATMENT Ca ndidiasis Treatment involves removal of any predisposing factors such as antibiotic therapy or chronic wetness and the use of appropriate topical or systemic antifungal agents. Effective topicals include nystatin or azoles (miconazole, clotrimazole, econazole, or ketoconazole). The associated inflammatory response accompanying candidal infection on glabrous skin can be treated with a mild glucocorticoid lotion or cream (2.5% hydrocortisone). Systemic therapy is usually reserved for immunosuppressed patients or individuals with chronic or recurrent disease who fail to respond to appropriate topical therapy. Oral agents approved for the treatment of candidiasis include itraconazole and fluconazole. Oral nystatin is effective only for candidiasis of the gastrointestinal tract. Griseofulvin and terbinafine are not effective. WARTS Warts are cutaneous neoplasms caused by papillomaviruses. More than 100 different human papillomaviruses (HPVs) have been described. A typical wart, verruca vulgaris, is sessile, dome-shaped, and usually about a centimeter in diameter. Its surface is hyperkeratotic, consisting of many small filamentous projections. The HPV types that cause typical verruca vulgaris also cause typical plantar warts, flat warts (verruca plana), and filiform warts. Plantar warts are endophytic and are covered by thick keratin. Paring of the wart will generally reveal a central core of keratinized debris and punctate bleeding points. Filiform warts are most commonly seen on the face, neck, and skinfolds and present as papillomatous lesions on a narrow base. Flat warts are only slightly elevated and have a velvety, nonverrucous surface. They have a propensity for the face, arms, and legs and are often spread by shaving. Genital warts begin as small papillomas that may grow to form large, fungating lesions. In women, they may involve the labia, perineum, or perianal skin. In addition, the mucosa of the vagina, urethra, and anus can be involved as well as the cervical epithelium. In men, the lesions often occur initially in the coronal sulcus but may be seen on the shaft of the penis, the scrotum, or the perianal skin or in the urethra. Appreciable evidence has accumulated indicating that HPV plays a role in the development of neoplasia of the uterine cervix and anogenital skin (Chap. 117). HPV types 16 and 18 have been most intensely studied and are the major risk factors for intraepithelial neoplasia and squamous cell carcinoma of the cervix, anus, vulva, and penis. The risk is higher among patients immunosuppressed after solid organ transplantation and among those infected with HIV. Recent evidence also implicates other HPV types. Histologic examination of biopsied samples from affected sites may reveal changes associated with typical warts and/or features typical of intraepidermal carcinoma (Bowen’s disease). Squamous cell carcinomas associated with HPV infections have also been observed in extragenital skin (Chap. 105), most commonly in patients immunosuppressed after organ transplantation. Patients on long-term immunosuppression should be monitored for the development of squamous cell carcinoma and other cutaneous malignancies. TREATMENT Warts Treatment of warts, other than anogenital warts, should be tempered by the observation that a majority of warts in normal individuals resolve spontaneously within 1–2 years. There are many modalities available to treat warts, but no single therapy is universally effective. Factors that influence the choice of therapy include the location of the wart, the extent of disease, the age and immunologic status of the patient, and the patient’s desire for therapy. Perhaps the most useful and convenient method for treating warts in almost any location is cryotherapy with liquid nitrogen. Equally effective for nongenital warts, but requiring much more patient compliance, is the use of keratolytic agents such as salicylic acid plasters or solutions. For genital warts, in-office application of a podophyllin solution is moderately effective but may be associated with marked local reactions. Prescription preparations of dilute, purified podophyllin are available for home use. Topical imiquimod, a potent inducer of local cytokine release, has been approved for treatment of genital warts. A new topical compound composed of green tea extracts (sinecatechins) is also available. Conventional and laser surgical procedures may be required for recalcitrant warts. Recurrence of warts appears to be common to all these modalities. A highly effective vaccine for selected types of HPV has been approved by the FDA, and its use appears to reduce the incidence of anogenital and cervical carcinoma. HERPES SIMPLEX See Chap. 216. HERPES ZOSTER See Chap. 217. ACNE ACNE VULGARIS Acne vulgaris is a self-limited disorder primarily of teenagers and young adults, although perhaps 10–20% of adults may continue to experience some form of the disorder. The permissive factor for the expression of the disease in adolescence is the increase in sebum production by sebaceous glands after puberty. Small cysts, called comedones, form in hair follicles due to blockage of the follicular orifice by retention of keratinous material and sebum. The activity of bacteria (Propionibacterium acnes) within the comedones releases free fatty acids from sebum, causes inflammation within the cyst, and results in rupture of the cyst wall. An inflammatory foreign-body reaction develops as result of extrusion of oily and keratinous debris from the cyst. The clinical hallmark of acne vulgaris is the comedone, which may be closed (whitehead) or open (blackhead). Closed comedones appear as 1- to 2-mm pebbly white papules, which are accentuated when the skin is stretched. They are the precursors of inflammatory lesions of acne vulgaris. The contents of closed comedones are not easily expressed. Open comedones, which rarely result in inflammatory acne lesions, have a large dilated follicular orifice and are filled with easily expressible oxidized, darkened, oily debris. Comedones are usually accompanied by inflammatory lesions: papules, pustules, or nodules. The earliest lesions seen in adolescence are generally mildly inflamed or noninflammatory comedones on the forehead. Subsequently, more typical inflammatory lesions develop on the cheeks, nose, and chin (Fig. 71-7). The most common location for acne is the face, but involvement of the chest and back is common. Most disease remains mild and does not lead to scarring. A small number of patients develop large inflammatory cysts and nodules, which may drain and result in significant scarring. Regardless of the severity, acne may affect a patient’s quality of life. With adequate treatment, this effect may be transient. In the case of severe, scarring acne, the effects can be permanent and profound. Early therapeutic intervention in severe acne is essential. Exogenous and endogenous factors can alter the expression of acne vulgaris. Friction and trauma (from headbands or chin straps of athletic helmets), application of comedogenic topical agents (cosmetics 352 PART 2 Cardinal Manifestations and Presentation of Diseases Figure 71-8 Acne rosacea. Prominent facial erythema, telangiectasia, scattered papules, and small pustules are seen in this patient with acne rosacea. (Courtesy of Robert Swerlick, MD; with permission.) Figure 71-7 Acne vulgaris. An example of acne vulgaris with inflammatory papules, pustules, and comedones. (Courtesy of Kalman Watsky, MD; with permission.) or hair preparations), or chronic topical exposure to certain industrial compounds may elicit or aggravate acne. Glucocorticoids, topical or systemic, may also elicit acne. Other systemic medications such as oral contraceptive pills, lithium, isoniazid, androgenic steroids, halogens, phenytoin, and phenobarbital may produce acneiform eruptions or aggravate preexisting acne. Genetic factors and polycystic ovary disease may also play a role. TREATMENT Acne Vulgaris Treatment of acne vulgaris is directed toward elimination of comedones by normalizing follicular keratinization, decreasing sebaceous gland activity, decreasing the population of P. acnes, and decreasing inflammation. Minimal to moderate pauci-inflammatory disease may respond adequately to local therapy alone. Although areas affected with acne should be kept clean, overly vigorous scrubbing may aggravate acne due to mechanical rupture of comedones. Topical agents such as retinoic acid, benzoyl peroxide, or salicylic acid may alter the pattern of epidermal desquamation, preventing the formation of comedones and aiding in the resolution of preexisting cysts. Topical antibacterial agents (such as azelaic acid, erythromycin, clindamycin, or dapsone) are also useful adjuncts to therapy. Patients with moderate to severe acne with a prominent inflammatory component will benefit from the addition of systemic therapy, such as tetracycline in doses of 250–500 mg bid or doxycycline in doses of 100 mg bid. Minocycline is also useful. Such antibiotics appear to have anti-inflammatory effects independent of their antibacterial effects. Female patients who do not respond to oral antibiotics may benefit from hormonal therapy. Several oral contraceptives are now approved by the FDA for use in the treatment of acne vulgaris. Patients with severe nodulocystic acne unresponsive to the therapies discussed above may benefit from treatment with the synthetic retinoid isotretinoin. Its dose is based on the patient’s weight, and it is given once daily for 5 months. Results are excellent in appropriately selected patients. Its use is highly regulated due to its potential for severe adverse events, primarily teratogenicity and depression. In addition, patients receiving this medication develop extremely dry skin and cheilitis and must be followed for development of hypertriglyceridemia. At present, prescribers must enroll in a program designed to prevent pregnancy and adverse events while patients are taking isotretinoin. These measures are imposed to ensure that all prescribers are familiar with the risks of isotretinoin; that all female patients have two negative pregnancy tests prior to initiation of therapy and a negative pregnancy test prior to each refill; and that all patients have been warned about the risks associated with isotretinoin. ACNE ROSACEA Acne rosacea, commonly referred to simply as rosacea, is an inflammatory disorder predominantly affecting the central face. Persons most often affected are Caucasians of northern European background, but rosacea also occurs in patients with dark skin.  such as a deepened voice and enlarged clitoris, the possibility of an ovarian or adrenal gland tumor should be considered. Exposure to various drugs can also cause diffuse hair loss, usually by inducing a telogen effluvium. An exception is the anagen effluvium observed with antimitotic agents such as daunorubicin. Alopecia is a side effect of the following drugs: warfarin, heparin, propylthiouracil, carbimazole, isotretinoin, acitretin, lithium, beta blockers, interferons, colchicine, and amphetamines. Fortunately, spontaneous regrowth usually follows discontinuation of the offending agent. Less commonly, nonscarring alopecia is associated with lupus erythematosus and secondary syphilis. In systemic lupus there are two forms of alopecia—one is scarring secondary to discoid lesions (see below), and the other is nonscarring. The latter form coincides with flares of systemic disease and may involve the entire scalp or just the frontal scalp, with the appearance of multiple short hairs (“lupus hairs”) as a sign of initial regrowth. Scattered, poorly circumscribed patches of alopecia with a “moth-eaten” appearance are a manifestation Table 72-3 Erythroderma (Primary Cuta neous Disorders) Initial Lesions Location of Initial Lesions Other Findings Diagnostic Aids Treatment Psoriasisa Pink-red, silvery scale, sharply demarcated Elbows, knees, scalp, presacral area, intergluteal fold Nail dystrophy, arthritis, pustules; SAPHO syndrome, especially with palmoplantar pustulosis Skin biopsy Topical glucocorticoids, vitamin D; UV-B (narrowband) > PUVA; oral retinoid; MTX, cyclosporine, anti-TNF agents, anti-IL-12/23 Ab Dermatitisa Atopic Acute: Erythema, fine scale, crust, indistinct borders, excoriations Chronic: Lichenification (increased skin markings), excoriations Antecubital and popliteal fossae, neck, hands, eyelids Pruritus Personal and/or family history of atopy, including asthma, allergic rhinitis or conjunctivitis, and atopic dermatitis Exclude secondary infection with Staphylococcus aureus or HSV Exclude superimposed irritant or allergic contact dermatitis Skin biopsy Topical glucocorticoids, tacrolimus, pimecrolimus, tar, and antipruritics; oral antihistamines; open wet dressings; UV-B ± UV-A > PUVA; oral/IM glucocorticoids (short-term); MTX; mycophenolate mofetil; azathioprine; cyclosporine Topical or oral antibiotics Contact Local: Erythema, crusting, vesicles, and bullae Systemic: Erythema, fine scale, crust Depends on offending agent Generalized vs major intertriginous zones (especially groin) Irritant—onset often within hours Allergic—delayed-type hypersensitivity; lag time of 48 h Patient has history of allergic contact dermatitis to topical agent and then receives systemic medication that is structurally related, e.g., thiuram (skin), disulfiram (oral) Patch testing; open use test Patch testing Remove irritant or allergen; topical glucocorticoids; oral antihistamines; oral/IM glucocorticoids (short-term) Same as local Seborrheic (rare in adults) Pink-red to pinkorange, greasy scale Scalp, nasolabial folds, eyebrows, intertriginous zones Flares with stress, HIV infection Associated with Parkinson’s disease Skin biopsy Topical glucocorticoids and imidazoles Stasis (with autosensitization) Erythema, crusting, excoriations Lower extremities Pruritus, lower extremity edema, varicosities, hemosiderin deposits History of venous ulcers, thrombophlebitis, and/or cellulitis Exclude cellulitis Exclude superimposed contact dermatitis, e.g., topical neomycin Skin biopsy Topical glucocorticoids; open wet dressings; leg elevation; pressure stockings; pressure wraps if associated ulcers Pityriasis rubra pilaris Orange-red (salmoncolored), perifollicular papules Generalized, but characteristic “skip” areas of normal skin Wax-like palmoplantar keratoderma Exclude cutaneous T cell lymphoma Skin biopsy Isotretinoin or acitretin; MTX; perhaps anti-IL-12/23 Ab, IV anti-TNF agent a Discussed in detail in Chap. 71. Abbreviations: Ab, antibody; HSV, herpes simplex virus; IL, interleukin; IM, intramuscular; IV, intravenous; MTX, methotrexate; PUVA, psoralens + ultraviolet A irradiation; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis (also referred to as chronic recurrent multifocal osteomyelitis); TNF, tumor necrosis factor; UV-A, ultraviolet A irradiation; UV-B, ultraviolet B irradiation. 355 CHAPTER 72 Skin Manifestations of Internal Disease of the secondary stage of syphilis. Diffuse thinning of the hair is also associated with hypothyroidism and hyperthyroidism (Table 72-4). Scarring alopecia is more frequently the result of a primary cutaneous disorder such as lichen planus, folliculitis decalvans, chronic cutaneous (discoid) lupus, or linear scleroderma (morphea) than it is a sign of systemic disease. Although the scarring lesions of discoid lupus can be seen in patients with systemic lupus, in the majority of patients, the disease process is limited to the skin. Less common causes of scarring alopecia include sarcoidosis (see “Papulonodular Skin Lesions,” below) and cutaneous metastases. In the early phases of discoid lupus, lichen planus, and folliculitis decalvans, there are circumscribed areas of alopecia. Fibrosis and subsequent loss of hair follicles are observed primarily in the center of these alopecic patches, whereas the inflammatory process is most prominent at the periphery. The areas of active inflammation in discoid lupus are erythematous with scale, whereas the areas of previous inflammation are often hypopigmented with a rim of hyperpigmentation. In lichen planus, perifollicular macules at the periphery are usually violet-colored. A complete examination of the skin and oral mucosa combined with a biopsy and direct immunofluorescence microscopy of inflamed skin will aid in distinguishing these two entities. The peripheral active lesions in folliculitis decalvans are follicular pustules; these patients can develop a reactive arthritis. FIGURATE SKIN LESIONS (Table 72-6) In figurate eruptions, the lesions form rings and arcs that are usually erythematous but can be skin-colored to brown. Most commonly, they are due to primary cutaneous diseases such as tinea, urticaria, granuloma annulare, and erythema annulare centrifugum (Chaps. 71 and 73). An underlying systemic illness is found in a second, less common group of migratory annular erythemas. It includes erythema migrans, erythema gyratum repens, erythema marginatum, and necrolytic migratory erythema. In erythema gyratum repens, one sees numerous mobile concentric arcs and wavefronts that resemble the grain in wood. A search for an Table 72-4 Causes of Alopecia I. Nonscarring alopecia A. Primary cutaneous disorders 1. Androgenetic alopecia 2. Telogen effluvium 3. Alopecia areata 4. Tinea capitis 5. Traumatic alopeciaa B. Drugs C. Systemic diseases 1. Systemic lupus erythematosus 2. Secondary syphilis 3. Hypothyroidism 4. Hyperthyroidism 5. Hypopituitarism 6. Deficiencies of protein, biotin, zinc, and perhaps iron II. Scarring alopecia A. Primary cutaneous disorders 1. Cutaneous lupus (chronic discoid lesions)b 2. Lichen planus 3. Central centrifugal cicatricial alopecia 4. Folliculitis decalvans 5. Linear scleroderma (morphea)c B. Systemic diseases 1. Discoid lesions in the setting of systemic lupus erythematosusb 2. Sarcoidosis 3. Cutaneous metastases a Most patients with trichotillomania, pressure-induced alopecia, or early stages of traction alopecia. b While the majority of patients with discoid lesions have only cutaneous disease, these lesions do represent one of the 11 American College of Rheumatology criteria (1982) for systemic lupus erythematosus. c Can involve underlying muscles and osseous structures. Table 72-5 Nonscarr ing Alopecia (Primary Cuta neous Disorders) Clinical Characteristics Pathogenesis Treatment Telogen effluvium Diffuse shedding of normal hairs Follows major stress (high fever, severe infection) or change in hormone levels (postpartum) Reversible without treatment Stress causes more of the asynchronous growth cycles of individual hairs to become synchronous; therefore, larger numbers of growing (anagen) hairs simultaneously enter the dying (telogen) phase Observation; discontinue any drugs that have alopecia as a side effect; must exclude underlying metabolic causes, e.g., hypothyroidism, hyperthyroidism Androgenetic alopecia (male pattern; female pattern) Miniaturization of hairs along the midline of the scalp Recession of the anterior scalp line in men and some women Increased sensitivity of affected hairs to the effects of androgens Increased levels of circulating androgens (ovarian or adrenal source in women) If no evidence of hyperandrogenemia, then topical minoxidil; finasteridea; spironolactone (women); hair transplant Alopecia areata Well-circumscribed, circular areas of hair loss, 2–5 cm in diameter In extensive cases, coalescence of lesions and/or involvement of other hair-bearing surfaces of the body Pitting or sandpapered appearance of the nails The germinative zones of the hair follicles are surrounded by T lymphocytes Occasional associated diseases: hyperthyroidism, hypothyroidism, vitiligo, Down syndrome Topical anthralin or tazarotene; intralesional glucocorticoids; topical contact sensitizers Tinea capitis Varies from scaling with minimal hair loss to discrete patches with “black dots” (broken infected hairs) to boggy plaque with pustules (kerion)b Invasion of hairs by dermatophytes, most commonly Trichophyton tonsurans Oral griseofulvin or terbinafine plus 2.5% selenium sulfide or ketoconazole shampoo; examine family members Traumatic alopeciac Broken hairs, often of varying lengths Irregular outline Traction with curlers, rubber bands, braiding Exposure to heat or chemicals (e.g., hair straighteners) Mechanical pulling (trichotillomania) Discontinuation of offending hair style or chemical treatments; diagnosis of trichotillomania may require observation of shaved hairs (for growth) or biopsy, possibly followed by psychotherapy aTo date, Food and Drug Administration–approved for men. bScarring alopecia can occur at sites of kerions. cMay also be scarring, especially late-stage traction alopecia. 356 PART 2 Cardinal Manifestations and Presentation of Diseases Table 72-6 Causes of Figurate Skin Lesions I. Primary cutaneous disorders A. Tinea B. Urticaria (primary in ≥90% of patients) C. Granuloma annulare D. Erythema annulare centrifugum E. Psoriasis II. Systemic diseases A. Migratory 1. Erythema migrans (CDC case definition is ≥5 cm in diameter) 2. Urticaria (≤10% of patients) 3. Erythema gyratum repens 4. Erythema marginatum 5. Pustular psoriasis (generalized) 6. Necrolytic migratory erythema (glucagonoma syndrome)a B. Nonmigratory 1. Sarcoidosis 2. Subacute cutaneous lupus erythematosus 3. Secondary syphilis 4. Cutaneous T cell lymphoma (especially mycosis fungoides) aMigratory erythema with erosions; favors lower extremities and girdle area. Abbreviation: CDC, Centers for Disease Control and Prevention. Table 72-7 Causes of Acneiform Eruptions I. Primary cutaneous disorders A. Acne vulgaris B. Acne rosacea II. Drugs, e.g., anabolic steroids, glucocorticoids, lithium, EGFRa inhibitors, iodides III. Systemic diseases A. Increased androgen production 1. Adrenal origin, e.g., Cushing’s disease, 21-hydroxylase deficiency 2. Ovarian origin, e.g., polycystic ovary syndrome, ovarian hyperthecosis B. Cryptococcosis, disseminated C. Dimorphic fungal infections D. Behçet’s disease aEGFR, epidermal growth factor receptor. underlying malignancy is mandatory in a patient with this eruption. Erythema migrans is the cutaneous manifestation of Lyme disease, which is caused by the spirochete Borrelia burgdorferi. In the initial stage (3–30 days after tick bite), a single annular lesion is usually seen, which can expand to ≥10 cm in diameter. Within several days, up to half of the patients develop multiple smaller erythematous lesions at sites distant from the bite. Associated symptoms include fever, headache, photophobia, myalgias, arthralgias, and malar rash. Erythema marginatum is seen in patients with rheumatic fever, primarily on the trunk. Lesions are pink-red in color, flat to minimally elevated, and transient. There are additional cutaneous diseases that present as annular eruptions but lack an obvious migratory component. Examples include CTCL, subacute cutaneous lupus, secondary syphilis, and sarcoidosis (see “Papulonodular Skin Lesions,” below). ACNE (Table 72-7) In addition to acne vulgaris and acne rosacea, the two major forms of acne (Chap. 71), there are drugs and systemic diseases that can lead to acneiform eruptions. Patients with the carcinoid syndrome have episodes of flushing of the head, neck, and sometimes the trunk. Resultant skin changes of the face, in particular telangiectasias, may mimic the clinical appearance of acne rosacea. PUSTULAR LESIONS Acneiform eruptions (see “Acne,” above) and folliculitis represent the most common pustular dermatoses. An important consideration in the evaluation of follicular pustules is a determination of the associated pathogen, e.g., normal flora, Staphylococcus aureus, Pseudomonas aeruginosa (“hot tub” folliculitis), Malassezia, dermatophytes (Majocchi’s granuloma), and Demodex spp. Noninfectious forms of folliculitis include HIV- or immunosuppression-associated eosinophilic folliculitis and folliculitis secondary to drugs such as glucocorticoids, lithium, and epidermal growth factor receptor (EGFR) inhibitors. Administration of high-dose systemic glucocorticoids can result in a widespread eruption of follicular pustules on the trunk, characterized by lesions in the same stage of development. With regard to underlying systemic diseases, nonfollicular-based pustules are a characteristic component of pustular psoriasis (sterile) and can be seen in septic emboli of bacterial or fungal origin (see “Purpura,” below). In patients with acute generalized exanthematous pustulosis (AGEP) due primarily to medications (e.g., cephalosporins), there are large areas of erythema studded with multiple sterile pustules in addition to neutrophilia. TELANGIECTASIAS (Table 72-8) To distinguish the various types of telangiectasias, it is important to examine the shape and configuration of the dilated blood vessels. Linear telangiectasias are seen on the face of patients Table 72-8 Causes of Tela ngiectas ias I. Primary cutaneous disorders A. Linear/branching 1. Acne rosacea 2. Actinically damaged skin 3. Venous hypertension 4. Generalized essential telangiectasia 5. Cutaneous collagenous vasculopathy 6. Within basal cell carcinomas or cutaneous lymphoma B. Poikiloderma 1. Ionizing radiationa 2. Parapsoriasis, large plaque C. Spider angioma 1. Idiopathic 2. Pregnancy II. Systemic diseases A. Linear/branching 1. Carcinoid 2. Ataxia-telangiectasia 3. Mastocytosis B. Poikiloderma 1. Dermatomyositis 2. Mycosis fungoides 3. Xeroderma pigmentosum C. Mat 1. Systemic sclerosis (scleroderma) D. Periungual/cuticular 1. Lupus erythematosus 2. Systemic sclerosis (scleroderma) 3. Dermatomyositis 4. Hereditary hemorrhagic telangiectasia E. Papular 1. Hereditary hemorrhagic telangiectasia F. Spider angioma 1. Cirrhosis aBecoming less common. 357 CHAPTER 72 Skin Manifestations of Internal Disease with actinically damaged skin and acne rosacea, and they are found on the legs of patients with venous hypertension and generalized essential telangiectasia. Patients with an unusual form of mastocytosis (telangiectasia macularis eruptiva perstans) and the carcinoid syndrome (see “Acne,” above) also have linear telangiectasias. Lastly, linear telangiectasias are found in areas of cutaneous inflammation. For example, lesions of discoid lupus frequently have telangiectasias within them. Poikiloderma is a term used to describe a patch of skin with: (1) reticulated hypo- and hyperpigmentation, (2) wrinkling secondary to epidermal atrophy, and (3) telangiectasias. Poikiloderma does not imply a single disease entity—although it is becoming less common, it is seen in skin damaged by ionizing radiation as well as in patients with autoimmune connective tissue diseases, primarily dermatomyositis (DM), and rare genodermatoses (e.g., Kindler syndrome). In systemic sclerosis (scleroderma) the dilated blood vessels have a unique configuration and are known as mat telangiectasias. The lesions are broad macules that usually measure 2–7 mm in diameter but occasionally are larger. Mats have a polygonal or oval shape, and their erythematous color may appear uniform, but, upon closer inspection, the erythema is the result of delicate telangiectasias. The most common locations for mat telangiectasias are the face, oral mucosa, and hands—peripheral sites that are prone to intermittent ischemia. The limited form of systemic sclerosis, often referred to as the CREST (calcinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) variant (Chap. 382), is associated with a chronic course and anticentromere antibodies. Mat telangiectasias are an important clue to the diagnosis of this variant as well as the diffuse form of systemic sclerosis because they may be the only cutaneous finding. Periungual telangiectasias are pathognomonic signs of the three major autoimmune connective tissue diseases: lupus erythematosus, systemic sclerosis, and DM. They are easily visualized by the naked eye and occur in at least two-thirds of these patients. In both DM and lupus, there is associated nailfold erythema, and in DM, the erythema is often accompanied by “ragged” cuticles and fingertip tenderness. Under 10× magnification, the blood vessels in the nailfolds of lupus patients are tortuous and resemble “glomeruli,” whereas in systemic sclerosis and DM, there is a loss of capillary loops and those that remain are markedly dilated. In hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease), the lesions usually appear during adolescence (mucosal) and adulthood (cutaneous) and are most commonly seen on the mucous membranes (nasal, orolabial), face, and distal extremities, including under the nails. They represent arteriovenous (AV) malformations of the dermal microvasculature, are dark red in color, and are usually slightly elevated. When the skin is stretched over an individual lesion, an eccentric punctum with radiating legs is seen. Although the degree of systemic involvement varies in this autosomal dominant disease (due primarily to mutations in either the endoglin or activin receptor– like kinase gene), the major symptoms are recurrent epistaxis and gastrointestinal bleeding. The fact that these mucosal telangiectasias are actually AV communications helps to explain their tendency to bleed. HYPOPIGMENTATION (Table 72-9) Disorders of hypopigmentation are often classified as either diffuse or localized. The classic example of diffuse hypopigmentation is oculocutaneous albinism (OCA). The most common forms are due to mutations in the tyrosinase gene (type I) or the P gene (type II); patients with type IA OCA have a total lack of enzyme activity. At birth, different forms of OCA can appear similar—white hair, grayblue eyes, and pink-white skin. However, the patients with no tyrosinase activity maintain this phenotype, whereas those with decreased activity will acquire some pigmentation of the eyes, hair, and skin as they age. The degree of pigment formation is also a function of racial background, and the pigmentary dilution is more readily apparent when patients are compared to their first-degree relatives. The ocular findings in OCA correlate with the degree of hypopigmentation and include decreased visual acuity, nystagmus, photophobia, strabismus, and a lack of normal binocular vision. The differential diagnosis of localized hypomelanosis includes the following primary cutaneous disorders: idiopathic guttate hypomelanosis, postinflammatory hypopigmentation, tinea (pityriasis) versicolor, vitiligo, chemical- or drug-induced leukoderma, nevus depigmentosus (see below), and piebaldism (Table 72-10). In this group of diseases, the areas of involvement are macules or patches with a decrease or absence of pigmentation. Patients with vitiligo also have an increased incidence of several autoimmune disorders, including Hashimoto’s thyroiditis, Graves’ disease, pernicious anemia, Addison’s disease, uveitis, alopecia areata, chronic mucocutaneous candidiasis, and the autoimmune polyendocrine syndromes (types I and II). Diseases of the thyroid gland are the most frequently associated disorders, occurring in up to 30% of patients with vitiligo. Circulating autoantibodies are often found, and the most common ones are antithyroglobulin, antimicrosomal, and antithyroid-stimulating hormone receptor antibodies. There are four systemic diseases that should be considered in a patient with skin findings suggestive of vitiligo—Vogt-Koyanagi- Harada syndrome, systemic sclerosis, onchocerciasis, and melanomaassociated leukoderma. A history of aseptic meningitis, nontraumatic uveitis, tinnitus, hearing loss, and/or dysacousia points to the diagnosis of the Vogt-Koyanagi-Harada syndrome. In these patients, the face and scalp are the most common locations of pigment loss. The Table 72-9 Causes of Hypopigmentat ion I. Primary cutaneous disorders A. Diffuse 1. Generalized vitiligoa B. Localized 1. Idiopathic guttate hypomelanosis 2. Postinflammatory 3. Tinea (pityriasis) versicolor 4. Vitiligoa 5. Chemical- or drug-induced leukoderma 6. Nevus depigmentosus 7. Piebaldisma II. Systemic diseases A. Diffuse 1. Oculocutaneous albinismb 2. Hermansky-Pudlak syndromeb,c 3. Chédiak-Higashi syndromeb,d 4. Phenylketonuria B. Localized 1. Systemic sclerosis (scleroderma) 2. Melanoma-associated leukoderma, spontaneous or immunotherapy- induced 3. Vogt-Koyanagi-Harada syndrome 4. Onchocerciasis 5. Sarcoidosis 6. Cutaneous T cell lymphoma (especially mycosis fungoides) 7. Tuberculoid and indeterminate leprosy 8. Linear nevoid hypopigmentation (hypomelanosis of Ito)e 9. Incontinentia pigmenti (stage IV) 10. Tuberous sclerosis 11. Waardenburg syndrome and Shah-Waardenburg syndrome aAbsence of melanocytes in areas of leukoderma. bNormal number of melanocytes. cPlatelet storage defect and restrictive lung disease secondary to deposits of ceroid-like material or immunodeficiency; due to mutations in β subunit of adaptor protein 3 as well as subunits of biogenesis of lysosome-related organelles complex (BLOC)-1, -2, and -3. dGiant lysosomal granules and recurrent infections. eMinority of patients in a nonreferral setting have systemic abnormalities (musculoskeletal, central nervous system, ocular). 358 PART 2 Cardinal Manifestations and Presentation of Diseases Table 72-10 Hypopigmentat ion (Primary Cuta neous Disorders, Local ized) Clinical Characteristics Wood’s Lamp Examination (UV-A; Peak = 365 nm) Skin Biopsy Specimen Pathogenesis Treatment Idiopathic guttate hypomelanosis Common; acquired; 1–4 mm in diameter Shins and extensor forearms Less enhancement than vitiligo Abrupt decrease in epidermal melanin content Possible somatic mutations as a reflection of aging or UV exposure None Postinflammatory hypopigmentation Can develop within active lesions, as in subacute cutaneous lupus, or after the lesion fades, as in atopic dermatitis Depends on particular disease Usually less enhancement than in vitiligo Type of inflammatory infiltrate depends on specific disease Block in transfer of melanin from melanocytes to keratinocytes could be secondary to edema or decrease in contact time Destruction of melanocytes if inflammatory cells attack basal layer of epidermis Treat underlying inflammatory disease Pityriasis (tinea) versicolor Common disorder Upper trunk and neck (shawl-like distribution), groin Young adults Macules have fine white scale when scratched Golden fluorescence Hyphal forms and budding yeast in stratum corneum Invasion of stratum corneum by the yeast Malassezia Yeast is lipophilic and produces C9 and C11 dicarboxylic acids, which in vitro inhibit tyrosinase Selenium sulfide 2.5%; topical imidazoles; oral triazoles Vitiligo Acquired; progressive Symmetric areas of complete pigment loss Periorificial—around mouth, nose, eyes, nipples, umbilicus, anus Other areas—flexor wrists, extensor distal extremities Segmental form is less common—unilateral, dermatomal-like More apparent Chalk-white Absence of melanocytes Mild inflammation Autoimmune phenomenon that results in destruction of melanocytes— primarily cellular (circulating skin-homing autoreactive T cells) Topical glucocorticoids; topical calcineurin inhibitors; NBUV-B; PUVA; transplants, if stable; depigmentation (topical MBEH), if widespread Chemical- or druginduced leukoderma Similar appearance to vitiligo Often begins on hands when associated with chemical exposure Satellite lesions in areas not exposed to chemicals More apparent Chalk-white Decreased number or absence of melanocytes Exposure to chemicals that selectively destroy melanocytes, in particular phenols and catechols (germicides; adhesives) or ingestion of drugs such as imatinib Release of cellular antigens and activation of circulating lymphocytes may explain satellite phenomenon Possible inhibition of KIT receptor Avoid exposure to offending agent, then treat as vitiligo Drug-induced variant may undergo repigmentation when medication is discontinued Piebaldism Autosomal dominant Congenital, stable White forelock Areas of amelanosis contain normally pigmented and hyperpigmented macules of various sizes Symmetric involvement of central forehead, ventral trunk, and mid regions of upper and lower extremities Enhancement of leukoderma and hyperpigmented macules Amelanotic areas—few to no melanocytes Defect in migration of melanoblasts from neural crest to involved skin or failure of melanoblasts to survive or differentiate in these areas Mutations within the c-kit protooncogene that encodes the tyrosine kinase receptor for stem cell growth factor (kit ligand) None; occasionally transplants Abbreviations: MBEH, monobenzylether of hydroquinone; NBUV-B, narrow band ultraviolet B; PUVA, psoralens + ultraviolet A irradiation. 359 CHAPTER 72 Skin Manifestations of Internal Disease vitiligo-like leukoderma seen in patients with systemic sclerosis has a clinical resemblance to idiopathic vitiligo that has begun to repigment as a result of treatment; that is, perifollicular macules of normal pigmentation are seen within areas of depigmentation. The basis of this leukoderma is unknown; there is no evidence of inflammation in areas of involvement, but it can resolve if the underlying connective tissue disease becomes inactive. In contrast to idiopathic vitiligo, melanomaassociated leukoderma often begins on the trunk, and its appearance, if spontaneous, should prompt a search for metastatic disease. It is also seen in patients undergoing immunotherapy for melanoma, including ipilimumab, with cytotoxic T lymphocytes presumably recognizing cell surface antigens common to melanoma cells and melanocytes, and is associated with a greater likelihood of a clinical response. There are two systemic disorders (neurocristopathies) that may have the cutaneous findings of piebaldism (Table 72-9). They are Shah-Waardenburg syndrome and Waardenburg syndrome. A possible explanation for both disorders is an abnormal embryonic migration or survival of two neural crest–derived elements, one of them being melanocytes and the other myenteric ganglion cells (leading to Hirschsprung disease in Shah-Waardenburg syndrome) or auditory nerve cells (Waardenburg syndrome). The latter syndrome is characterized by congenital sensorineural hearing loss, dystopia canthorum (lateral displacement of the inner canthi but normal interpupillary distance), heterochromic irises, and a broad nasal root, in addition to the piebaldism. The facial dysmorphism can be explained by the neural crest origin of the connective tissues of the head and neck. Patients with Waardenburg syndrome have been shown to have mutations in four genes, including PAX-3 and MITF, all of which encode DNAbinding proteins, whereas patients with Hirschsprung disease plus white spotting have mutations in one of three genes—endothelin 3, endothelin B receptor, and SOX-10. In tuberous sclerosis, the earliest cutaneous sign is macular hypomelanosis, referred to as an ash leaf spot. These lesions are often present at birth and are usually multiple; however, detection may require Wood’s lamp examination, especially in fair-skinned individuals. The pigment within them is reduced, but not absent. The average size is 1–3 cm, and the common shapes are polygonal and lance-ovate. Examination of the patient for additional cutaneous signs such as multiple angiofibromas of the face (adenoma sebaceum), ungual and gingival fibromas, fibrous plaques of the forehead, and connective tissue nevi (shagreen patches) is recommended. It is important to remember that an ash leaf spot on the scalp will result in a circumscribed patch of lightly pigmented hair. Internal manifestations include seizures, mental retardation, central nervous system (CNS) and retinal hamartomas, pulmonary lymphangioleiomyomatosis (women), renal angiomyolipomas, and cardiac rhabdomyomas. The latter can be detected in up to 60% of children

PART 2 Cardinal Manifestations and Presentation of Diseases Staphylococcal scalded-skin syndrome (SSSS) and bullous impetigo are two blistering disorders associated with staphylococcal (phage group II) infection. In SSSS, the initial findings are redness and tenderness of the central face, neck, trunk, and intertriginous zones. This is followed by short-lived flaccid bullae and a slough or exfoliation of the superficial epidermis. Crusted areas then develop, characteristically around the mouth in a radial pattern. SSSS is distinguished from TEN by the following features: younger age group (primarily infants), more superficial site of blister formation, no oral lesions, shorter course, lower morbidity and mortality rates, and an association with staphylococcal exfoliative toxin (“exfoliatin”), not drugs. A rapid diagnosis of SSSS versus TEN can be made by a frozen section of the blister roof or exfoliative cytology of the blister contents. In SSSS, the site of staphylococcal infection is usually extracutaneous (conjunctivitis, rhinorrhea, otitis media, pharyngitis, tonsillitis), and the cutaneous lesions are sterile, whereas in bullous impetigo, the skin lesions are the site of infection. Impetigo is more localized than SSSS and usually presents with honey-colored crusts. Occasionally, superficial purulent blisters also form. Cutaneous emboli from gram-negative infections may present as isolated bullae, but the base of the lesion is purpuric or necrotic, and it may develop into an ulcer (see “Purpura,” below). Several metabolic disorders are associated with blister formation, including diabetes mellitus, renal failure, and porphyria. Local hypoxemia secondary to decreased cutaneous blood flow can also produce blisters, which explains the presence of bullae over pressure points in comatose patients (coma bullae). In diabetes mellitus, tense bullae with clear sterile viscous fluid arise on normal skin. The lesions can be as large as 6 cm in diameter and are located on the distal extremities. There are several types of porphyria, but the most common form with cutaneous findings is porphyria cutanea tarda (PCT). In sunexposed areas (primarily the face and hands), the skin is very fragile, with trauma leading to erosions mixed with tense vesicles. These lesions then heal with scarring and formation of milia; the latter are firm, 1- to 2-mm white or yellow papules that represent epidermoid inclusion cysts. Associated findings can include hypertrichosis of the lateral malar region (men) or face (women) and, in sun-exposed areas, hyperpigmentation and firm sclerotic plaques. An elevated level of urinary uroporphyrins confirms the diagnosis and is due to a decrease in uroporphyrinogen decarboxylase activity. PCT can be exacerbated by alcohol, hemochromatosis and other forms of iron overload, chlorinated hydrocarbons, hepatitis C and HIV infections, and hepatomas. The differential diagnosis of PCT includes (1) porphyria variegata— the skin signs of PCT plus the systemic findings of acute intermittent porphyria; it has a diagnostic plasma porphyrin fluorescence emission at 626 nm; (2) drug-induced pseudoporphyria—the clinical and histologic findings are similar to PCT, but porphyrins are normal; etiologic agents include naproxen and other NSAIDs, furosemide, tetracycline, and voriconazole; (3) bullous dermatosis of hemodialysis—the same appearance as PCT, but porphyrins are usually normal or occasionally borderline elevated; patients have chronic renal failure and are on hemodialysis; (4) PCT associated with hepatomas and hemodialysis; and (5) epidermolysis bullosa acquisita (Chap. 73). EXANTHEMS (Table 72-13) Exanthems are characterized by an acute generalized eruption. The most common presentation is erythematous macules and papules (morbilliform) and less often confluent blanching erythema (scarlatiniform). Morbilliform eruptions are usually due to either drugs or viral infections. For example, up to 5% of patients receiving penicillins, sulfonamides, phenytoin, or nevirapine will develop a maculopapular eruption. Accompanying signs may include pruritus, fever, eosinophilia, and transient lymphadenopathy. Similar maculopapular eruptions are seen in the classic childhood viral exanthems, including (1) rubeola (measles)—a prodrome of coryza, cough, and conjunctivitis followed by Koplik’s spots on the buccal mucosa; the eruption begins behind the ears, at the hairline, and on the forehead and then spreads down the body, often becoming confluent; (2) rubella—the eruption begins on the forehead and face and then spreads down the body; it resolves in the same order and is associated with retroauricular and suboccipital lymphadenopathy; and (3) erythema infectiosum (fifth disease)—erythema of the cheeks is followed by a reticulated pattern on the extremities; it is secondary to a parvovirus B19 infection, and an associated arthritis is seen in adults. Both measles and rubella can occur in unvaccinated adults, and an atypical form of measles is seen in adults immunized with either killed measles vaccine or killed vaccine followed in time by live vaccine. In contrast to classic measles, the eruption of atypical measles begins on the palms, soles, wrists, and ankles, and the lesions may become purpuric. The patient with atypical measles can have pulmonary involvement and be quite ill. Rubelliform and roseoliform eruptions are also associated with Epstein-Barr virus (5–15% of patients), echovirus, coxsackievirus, cytomegalovirus, adenovirus, dengue virus, and West Nile virus infections. Detection of specific IgM antibodies or fourfold elevations in IgG antibodies allow the proper diagnosis, but polymerase chain reaction (PCR) is gradually replacing serologic assays. Occasionally, a maculopapular drug eruption is a reflection of an underlying viral infection. For example, ~95% of the patients with infectious mononucleosis who are given ampicillin will develop a rash. Of note, early in the course of infections with Rickettsia and meningococcus, prior to the development of petechiae and purpura, the lesions may be erythematous macules and papules. This is also the case in chickenpox prior to the development of vesicles. Maculopapular eruptions are associated with early HIV infection, early secondary syphilis, typhoid fever, and acute graft-versus-host disease. In the last, lesions frequently begin on the dorsal hands and forearms; the macular rose spots of typhoid fever involve primarily the anterior trunk. The prototypic scarlatiniform eruption is seen in scarlet fever and is due to an erythrogenic toxin produced by bacteriophage-containing group A β-hemolytic streptococci, most commonly in the setting of pharyngitis. This eruption is characterized by diffuse erythema, which begins on the neck and upper trunk, and red follicular puncta. Additional findings include a white strawberry tongue (white coating with red papillae) followed by a red strawberry tongue (red tongue Table 72-13 Causes of Exanthems I. Morbilliform A. Drugs B. Viral 1. Rubeola (measles) 2. Rubella 3. Erythema infectiosum (erythema of cheeks; reticulated on extremities) 4. Epstein-Barr virus, echovirus, coxsackievirus, CMV, adenovirus, HHV-6/ HHV-7a, dengue virus, and West Nile virus infections 5. HIV seroconversion exanthem (plus mucosal ulcerations) C. Bacterial 1. Typhoid fever 2. Early secondary syphilis 3. Early Rickettsia infections 4. Early meningococcemia 5. Ehrlichiosis D. Acute graft-versus-host disease E. Kawasaki disease II. Scarlatiniform A. Scarlet fever B. Toxic shock syndrome C. Kawasaki disease D. Early staphylococcal scalded-skin syndrome aPrimary infection in infants and reactivation in the setting of immunosuppression. Abbreviations: CMV, cytomegalovirus; HHV, human herpesvirus; HIV, human immunodeficiency virus. 363 CHAPTER 72 Skin Manifestations of Internal Disease with red papillae); petechiae of the palate; a facial flush with circumoral pallor; linear petechiae in the antecubital fossae; and desquamation of the involved skin, palms, and soles 5–20 days after onset of the eruption. A similar desquamation of the palms and soles is seen in toxic shock syndrome (TSS), in Kawasaki disease, and after severe febrile illnesses. Certain strains of staphylococci also produce an erythrotoxin that leads to the same clinical findings as in streptococcal scarlet fever, except that the anti-streptolysin O or -DNase B titers are not elevated. In toxic shock syndrome, staphylococcal (phage group I) infections produce an exotoxin (TSST-1) that causes the fever and rash as well as enterotoxins. Initially, the majority of cases were reported in menstruating women who were using tampons. However, other sites of infection, including wounds and nasal packing, can lead to TSS. The diagnosis of TSS is based on clinical criteria (Chap. 172), and three of these involve mucocutaneous sites (diffuse erythema of the skin, desquamation of the palms and soles 1–2 weeks after onset of illness, and involvement of the mucous membranes). The latter is characterized as hyperemia of the vagina, oropharynx, or conjunctivae. Similar systemic findings have been described in streptococcal toxic shock syndrome (Chap. 173), and although an exanthem is seen less often than in TSS due to a staphylococcal infection, the underlying infection is often in the soft tissue (e.g., cellulitis). The cutaneous eruption in Kawasaki disease (Chap. 385) is polymorphous, but the two most common forms are morbilliform and scarlatiniform. Additional mucocutaneous findings include bilateral conjunctival injection; erythema and edema of the hands and feet followed by desquamation; and diffuse erythema of the oropharynx, red strawberry tongue, and dry fissured lips. This clinical picture can resemble TSS and scarlet fever, but clues to the diagnosis of Kawasaki disease are cervical lymphadenopathy, cheilitis, and thrombocytosis. The most serious associated systemic finding in this disease is coronary aneurysms secondary to arteritis. Scarlatiniform eruptions are also seen in the early phase of SSSS (see “Vesicles/Bullae,” above), in young adults with Arcanobacterium haemolyticum infection, and as reactions to drugs. URTICARIA (Table 72-14) Urticaria (hives) are transient lesions that are composed of a central wheal surrounded by an erythematous halo or flare. Individual lesions are round, oval, or figurate and are often pruritic. Acute and chronic urticaria have a wide variety of allergic etiologies and reflect edema in the dermis. Urticarial lesions can also be seen in patients with mastocytosis (urticaria pigmentosa), hypo- or hyperthyroidism, and systemic-onset juvenile idiopathic arthritis (Still’s disease). In both juvenile- and adult-onset Still’s disease, the lesions coincide with the fever spike, are transient, and are due to dermal infiltrates of neutrophils. The common physical urticarias include dermatographism, solar urticaria, cold urticaria, and cholinergic urticaria. Patients with dermatographism exhibit linear wheals following minor pressure or scratching of the skin. It is a common disorder, affecting ~5% of the population. Solar urticaria characteristically occurs within minutes of sun exposure and is a skin sign of one systemic disease—erythropoietic protoporphyria. In addition to the urticaria, these patients have subtle pitted scarring of the nose and hands. Cold urticaria is precipitated by exposure to the cold, and therefore exposed areas are usually affected. In occasional patients, the disease is associated with abnormal circulating proteins—more commonly cryoglobulins and less commonly cryofibrinogens. Additional systemic symptoms include wheezing and syncope, thus explaining the need for these patients to avoid swimming in cold water. Autosomal dominantly inherited cold urticaria is associated with dysfunction of cryopyrin. Cholinergic urticaria is precipitated by heat, exercise, or emotion and is characterized by small wheals with relatively large flares. It is occasionally associated with wheezing. Whereas urticarias are the result of dermal edema, subcutaneous edema leads to the clinical picture of angioedema. Sites of involvement include the eyelids, lips, tongue, larynx, and gastrointestinal tract as well as the subcutaneous tissue. Angioedema occurs alone or in combination with urticaria, including urticarial vasculitis and the physical urticarias. Both acquired and hereditary (autosomal dominant) forms of angioedema occur (Chap. 376), and in the latter, urticaria is rarely, if ever, seen. Urticarial vasculitis is an immune complex disease that may be confused with simple urticaria. In contrast to simple urticaria, individual lesions tend to last longer than 24 h and usually develop central petechiae that can be observed even after the urticarial phase has resolved. The patient may also complain of burning rather than pruritus. On biopsy, there is a leukocytoclastic vasculitis of the small dermal blood vessels. Although many cases of urticarial vasculitis are idiopathic in origin, it can be a reflection of an underlying systemic illness such as lupus erythematosus, Sjögren’s syndrome, or hereditary complement deficiency. There is a spectrum of urticarial vasculitis that ranges from purely cutaneous to multisystem involvement. The most common systemic signs and symptoms are arthralgias and/or arthritis, nephritis, and crampy abdominal pain, with asthma and chronic obstructive lung disease seen less often. Hypocomplementemia occurs in one- to two-thirds of patients, even in the idiopathic cases. Urticarial vasculitis can also be seen in patients with hepatitis B and hepatitis C infections, serum sickness, and serum sickness–like illnesses (e.g., due to cefaclor, minocycline). PAPULONODULAR SKIN LESIONS (Table 72-15) In the papulonodular diseases, the lesions are elevated above the surface of the skin and may coalesce to form larger plaques. The location, consistency, and color of the lesions are the keys to their diagnosis; this section is organized on the basis of color. WHITE LESIONS In calcinosis cutis, there are firm white to white-yellow papules with an irregular surface. When the contents are expressed, a chalky white material is seen. Dystrophic calcification is seen at sites of previous inflammation or damage to the skin. It develops in acne scars as well as on the distal extremities of patients with systemic sclerosis and in the subcutaneous tissue and intermuscular fascial planes in DM. The latter is more extensive and is more commonly seen in children. An elevated calcium phosphate product, most commonly due to secondary hyperparathyroidism in the setting of renal failure, can lead to nodules of metastatic calcinosis cutis, which tend to be subcutaneous and periarticular. These patients can also develop calcification of muscular arteries and subsequent ischemic necrosis (calciphylaxis). Osteoma cutis, in the form of small papules, most commonly occurs on the face Table 72-14 Causes of Urt icar ia and Angioedema I. Primary cutaneous disorders A. Acute and chronic urticariaa B. Physical urticaria 1. Dermatographism 2. Solar urticariab 3. Cold urticariab 4. Cholinergic urticariab C. Angioedema (hereditary and acquired)b,c II. Systemic diseases A. Urticarial vasculitis B. Hepatitis B or C infection C. Serum sickness D. Angioedema (hereditary and acquired) aA small minority develop anaphylaxis. bAlso systemic. cAcquired angioedema can be idiopathic, associated with a lymphoproliferative disorder, or due to a drug, e.g., angiotensin-converting enzyme (ACE) inhibitors. 364 PART 2 Cardinal Manifestations and Presentation of Diseases of individuals with a history of acne vulgaris, whereas plate-like lesions occur in rare genetic syndromes (Chap. 82). SKIN-COLORED LESIONS There are several types of skin-colored lesions, including epidermoid inclusion cysts, lipomas, rheumatoid nodules, neurofibromas, angiofibromas, neuromas, and adnexal tumors such as tricholemmomas. Both epidermoid inclusion cysts and lipomas are very common mobile subcutaneous nodules—the former are rubbery and drain cheeselike material (sebum and keratin) if incised. Lipomas are firm and somewhat lobulated on palpation. When extensive facial epidermoid inclusion cysts develop during childhood or there is a family history of such lesions, the patient should be examined for other signs of Gardner syndrome, including osteomas and desmoid tumors. Rheumatoid nodules are firm 0.5- to 4-cm nodules that favor the extensor aspect of joints, especially the elbows. They are seen in ~20% of patients with rheumatoid arthritis and 6% of patients with Still’s disease. Biopsies of the nodules show palisading granulomas. Similar lesions that are smaller and shorter-lived are seen in rheumatic fever. Neurofibromas (benign Schwann cell tumors) are soft papules or nodules that exhibit the “button-hole” sign; that is, they invaginate into the skin with pressure in a manner similar to a hernia. Single lesions are seen in normal individuals, but multiple neurofibromas, usually in combination with six or more CALMs measuring >1.5 cm (see “Hyperpigmentation,” above), axillary freckling, and multiple Lisch nodules, are seen in von Recklinghausen’s disease (NF type I) (Chap. 118). In some patients, the neurofibromas are localized and unilateral due to somatic mosaicism. Angiofibromas are firm pink to skin-colored papules that measure from 3 mm to a few centimeters in diameter. When multiple lesions are located on the central cheeks (adenoma sebaceum), the patient has tuberous sclerosis or multiple endocrine neoplasia (MEN) syndrome, type 1. The former is an autosomal disorder due to mutations in two different genes, and the associated findings are discussed in the section on ash leaf spots as well as in Chap. 118. Neuromas (benign proliferations of nerve fibers) are also firm, skincolored papules. They are more commonly found at sites of amputation and as rudimentary supernumerary digits. However, when there are multiple neuromas on the eyelids, lips, distal tongue, and/or oral mucosa, the patient should be investigated for other signs of the MEN syndrome, type 2b. Associated findings include marfanoid habitus, protuberant lips, intestinal ganglioneuromas, and medullary thyroid carcinoma (>75% of patients; Chap. 408). Adnexal tumors are derived from pluripotent cells of the epidermis that can differentiate toward hair, sebaceous, apocrine, or eccrine glands or remain undifferentiated. Basal cell carcinomas (BCCs) are examples of adnexal tumors that have little or no evidence of differentiation. Clinically, they are translucent papules with rolled borders, telangiectasias, and central erosion. BCCs commonly arise in sundamaged skin of the head and neck as well as the upper trunk. When a Table 72-15 Papulonodular Skin Lesions Acc ording to Color Groups I. White A. Calcinosis cutis B. Osteoma cutis (also skin-colored or blue) II. Skin-colored A. Rheumatoid nodules B. Neurofibromas (von Recklinghausen's disease) C. Angiofibromas (tuberous sclerosis, MEN syndrome, type 1) D. Neuromas (MEN syndrome, type 2b) E. Adnexal tumors 1. Basal cell carcinomas (nevoid basal cell carcinoma syndrome) 2. Tricholemmomas (Cowden disease) F. Osteomas (arise in skull and jaw in Gardner syndrome) G. Primary cutaneous disorders 1. Epidermal inclusion cystsa 2. Lipomas III. Pink/translucentb A. Amyloidosis, primary systemic B. Papular mucinosis/scleromyxedema C. Multicentric reticulohistiocytosis IV. Yellow A. Xanthomas B. Tophi C. Necrobiosis lipoidica D. Pseudoxanthoma elasticum E. Sebaceous adenomas (Muir-Torre syndrome) V. Redb A. Papules 1. Angiokeratomas (Fabry disease) 2. Bacillary angiomatosis (primarily in AIDS) B. Papules/plaques 1. Cutaneous lupus 2. Lymphoma cutis 3. Leukemia cutis 4. Sweet syndrome C. Nodules 1. Panniculitis 2. Medium-sized vessel vasculitis (e.g., cutaneous polyarteritis nodosa) D. Primary cutaneous disorders 1. Arthropod bites 2. Cherry hemangiomas 3. Infections, e.g., streptococcal cellulitis, sporotrichosis 4. Polymorphous light eruption 5. Lymphocytoma cutis (pseudolymphoma) VI. Red-brownb A. Sarcoidosis B. Urticaria pigmentosa C. Erythema elevatum diutinum (chronic leukocytoclastic vasculitis) D. Lupus vulgaris VII. Blueb A. Venous malformations (e.g., blue rubber bleb syndrome) B. Primary cutaneous disorders 1. Venous lake 2. Blue nevus VIII. Violaceous A. Lupus pernio (sarcoidosis) B. Lymphoma cutis C. Cutaneous lupus IX. Purple A. Kaposi’s sarcoma B. Angiosarcoma C. Palpable purpura (see Table 72-16) X. Brown-blackc XI. Any color A. Metastases aIf multiple with childhood onset, consider Gardner syndrome. bMay have darker hue in more darkly pigmented individuals. cSee also “Hyperpigmentation.” Abbreviation: MEN, multiple endocrine neoplasia. 365 CHAPTER 72 Skin Manifestations of Internal Disease patient has multiple BCCs, especially prior to age 30, the possibility of the nevoid basal cell carcinoma syndrome should be raised. It is inherited as an autosomal dominant trait and is associated with jaw cysts, palmar and plantar pits, frontal bossing, medulloblastomas, and calcification of the falx cerebri and diaphragma sellae. Tricholemmomas are also skin-colored adnexal tumors but differentiate toward hair follicles and can have a wartlike appearance. The presence of multiple tricholemmomas on the face and cobblestoning of the oral mucosa points to the diagnosis of Cowden disease (multiple hamartoma syndrome) due to mutations in the phosphatase and tensin homolog (PTEN) gene. Internal organ involvement (in decreasing order of frequency) includes fibrocystic disease and carcinoma of the breast, adenomas and carcinomas of the thyroid, and gastrointestinal polyposis. Keratoses of the palms, soles, and dorsal aspect of the hands are also seen. PINK LESIONS The cutaneous lesions associated with primary systemic amyloidosis are often pink in color and translucent. Common locations are the face, especially the periorbital and perioral regions, and flexural areas. On biopsy, homogeneous deposits of amyloid are seen in the dermis and in the walls of blood vessels; the latter lead to an increase in vessel wall fragility. As a result, petechiae and purpura develop in clinically normal skin as well as in lesional skin following minor trauma, hence the term pinch purpura. Amyloid deposits are also seen in the striated muscle of the tongue and result in macroglossia. Even though specific mucocutaneous lesions are present in only ~30% of the patients with primary systemic (AL) amyloidosis, the diagnosis can be made via histologic examination of abdominal subcutaneous fat, in conjunction with a serum free light chain assay. By special staining, amyloid deposits are seen around blood vessels or individual fat cells in 40–50% of patients. There are also three forms of amyloidosis that are limited to the skin and that should not be construed as cutaneous lesions of systemic amyloidosis. They are macular amyloidosis (upper back), lichen amyloidosis (usually lower extremities), and nodular amyloidosis. In macular and lichen amyloidosis, the deposits are composed of altered epidermal keratin. Early-onset macular and lichen amyloidosis have been associated with MEN syndrome, type 2a. Patients with multicentric reticulohistiocytosis also have pinkcolored papules and nodules on the face and mucous membranes as well as on the extensor surface of the hands and forearms. They have a polyarthritis that can mimic rheumatoid arthritis clinically. On histologic examination, the papules have characteristic giant cells that are not seen in biopsies of rheumatoid nodules. Pink to skin-colored papules that are firm, 2–5 mm in diameter, and often in a linear arrangement are seen in patients with papular mucinosis. This disease is also referred to as generalized lichen myxedematosus or scleromyxedema. The latter name comes from the induration of the face and extremities that may accompany the papular eruption. Biopsy specimens of the papules show localized mucin deposition, and serum protein electrophoresis plus immunofixation electrophoresis demonstrates a monoclonal spike of IgG, usually with a λ light chain. YELLOW LESIONS Several systemic disorders are characterized by yellow-colored cutaneous papules or plaques—hyperlipidemia (xanthomas), gout (tophi), diabetes (necrobiosis lipoidica), pseudoxanthoma elasticum, and Muir- Torre syndrome (sebaceous tumors). Eruptive xanthomas are the most common form of xanthomas and are associated with hypertriglyceridemia (primarily hyperlipoproteinemia types I, IV, and V). Crops of yellow papules with erythematous halos occur primarily on the extensor surfaces of the extremities and the buttocks, and they spontaneously involute with a fall in serum triglycerides. Types II and III result in one or more of the following types of xanthoma: xanthelasma, tendon xanthomas, and plane xanthomas. Xanthelasma are found on the eyelids, whereas tendon xanthomas are frequently associated with the Achilles and extensor finger tendons; plane xanthomas are flat and favor the palmar creases, neck, upper trunk, and flexural folds. Tuberous xanthomas are frequently associated with hypertriglyceridemia, but they are also seen in patients with hypercholesterolemia and are found most frequently over the large joints or hand. Biopsy specimens of xanthomas show collections of lipid-containing macrophages (foam cells). Patients with several disorders, including biliary cirrhosis, can have a secondary form of hyperlipidemia with associated tuberous and plane xanthomas. However, patients with plasma cell dyscrasias have normolipemic plane xanthomas. This latter form of xanthoma may be ≥12 cm in diameter and is most frequently seen on the upper trunk or side of the neck. It is important to note that the most common setting for eruptive xanthomas is uncontrolled diabetes mellitus. The least specific sign for hyperlipidemia is xanthelasma, because at least 50% of the patients with this finding have normal lipid profiles. In tophaceous gout, there are deposits of monosodium urate in the skin around the joints, particularly those of the hands and feet. Additional sites of tophi formation include the helix of the ear and the olecranon and prepatellar bursae. The lesions are firm, yellow in color, and occasionally discharge a chalky material. Their size varies from 1 mm to 7 cm, and the diagnosis can be established by polarized light microscopy of the aspirated contents of a lesion. Lesions of necrobiosis lipoidica are found primarily on the shins (90%), and patients can have diabetes mellitus or develop it subsequently. Characteristic findings include a central yellow color, atrophy (transparency), telangiectasias, and a red to red-brown border. Ulcerations can also develop within the plaques. Biopsy specimens show necrobiosis of collagen and granulomatous inflammation. In pseudoxanthoma elasticum (PXE), due to mutations in the gene ABCC6, there is an abnormal deposition of calcium on the elastic fibers of the skin, eye, and blood vessels. In the skin, the flexural areas such as the neck, axillae, antecubital fossae, and inguinal area are the primary sites of involvement. Yellow papules coalesce to form reticulated plaques that have an appearance similar to that of plucked chicken skin. In severely affected skin, hanging, redundant folds develop. Biopsy specimens of involved skin show swollen and irregularly clumped elastic fibers with deposits of calcium. In the eye, the calcium deposits in Bruch’s membrane lead to angioid streaks and choroiditis; in the arteries of the heart, kidney, gastrointestinal tract, and extremities, the deposits lead to angina, hypertension, gastrointestinal bleeding, and claudication, respectively. Adnexal tumors that have differentiated toward sebaceous glands include sebaceous adenoma, sebaceous carcinoma, and sebaceous hyperplasia. Except for sebaceous hyperplasia, which is commonly seen on the face, these tumors are fairly rare. Patients with Muir-Torre syndrome have one or more sebaceous adenoma(s), and they can also have sebaceous carcinomas and sebaceous hyperplasia as well as keratoacanthomas. The internal manifestations of Muir-Torre syndrome include multiple carcinomas of the gastrointestinal tract (primarily colon) as well as cancers of the larynx, genitourinary tract, and breast. RED LESIONS Cutaneous lesions that are red in color have a wide variety of etiologies; in an attempt to simplify their identification, they will be subdivided into papules, papules/plaques, and subcutaneous nodules. Common red papules include arthropod bites and cherry hemangiomas; the latter are small, bright-red, dome-shaped papules that represent a benign proliferation of capillaries. In patients with AIDS (Chap. 226), the development of multiple red hemangioma-like lesions points to bacillary angiomatosis, and biopsy specimens show clusters of bacilli that stain positive with the Warthin-Starry stain; the pathogens have been identified as Bartonella henselae and Bartonella quintana. Disseminated visceral disease is seen primarily in immunocompromised hosts but can occur in immunocompetent individuals. Multiple angiokeratomas are seen in Fabry disease, an X-linked recessive lysosomal storage disease that is due to a deficiency of α-galactosidase A. The lesions are red to red-blue in color and can be quite small in size (1–3 mm), with the most common location being the lower trunk. Associated findings include chronic renal disease, peripheral neuropathy, and corneal opacities (cornea verticillata). Electron photomicrographs of angiokeratomas and clinically normal skin demonstrate lamellar lipid deposits in fibroblasts, pericytes, and endothelial 366 PART 2 Cardinal Manifestations and Presentation of Diseases cells that are diagnostic of this disease. Widespread acute eruptions of erythematous papules are discussed in the section on exanthems. There are several infectious diseases that present as erythematous papules or nodules in a lymphocutaneous or sporotrichoid pattern, i.e., in a linear arrangement along the lymphatic channels. The two most common etiologies are Sporothrix schenckii (sporotrichosis) and the atypical mycobacterium Mycobacterium marinum. The organisms are introduced as a result of trauma, and a primary inoculation site is often seen in addition to the lymphatic nodules. Additional causes include Nocardia, Leishmania, and other atypical mycobacteria and dimorphic fungi; culture of lesional tissue will aid in the diagnosis. The diseases that are characterized by erythematous plaques with scale are reviewed in the papulosquamous section, and the various forms of dermatitis are discussed in the section on erythroderma. Additional disorders in the differential diagnosis of red papules/ plaques include cellulitis, polymorphous light eruption (PMLE), cutaneous lymphoid hyperplasia (lymphocytoma cutis), cutaneous lupus, lymphoma cutis, and leukemia cutis. The first three diseases represent primary cutaneous disorders, although cellulitis may be accompanied by a bacteremia. PMLE is characterized by erythematous papules and plaques in a primarily sun-exposed distribution—dorsum of the hand, extensor forearm, and upper trunk. Lesions follow exposure to UV-B and/or UV-A, and in higher latitudes, PMLE is most severe in the late spring and early summer. A process referred to as “hardening” occurs with continued UV exposure, and the eruption fades, but in temperate climates, it will recur in the spring. PMLE must be differentiated from cutaneous lupus, and this is accomplished by observation of the natural history, histologic examination, and direct immunofluorescence of the lesions. Cutaneous lymphoid hyperplasia (pseudolymphoma) is a benign polyclonal proliferation of lymphocytes in the skin that presents as infiltrated pink-red to red-purple papules and plaques; it must be distinguished from lymphoma cutis. Several types of red plaques are seen in patients with systemic lupus, including (1) erythematous urticarial plaques across the cheeks and nose in the classic butterfly rash; (2) erythematous discoid lesions with fine or “carpet-tack” scale, telangiectasias, central hypopigmentation, peripheral hyperpigmentation, follicular plugging, and atrophy located on the face, scalp, external ears, arms, and upper trunk; and (3) psoriasiform or annular lesions of subacute cutaneous lupus with hypopigmented centers located primarily on the extensor arms and upper trunk. Additional mucocutaneous findings include (1) a violaceous flush on the face and V of the neck; (2) photosensitivity; (3) urticarial vasculitis (see “Urticaria,” above); (4) lupus panniculitis (see below); (5) diffuse alopecia; (6) alopecia secondary to discoid lesions; (7) periungual telangiectasias and erythema; (8) EM-like lesions that may become bullous; (9) oral ulcers; and (10) distal ulcerations secondary to Raynaud’s phenomenon, vasculitis, or livedoid vasculopathy. Patients with only discoid lesions usually have the form of lupus that is limited to the skin. However, up to 10% of these patients eventually develop systemic lupus. Direct immunofluorescence of involved skin, in particular discoid lesions, shows deposits of IgG or IgM and C3 in a granular distribution along the dermal-epidermal junction. In lymphoma cutis, there is a proliferation of malignant lymphocytes in the skin, and the clinical appearance resembles that of cutaneous lymphoid hyperplasia—infiltrated pink-red to red-purple papules and plaques. Lymphoma cutis can occur anywhere on the surface of the skin, whereas the sites of predilection for lymphocytomas include the malar ridge, tip of the nose, and earlobes. Patients with non- Hodgkin’s lymphomas have specific cutaneous lesions more often than those with Hodgkin’s disease, and, occasionally, the skin nodules precede the development of extracutaneous non-Hodgkin’s lymphoma or represent the only site of involvement (e.g., primary cutaneous B cell lymphoma). Arcuate lesions are sometimes seen in lymphoma and lymphocytoma cutis as well as in CTCL. Adult T cell leukemia/ lymphoma that develops in association with HTLV-1 infection is characterized by cutaneous plaques, hypercalcemia, and circulating CD25+ lymphocytes. Leukemia cutis has the same appearance as lymphoma cutis, and specific lesions are seen more commonly in monocytic leukemias than in lymphocytic or granulocytic leukemias. Cutaneous chloromas (granulocytic sarcomas) may precede the appearance of circulating blasts in acute myelogenous leukemia and, as such, represent a form of aleukemic leukemia cutis. Sweet syndrome is characterized by pink-red to red-brown edematous plaques that are frequently painful and occur primarily on the head, neck, and upper (and, less often, lower) extremities. The patients also have fever, neutrophilia, and a dense dermal infiltrate of neutrophils in the lesions. In ~10% of the patients, there is an associated malignancy, most commonly acute myelogenous leukemia. Sweet syndrome has also been reported with inflammatory bowel disease, systemic lupus erythematosus, and solid tumors (primarily of the genitourinary tract) as well as drugs (e.g., all-trans-retinoic acid, granulocyte colony-stimulating factor [G-CSF]). The differential diagnosis includes neutrophilic eccrine hidradenitis; bullous forms of pyoderma gangrenosum; and, occasionally, cellulitis. Extracutaneous sites of involvement include joints, muscles, eye, kidney (proteinuria, occasionally glomerulonephritis), and lung (neutrophilic infiltrates). The idiopathic form of Sweet syndrome is seen more often in women, following a respiratory tract infection. Common causes of erythematous subcutaneous nodules include inflamed epidermoid inclusion cysts, acne cysts, and furuncles. Panniculitis, an inflammation of the fat, also presents as subcutaneous nodules and is frequently a sign of systemic disease. There are several forms of panniculitis, including erythema nodosum, erythema induratum/nodular vasculitis, lupus panniculitis, lipodermatosclerosis, α1-antitrypsin deficiency, factitial, and fat necrosis secondary to pancreatic disease. Except for erythema nodosum, these lesions may break down and ulcerate or heal with a scar. The shin is the most common location for the nodules of erythema nodosum, whereas the calf is the most common location for lesions of erythema induratum. In erythema nodosum, the nodules are initially red but then develop a blue color as they resolve. Patients with erythema nodosum but no underlying systemic illness can still have fever, malaise, leukocytosis, arthralgias, and/or arthritis. However, the possibility of an underlying illness should be excluded, and the most common associations are streptococcal infections, upper respiratory viral infections, sarcoidosis, and inflammatory bowel disease, in addition to drugs (oral contraceptives, sulfonamides, penicillins, bromides, iodides). Less common associations include bacterial gastroenteritis (Yersinia, Salmonella) and coccidioidomycosis followed by tuberculosis, histoplasmosis, brucellosis, and infections with Chlamydophila pneumoniae or Chlamydia trachomatis, Mycoplasma pneumoniae, or hepatitis B virus. Erythema induratum and nodular vasculitis have overlapping features clinically and histologically, and whether they represent two separate entities or the ends of a single disease spectrum is a point of debate; in general, the latter is usually idiopathic and the former is associated with the presence of Mycobacterium tuberculosis DNA by PCR within skin lesions. The lesions of lupus panniculitis are found primarily on the cheeks, upper arms, and buttocks (sites of abundant fat) and are seen in both the cutaneous and systemic forms of lupus. The overlying skin may be normal, erythematous, or have the changes of discoid lupus. The subcutaneous fat necrosis that is associated with pancreatic disease is presumably secondary to circulating lipases and is seen in patients with pancreatic carcinoma as well as in patients with acute and chronic pancreatitis. In this disorder, there may be an associated arthritis, fever, and inflammation of visceral fat. Histologic examination of deep incisional biopsy specimens will aid in the diagnosis of the particular type of panniculitis. Subcutaneous erythematous nodules are also seen in cutaneous polyarteritis nodosa and as a manifestation of systemic vasculitis when there is involvement of medium-sized vessels, e.g., systemic polyarteritis nodosa, allergic granulomatosis, or granulomatosis with polyangiitis (Wegener’s) (Chap. 385). Cutaneous polyarteritis nodosa presents with painful subcutaneous nodules and ulcers within a red-purple, netlike pattern of livedo reticularis. The latter is due to slowed blood flow through the superficial horizontal venous plexus. The majority of lesions are found on the lower extremities, and while arthralgias and myalgias may accompany cutaneous polyarteritis nodosa, there is no evidence of systemic involvement. In both the cutaneous and systemic 367 CHAPTER 72 Skin Manifestations of Internal Disease forms of vasculitis, skin biopsy specimens of the associated nodules will show the changes characteristic of a necrotizing vasculitis and/or granulomatous inflammation. RED-BROWN LESIONS The cutaneous lesions in sarcoidosis (Chap. 390) are classically red to red-brown in color, and with diascopy (pressure with a glass slide), a yellow-brown residual color is observed that is secondary to the granulomatous infiltrate. The waxy papules and plaques may be found anywhere on the skin, but the face is the most common location. Usually there are no surface changes, but occasionally the lesions will have scale. Biopsy specimens of the papules show “naked” granulomas in the dermis, i.e., granulomas surrounded by a minimal number of lymphocytes. Other cutaneous findings in sarcoidosis include annular lesions with an atrophic or scaly center, papules within scars, hypopigmented papules and patches, alopecia, acquired ichthyosis, erythema nodosum, and lupus pernio (see below). The differential diagnosis of sarcoidosis includes foreign-body granulomas produced by chemicals such as beryllium and zirconium, late secondary syphilis, and lupus vulgaris. Lupus vulgaris is a form of cutaneous tuberculosis that is seen in previously infected and sensitized individuals. There is often underlying active tuberculosis elsewhere, usually in the lungs or lymph nodes. Lesions occur primarily in the head and neck region and are red-brown plaques with a yellowbrown color on diascopy. Secondary scarring and squamous cell carcinomas can develop within the plaques. Cultures or PCR analysis of the lesions should be performed, along with an interferon γ release assay of peripheral blood, because it is rare for the acid-fast stain to show bacilli within the dermal granulomas. A generalized distribution of red-brown macules and papules is seen in the form of mastocytosis known as urticaria pigmentosa (Chap. 376). Each lesion represents a collection of mast cells in the dermis, with hyperpigmentation of the overlying epidermis. Stimuli such as rubbing cause these mast cells to degranulate, and this leads to the formation of localized urticaria (Darier’s sign). Additional symptoms can result from mast cell degranulation and include headache, flushing, diarrhea, and pruritus. Mast cells also infiltrate various organs such as the liver, spleen, and gastrointestinal tract, and accumulations of mast cells in the bones may produce either osteosclerotic or osteolytic lesions on radiographs. In the majority of these patients, however, the internal involvement remains indolent. A subtype of chronic cutaneous small-vessel vasculitis, erythema elevatum diutinum (EED), also presents with papules that are red-brown in color. The papules coalesce into plaques on the extensor surfaces of knees, elbows, and the small joints of the hand. Flares of EED have been associated with streptococcal infections. BLUE LESIONS Lesions that are blue in color are the result of vascular ectasias, hyperplasias and tumors or melanin pigment within the dermis. Venous lakes (ectasias) are compressible dark-blue lesions that are found commonly in the head and neck region. Venous malformations are also compressible blue papulonodules and plaques that can occur anywhere on the body, including the oral mucosa. When there are multiple rather than single congenital lesions, the patient may have the blue rubber bleb syndrome or Maffucci’s syndrome. Patients with the blue rubber bleb syndrome also have vascular anomalies of the gastrointestinal tract that may bleed, whereas patients with Maffucci’s syndrome have associated osteochondromas. Blue nevi (moles) are seen when there are collections of pigment-producing nevus cells in the dermis. These benign papular lesions are dome-shaped and occur most commonly on the dorsum of the hand or foot or in the head and neck region. VIOLACEOUS LESIONS Violaceous papules and plaques are seen in lupus pernio, lymphoma cutis, and cutaneous lupus. Lupus pernio is a particular type of sarcoidosis that involves the tip and alar rim of the nose as well as the earlobes, with lesions that are violaceous in color rather than red-brown. This form of sarcoidosis is associated with involvement of the upper respiratory tract. The plaques of lymphoma cutis and cutaneous lupus may be red or violaceous in color and were discussed above. PURPLE LESIONS Purple-colored papules and plaques are seen in vascular tumors, such as Kaposi’s sarcoma (Chap. 226) and angiosarcoma, and when there is extravasation of red blood cells into the skin in association with inflammation, as in palpable purpura (see “Purpura,” below). Patients with congenital or acquired AV fistulas and venous hypertension can develop purple papules on the lower extremities that can resemble Kaposi’s sarcoma clinically and histologically; this condition is referred to as pseudo-Kaposi’s sarcoma (acral angiodermatitis). Angiosarcoma is found most commonly on the scalp and face of elderly patients or within areas of chronic lymphedema and presents as purple papules and plaques. In the head and neck region, the tumor often extends beyond the clinically defined borders and may be accompanied by facial edema. BROWN AND BLACK LESIONS Brown- and black-colored papules are reviewed in “Hyperpigmentation,” above. CUTANEOUS METASTASES These are discussed last because they can have a wide range of colors. Most commonly, they present as either firm, skin-colored subcutaneous nodules or firm, red to red-brown papulonodules. The lesions of lymphoma cutis range from pink-red to plum in color, whereas metastatic melanoma can be pink, blue, or black in color. Cutaneous metastases develop from hematogenous or lymphatic spread and are most often due to the following primary carcinomas: in men, melanoma, oropharynx, lung, and colon; and in women, breast, melanoma, and ovary. These metastatic lesions may be the initial presentation of the carcinoma, especially when the primary site is the lung. PURPURA (Table 72-16) Purpura are seen when there is an extravasation of red blood cells into the dermis and, as a result, the lesions do not blanch with pressure. This is in contrast to those erythematous or violetcolored lesions that are due to localized vasodilatation—they do blanch with pressure. Purpura (≥3 mm) and petechiae (≤2 mm) are divided into two major groups: palpable and nonpalpable. The most frequent causes of nonpalpable petechiae and purpura are primary cutaneous disorders such as trauma, solar (actinic) purpura, and capillaritis. Less common causes are steroid purpura and livedoid vasculopathy (see “Ulcers,” below). Solar purpura are seen primarily on the extensor forearms, whereas steroid purpura secondary to potent topical glucocorticoids or endogenous or exogenous Cushing’s syndrome can be more widespread. In both cases, there is alteration of the supporting connective tissue that surrounds the dermal blood vessels. In contrast, the petechiae that result from capillaritis are found primarily on the lower extremities. In capillaritis, there is an extravasation of erythrocytes as a result of perivascular lymphocytic inflammation. The petechiae are bright red, 1–2 mm in size, and scattered within yellowbrown patches. The yellow-brown color is caused by hemosiderin deposits within the dermis. Systemic causes of nonpalpable purpura fall into several categories, and those secondary to clotting disturbances and vascular fragility will be discussed first. The former group includes thrombocytopenia (Chap. 140), abnormal platelet function as is seen in uremia, and clotting factor defects. The initial site of presentation for thrombocytopenia- induced petechiae is the distal lower extremity. Capillary fragility leads to nonpalpable purpura in patients with systemic amyloidosis (see “Papulonodular Skin Lesions,” above), disorders of collagen production such as Ehlers-Danlos syndrome, and scurvy. In scurvy, there are flattened corkscrew hairs with surrounding hemorrhage on the lower extremities, in addition to gingivitis. Vitamin C is a cofactor for lysyl hydroxylase, an enzyme involved in the posttranslational modification of procollagen that is necessary for cross-link formation. 368 PART 2 Cardinal Manifestations and Presentation of Diseases In contrast to the previous group of disorders, the purpura (noninflammatory with a retiform outline) seen in the following group of diseases are associated with thrombi formation within vessels. It is important to note that these thrombi are demonstrable in skin biopsy specimens. This group of disorders includes disseminated intravascular coagulation (DIC), monoclonal cryoglobulinemia, thrombocytosis, thrombotic thrombocytopenic purpura, antiphospholipid antibody syndrome, and reactions to warfarin and heparin (heparin-induced thrombocytopenia and thrombosis). DIC is triggered by several types of infection (gramnegative, gram-positive, viral, and rickettsial) as well as by tissue injury and neoplasms. Widespread purpura and hemorrhagic infarcts of the distal extremities are seen. Similar lesions are found in purpura fulminans, which is a form of DIC associated with fever and hypotension that occurs more commonly in children following an infectious illness such as varicella, scarlet fever, or an upper respiratory tract infection. In both disorders, hemorrhagic bullae can develop in involved skin. Monoclonal cryoglobulinemia is associated with plasma cell dyscrasias, chronic lymphocytic leukemia, and lymphoma. Purpura, primarily of the lower extremities, and hemorrhagic infarcts of the fingers, toes, and ears are seen in these patients. Exacerbations of disease activity can follow cold exposure or an increase in serum viscosity. Biopsy specimens show precipitates of the cryoglobulin within dermal vessels. Similar deposits have been found in the lung, brain, and renal glomeruli. Patients with thrombotic thrombocytopenic purpura can also have hemorrhagic infarcts as a result of intravascular thromboses. Additional signs include microangiopathic hemolytic anemia and fluctuating neurologic abnormalities, especially headaches and confusion. Administration of warfarin can result in painful areas of erythema that become purpuric and then necrotic with an adherent black eschar; the condition is referred to as warfarin-induced necrosis. This reaction is seen more often in women and in areas with abundant subcutaneous fat—breasts, abdomen, buttocks, thighs, and calves. The erythema and purpura develop between the third and tenth day of therapy, most likely as a result of a transient imbalance in the levels of anticoagulant and procoagulant vitamin K–dependent factors. Continued therapy does not exacerbate preexisting lesions, and patients with an inherited or acquired deficiency of protein C are at increased risk for this particular reaction as well as for purpura fulminans and calciphylaxis. Purpura secondary to cholesterol emboli are usually seen on the lower extremities of patients with atherosclerotic vascular disease. They often follow anticoagulant therapy or an invasive vascular procedure such as an arteriogram but also occur spontaneously from disintegration of atheromatous plaques. Associated findings include livedo reticularis, gangrene, cyanosis, and ischemic ulcerations. Multiple step sections of the biopsy specimen may be necessary to demonstrate the cholesterol clefts within the vessels. Petechiae are also an important sign of fat embolism and occur primarily on the upper body 2–3 days after a major injury. By using special fixatives, the emboli can be demonstrated in biopsy specimens of the petechiae. Emboli of tumor or thrombus are seen in patients with atrial myxomas and marantic endocarditis. In the Gardner-Diamond syndrome (autoerythrocyte sensitivity), female patients develop large ecchymoses within areas of painful, warm erythema. Intradermal injections of autologous erythrocytes or phosphatidyl serine derived from the red cell membrane can reproduce the lesions in some patients; however, there are instances where a reaction is seen at an injection site of the forearm but not in the midback region. The latter has led some observers to view Gardner- Diamond syndrome as a cutaneous manifestation of severe emotional stress. More recently, the possibility of platelet dysfunction (as assessed via aggregation studies) has been raised. Waldenström’s hypergammaglobulinemic purpura is a chronic disorder characterized by petechiae on the lower extremities. There are circulating complexes of IgG–anti- IgG molecules, and exacerbations are associated with prolonged standing or walking. Palpable purpura are further subdivided into vasculitic and embolic. In the group of vasculitic disorders, cutaneous small-vessel vasculitis, also known as leukocytoclastic vasculitis (LCV), is the one most commonly associated with palpable purpura (Chap. 385). Underlying etiologies include drugs (e.g., antibiotics), infections (e.g., hepatitis C virus), and autoimmune connective tissue diseases (e.g., rheumatoid arthritis, Sjögren’s syndrome, lupus). Henoch-Schönlein purpura (HSP) is a subtype of acute LCV that is seen more commonly in children and adolescents following an upper respiratory infection. The majority of lesions are found on the lower extremities and buttocks. Systemic manifestations include fever, arthralgias (primarily of the knees and ankles), abdominal pain, gastrointestinal bleeding, and nephritis. Direct immunofluorescence examination shows deposits of IgA within dermal blood vessel walls. Renal disease is of particular concern in adults with HSP. In polyarteritis nodosa, specific cutaneous lesions result from a vasculitis of arterial vessels (arteritis), or there Table 72-16 Causes of Purpura I. Primary cutaneous disorders A. Nonpalpable 1. Trauma 2. Solar (actinic, senile) purpura 3. Steroid purpura 4. Capillaritis 5. Livedoid vasculopathy in the setting of venous hypertensiona II. Systemic diseases A. Nonpalpable 1. Clotting disturbances a. Thrombocytopenia (including ITP) b. Abnormal platelet function c. Clotting factor defects 2. Vascular fragility a. Amyloidosis (within normal-appearing skin) b. Ehlers-Danlos syndrome c. Scurvy 3. Thrombi a. Disseminated intravascular coagulation b. Warfarin (Coumadin)-induced necrosis c. Heparin-induced thrombocytopenia and thrombosis d. Antiphospholipid antibody syndrome e. Monoclonal cryoglobulinemia f. Vasculopathy induced by levamisole-adulterated cocaine g. Thrombotic thrombocytopenic purpura h. Thrombocytosis i Homozygous protein C or protein S deficiency 4. Emboli a. Cholesterol b. Fat 5. Possible immune complex a. Gardner-Diamond syndrome (autoerythrocyte sensitivity) b. Waldenström's hypergammaglobulinemic purpura B. Palpable 1. Vasculitis a. Cutaneous small-vessel vasculitis, including in the setting of systemic vasculitides b. Polyarteritis nodosa 2. Embolib a. Acute meningococcemia b. Disseminated gonococcal infection c. Rocky Mountain spotted fever d. Ecthyma gangrenosum aAlso associated with underlying disorders that lead to hypercoagulability, e.g., factor V Leiden, protein C dysfunction/deficiency. bBacterial (including rickettsial), fungal, or parasitic. Abbreviation: ITP, idiopathic thrombocytopenic purpura. 369 CHAPTER 72 Skin Manifestations of Internal Disease may be an associated LCV. Arteritis leads to an infarct of the skin, and this explains the irregular outline of the purpura (see below). Several types of infectious emboli can give rise to palpable purpura. These embolic lesions are usually irregular in outline as opposed to the lesions of LCV, which are circular in outline. The irregular outline is indicative of a cutaneous infarct, and the size corresponds to the area of skin that received its blood supply from that particular arteriole or artery. The palpable purpura in LCV are circular because the erythrocytes simply diffuse out evenly from the postcapillary venules as a result of inflammation. Infectious emboli are most commonly due to gram-negative cocci (meningococcus, gonococcus), gram-negative rods (Enterobacteriaceae), and gram-positive cocci (Staphylococcus). Additional causes include Rickettsia and, in immunocompromised patients, Aspergillus and other opportunistic fungi. The embolic lesions in acute meningococcemia are found primarily on the trunk, lower extremities, and sites of pressure, and a gunmetal-gray color often develops within them. Their size varies from a few millimeters to several centimeters, and the organisms can be cultured from the lesions. Associated findings include a preceding upper respiratory tract infection; fever; meningitis; DIC; and, in some patients, a deficiency of the terminal components of complement. In disseminated gonococcal infection (arthritis-dermatitis syndrome), a small number of inflammatory papules and vesicopustules, often with central purpura or hemorrhagic necrosis, are found on the distal extremities. Additional symptoms include arthralgias, tenosynovitis, and fever. To establish the diagnosis, a Gram stain of these lesions should be performed. Rocky Mountain spotted fever is a tick-borne disease that is caused by Rickettsia rickettsii. A several-day history of fever, chills, severe headache, and photophobia precedes the onset of the cutaneous eruption. The initial lesions are erythematous macules and papules on the wrists, ankles, palms, and soles. With time, the lesions spread centripetally and become purpuric. Lesions of ecthyma gangrenosum begin as edematous, erythematous papules or plaques and then develop central purpura and necrosis. Bullae formation also occurs in these lesions, and they are frequently found in the girdle region. The organism that is classically associated with ecthyma gangrenosum is Pseudomonas aeruginosa, but other gram-negative rods such as Klebsiella, Escherichia coli, and Serratia can produce similar lesions. In immunocompromised hosts, the list of potential pathogens is expanded to include Candida and other opportunistic fungi (e.g., Aspergillus, Fusarium). ULCERS The approach to the patient with a cutaneous ulcer is outlined in Table 72-17. Peripheral vascular diseases of the extremities are reviewed in Chap. 302, as is Raynaud’s phenomenon. Livedoid vasculopathy (livedoid vasculitis; atrophie blanche) represents a combination of a vasculopathy plus intravascular thrombosis. Purpuric lesions and livedo reticularis are found in association with painful ulcerations of the lower extremities. These ulcers are often slow to heal, but when they do, irregularly shaped white scars form. The majority of cases are secondary to venous hypertension, but possible underlying illnesses include cryofibrinogenemia and disorders of hypercoagulability, e.g., the antiphospholipid syndrome (Chaps. 142 and 379). In pyoderma gangrenosum, the border of untreated active ulcers has a characteristic appearance consisting of an undermined necrotic violaceous edge and a peripheral erythematous halo. The ulcers often begin as pustules that then expand rather rapidly to a size as large as 20 cm. Although these lesions are most commonly found on the lower extremities, they can arise anywhere on the surface of the body, including sites of trauma (pathergy). An estimated 30–50% of cases are idiopathic, and the most common associated disorders are ulcerative colitis and Crohn’s disease. Less commonly, pyoderma gangrenosum is associated with seropositive rheumatoid arthritis, acute and chronic myelogenous leukemia, hairy cell leukemia, myelofibrosis, or a monoclonal gammopathy, usually IgA. Because the histology of pyoderma gangrenosum may be nonspecific (dermal infiltrate of neutrophils when in untreated state), the diagnosis requires clinicopathologic correlation, in particular, the exclusion of similar-appearing ulcers such as necrotizing vasculitis, Meleney’s ulcer (synergistic infection at a site of trauma or surgery), dimorphic fungi, cutaneous amebiasis, spider bites, and factitial. In the myeloproliferative disorders, the ulcers may be more superficial with a pustulobullous border, and these lesions provide a connection between classic pyoderma gangrenosum and acute febrile neutrophilic dermatosis (Sweet syndrome). FEVER AND RASH The major considerations in a patient with a fever and a rash are inflammatory diseases versus infectious diseases. In the hospital setting, the most common scenario is a patient who has a drug rash plus a fever secondary to an underlying infection. However, it should be Table 72-17 Causes of Mucocuta neous Ulcers I. Primary cutaneous disorders A. Peripheral vascular disease (Chap. 302) 1. Venous 2. Arteriala B. Livedoid vasculopathy in the setting of venous hypertensionb C. Squamous cell carcinoma, e.g., within scars, basal cell carcinomas D. Infections, e.g., ecthyma caused by Streptococcus (Chap. 173) E. Physical, e.g., trauma, pressure F. Drugs, e.g., hydroxyurea II. Systemic diseases A. Lower legs 1. Small-vessel and medium-vessel vasculitisc 2. Hemoglobinopathies (Chap. 127) 3. Cryoglobulinemia,c cryofibrinogenemia 4. Cholesterol embolic 5. Necrobiosis lipoidicad 6. Antiphospholipid syndrome (Chap. 141) 7. Neuropathice (Chap. 417) 8. Panniculitis 9. Kaposi's sarcoma, acral angiodermatitis 10. Diffuse dermal angiomatosis B. Hands and feet 1. Raynaud's phenomenon (Chap. 302) 2. Buerger disease C. Generalized 1. Pyoderma gangrenosum, but most commonly legs 2. Calciphylaxis (Chap. 424) 3. Infections, e.g., dimorphic fungi, leishmaniasis 4. Lymphoma D. Face, especially perioral, and anogenital 1. Chronic herpes simplexf III. Mucosal A. Behçet's syndrome (Chap. 387) B. Erythema multiforme major, Stevens-Johnson syndrome, TEN C. Primary blistering disorders (Chap. 73) D. Lupus erythematosus, lichen planus E. Inflammatory bowel disease F. Acute HIV infection G. Reactive arthritis (formerly known as Reiter's syndrome) aUnderlying atherosclerosis. bAlso associated with underlying disorders that lead to hypercoagulability, e.g., factor V Leiden, protein C dysfunction/deficiency, antiphospholipid antibodies. cReviewed in section on Purpura. dReviewed in section on Papulonodular Skin Lesions. eFavors plantar surface of the foot. fSign of immunosuppression. Abbreviation: TEN, toxic epidermal necrolysis. emphasized that a drug reaction can lead to both a cutaneous eruption and a fever (“drug fever”), especially in the setting of DRESS, AGEP, or serum sickness–like reaction. Additional inflammatory diseases that are often associated with a fever include pustular psoriasis, erythroderma, and Sweet syndrome. Lyme disease, secondary syphilis, and viral and bacterial exanthems (see “Exanthems,” above) are examples of infectious diseases that produce a rash and a fever. Lastly, it is important to determine whether or not the cutaneous lesions represent septic emboli (see “Purpura,” above). Such lesions usually have evidence of ischemia in the form of purpura, necrosis, or impending necrosis (gunmetal-gray color). In the patient with thrombocytopenia, however, purpura can be seen in inflammatory reactions such as morbilliform drug eruptions and infectious lesions. Immunologically Mediated Skin Diseases Kim B. Yancey, Thomas J. Lawley A number of immunologically mediated skin diseases and immunologically mediated systemic disorders with cutaneous manifestations are now recognized as distinct entities with consistent clinical, histologic, and immunopathologic findings. Clinically, these disorders are characterized by morbidity (pain, pruritus, disfigurement) and, in some instances, result in death (largely due to loss of epidermal barrier function and/or secondary infection). The major features of the more common immunologically mediated skin diseases are summarized in this chapter (Table 73-1), as are the autoimmune systemic disorders with cutaneous manifestations. 73 Table 73-1 Immunologicall y Mediated Blistering Diseases Disease Clinical Manifestations Histology Immunopathology Autoantigensa Pemphigus vulgaris Flaccid blisters, denuded skin, oromucosal lesions Acantholytic blister formed in suprabasal layer of epidermis Cell surface deposits of IgG on keratinocytes Dsg3 (plus Dsg1 in patients with skin involvement) Pemphigus foliaceus Crusts and shallow erosions on scalp, central face, upper chest, and back Acantholytic blister formed in superficial layer of epidermis Cell surface deposits of IgG on keratinocytes Dsg1 Paraneoplastic pemphigus Painful stomatitis with papulosquamous or lichenoid eruptions that may progress to blisters Acantholysis, keratinocyte necrosis, and vacuolar interface dermatitis Cell surface deposits of IgG and C3 on keratinocytes and (variably) similar immunoreactants in epidermal BMZ Plakin protein family members and desmosomal cadherins (see text for details) Bullous pemphigoid Large tense blisters on flexor surfaces and trunk Subepidermal blister with eosinophil-rich infiltrate Linear band of IgG and/or C3 in epidermal BMZ BPAG1, BPAG2 Pemphigoid gestationis Pruritic, urticarial plaques rimmed by vesicles and bullae on the trunk and extremities Teardrop-shaped, subepidermal blisters in dermal papillae; eosinophil-rich infiltrate Linear band of C3 in epidermal BMZ BPAG2 (plus BPAG1 in some patients) Dermatitis herpetiformis Extremely pruritic small papules and vesicles on elbows, knees, buttocks, and posterior neck Subepidermal blister with neutrophils in dermal papillae Granular deposits of IgA in dermal papillae Epidermal transglutaminase Linear IgA disease Pruritic small papules on extensor surfaces; occasionally larger, arciform blisters Subepidermal blister with neutrophil-rich infiltrate Linear band of IgA in epidermal BMZ BPAG2 (see text for specific details) Epidermolysis bullosa acquisita Blisters, erosions, scars, and milia on sites exposed to trauma; widespread, inflammatory, tense blisters may be seen initially Subepidermal blister that may or may not include a leukocytic infiltrate Linear band of IgG and/or C3 in epidermal BMZ Type VII collagen Mucous membrane pemphigoid Erosive and/or blistering lesions of mucous membranes and possibly the skin; scarring of some sites Subepidermal blister that may or may not include a leukocytic infiltrate Linear band of IgG, IgA, and/or C3 in epidermal BMZ BPAG2, laminin-332, or others aAutoantigens bound by these patients’ autoantibodies are defined as follows: Dsg1, desmoglein 1; Dsg3, desmoglein 3; BPAG1, bullous pemphigoid antigen 1; BPAG2, bullous pemphigoid antigen 2. Abbreviation: BMZ, basement membrane zone. AUTOIMMUNE CUTANEOUS DISEASES PEMPHIGUS VULGARIS Pemphigus refers to a group of autoantibody-mediated intraepidermal blistering diseases characterized by loss of cohesion between epidermal cells (a process termed acantholysis). Manual pressure to the skin of these patients may elicit the separation of the epidermis (Nikolsky’s sign). This finding, while characteristic of pemphigus, is not specific to this group of disorders and is also seen in toxic epidermal necrolysis, Stevens-Johnson syndrome, and a few other skin diseases. Pemphigus vulgaris (PV) is a mucocutaneous blistering disease that predominantly occurs in patients >40 years of age. PV typically begins on mucosal surfaces and often progresses to involve the skin. This disease is characterized by fragile, flaccid blisters that rupture to produce extensive denudation of mucous membranes and skin (Fig. 73-1). The mouth, scalp, face, neck, axilla, groin, and trunk are typically involved. PV may be associated with severe skin pain; some patients experience pruritus as well. Lesions usually heal without scarring except at sites complicated by secondary infection or mechanically induced dermal wounds. Postinflammatory hyperpigmentation is usually present for some time at sites of healed lesions. Biopsies of early lesions demonstrate intraepidermal vesicle formation secondary to loss of cohesion between epidermal cells (i.e., acantholytic blisters). Blister cavities contain acantholytic epidermal cells, which appear as round homogeneous cells containing hyperchromatic nuclei. Basal keratinocytes remain attached to the epidermal basement membrane; hence, blister formation takes place within the suprabasal portion of the epidermis. Lesional skin may contain focal collections of intraepidermal eosinophils within blister cavities; dermal alterations are slight, often limited to an eosinophil-predominant leukocytic infiltrate. Direct immunofluorescence microscopy of lesional or intact patient skin shows deposits of IgG on the surface of keratinocytes; deposits of complement components are typically found in lesional but not in uninvolved skin. Deposits of IgG on keratinocytes are derived from circulating autoantibodies to cell-surface autoantigens. Such circulating autoantibodies 370 PART 2 Cardinal Manifestations and Presentation of Diseases 371 CHAPTER 73 Immunologically Mediated Skin Diseases can be demonstrated in 80–90% of PV patients by indirect immunofluorescence microscopy; monkey esophagus is the optimal substrate for these studies. Patients with PV have IgG autoantibodies to desmogleins (Dsgs), transmembrane desmosomal glycoproteins that belong to the cadherin family of calcium-dependent adhesion molecules. Such autoantibodies can be precisely quantitated by enzyme-linked immunosorbent assay (ELISA). Patients with early PV (i.e., mucosal disease) have IgG autoantibodies to Dsg3; patients with advanced PV (i.e., mucocutaneous disease) have IgG autoantibodies to both Dsg3 and Dsg1. Experimental studies have shown that autoantibodies from patients with PV are pathogenic (i.e., responsible for blister formation) and that their titer correlates with disease activity. Recent studies have shown that the anti-Dsg autoantibody profile in these patients’ sera as well as the tissue distribution of Dsg3 and Dsg1 determine the site of blister formation in patients with PV. Coexpression of Dsg3 and Dsg1 by epidermal cells protects against pathogenic IgG antibodies to either of these cadherins but not against pathogenic autoantibodies to both. PV can be life-threatening. Prior to the availability of glucocorticoids, mortality rates ranged from 60% to 90%; the current figure is ~5%. Common causes of morbidity and death are infection and complications of treatment with glucocorticoids. Bad prognostic factors include advanced age, widespread involvement, and the requirement for high doses of glucocorticoids (with or without other immunosuppressive agents) for control of disease. The course of PV in individual patients is variable and difficult to predict. Some patients experience remission, while others may require long-term treatment or succumb to complications of their disease or its treatment. The mainstay of treatment is systemic glucocorticoids. Patients with moderate to severe PV are usually started on prednisone at 1 mg/kg per day. If new lesions continue to appear after 1–2 weeks of treatment, the dose may need to be increased and/or prednisone may need to be combined with other immunosuppressive agents such as azathioprine (2–2.5 mg/kg per day), mycophenolate mofetil (20–35 mg/kg per day), or cyclophosphamide (1–2 mg/kg per day). Patients with severe, treatment-resistant disease may derive benefit from plasmapheresis (six high-volume exchanges [i.e., 2–3 L per exchange] over ~2 weeks), IV immunoglobulin (IVIg) (2 g/kg over 3–5 days every 6–8 weeks), or rituximab (375 mg/m2 per week × 4, or 1000 mg on days 1 and 15). It is important to bring severe or progressive disease under control quickly in order to lessen the severity and/or duration of this disorder. Accordingly, some have suggested that rituximab and daily glucocorticoids should be used early in PV patients to avert the development of treatmentresistant disease. PEMPHIGUS FOLIACEUS Pemphigus foliaceus (PF) is distinguished from PV by several features. In PF, acantholytic blisters are located high within the epidermis, usually just beneath the stratum corneum. Hence, PF is a more superficial blistering disease than PV. The distribution of lesions in the two disorders is much the same, except that in PF mucous membranes are almost always spared. Patients with PF rarely have intact blisters but rather exhibit shallow erosions associated with erythema, scale, and crust formation. Mild cases of PF resemble severe seborrheic dermatitis; severe PF may cause extensive exfoliation. Sun exposure (ultraviolet irradiation) may be an aggravating factor. PF has immunopathologic features in common with PV. Specifically, direct immunofluorescence microscopy of perilesional skin demonstrates IgG on the surface of keratinocytes. Similarly, patients with PF have circulating IgG autoantibodies directed against the surface of keratinocytes. In PF, autoantibodies are directed against Dsg1, a 160- kDa desmosomal cadherin. These autoantibodies can be quantitated by ELISA. As noted for PV, the autoantibody profile in patients with PF (i.e., anti-Dsg1 IgG) and the tissue distribution of this autoantigen (i.e., expression in oral mucosa that is compensated by coexpression of Dsg3) are thought to account for the distribution of lesions in this disease. Endemic forms of PF are found in south-central rural Brazil, where the disease is known as fogo salvagem (FS), as well as in selected sites in Latin America and Tunisia. Endemic PF, like other forms of this disease, is mediated by IgG autoantibodies to Dsg1. Clusters of FS overlap with those of leishmaniasis, a disease transmitted by bites of the sand fly Lutzomyia longipalis. Recent studies have shown that sand-fly salivary antigens (specifically, the LJM11 salivary protein) are recognized by IgG autoantibodies from FS patients (as well as by monoclonal antibodies to Dsg1 derived from these patients). Moreover, mice immunized with LJM11 produce antibodies to Dsg1. Thus, these findings suggest that insect bites may deliver salivary antigens that initiate a cross-reactive humoral immune response, which may lead to FS in genetically susceptible individuals. Although pemphigus has been associated with several autoimmune diseases, its association with thymoma and/or myasthenia gravis is particularly notable. To date, >30 cases of thymoma and/or myasthenia gravis have been reported in association with pemphigus, usually with PF. Patients may also develop pemphigus as a consequence of drug exposure; drug-induced pemphigus usually resembles PF rather than PV. Drugs containing a thiol group in their chemical structure (e.g., penicillamine, captopril, enalapril) are most commonly associated with drug-induced pemphigus. Nonthiol drugs linked to pemphigus include penicillins, cephalosporins, and piroxicam. It has A B Figure 73-1 Pemphigus vulgaris. A. Flaccid bullae are easily ruptured, resulting in multiple erosions and crusted plaques. B. Involvement of the oral mucosa, which is almost invariable, may present with erosions on the gingiva, buccal mucosa, palate, posterior pharynx, or tongue. (B, Courtesy of Robert Swerlick, MD; with permission.) 372 PART 2 Cardinal Manifestations and Presentation of Diseases been suggested that thiol-containing and non-thiol-containing drugs induce pemphigus via biochemical and immunologic mechanisms, respectively—hence, the better prognosis upon drug withdrawal in cases of pemphigus induced by thiol-containing medications. Some cases of drug-induced pemphigus are durable and require treatment with systemic glucocorticoids and/or immunosuppressive agents. PF is generally a less severe disease than PV and carries a better prognosis. Localized disease can sometimes be treated with topical or intralesional glucocorticoids; more active cases can usually be controlled with systemic glucocorticoids. Patients with severe, treatment- resistant disease may require more aggressive interventions, as described above for patients with PV. PARANEOPLASTIC PEMPHIGUS Paraneoplastic pemphigus (PNP) is an autoimmune acantholytic mucocutaneous disease associated with an occult or confirmed neoplasm. Patients with PNP typically have painful mucosal erosive lesions in association with papulosquamous and/or lichenoid eruptions that often progress to blisters. Palm and sole involvement are common in these patients and raise the possibility that prior reports of neoplasiaassociated erythema multiforme actually may have represented unrecognized cases of PNP. Biopsies of lesional skin from these patients show varying combinations of acantholysis, keratinocyte necrosis, and vacuolar-interface dermatitis. Direct immunofluorescence microscopy of a patient’s skin shows deposits of IgG and complement on the surface of keratinocytes and (variably) similar immunoreactants in the epidermal basement membrane zone. Patients with PNP have IgG autoantibodies to cytoplasmic proteins that are members of the plakin family (e.g., desmoplakins I and II, bullous pemphigoid antigen [BPAG]1, envoplakin, periplakin, and plectin) and to cell-surface proteins that are members of the cadherin family (e.g., Dsg1 and Dsg3). Passive transfer studies have shown that autoantibodies from patients with PNP are pathogenic in animal models. The predominant neoplasms associated with PNP are non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, thymoma, spindle cell tumors, Waldenström’s macroglobulinemia, and Castleman’s disease; the last-mentioned neoplasm is particularly common among children with PNP. Rare cases of seronegative PNP have been reported in patients with B cell malignancies previously treated with rituximab. In addition to severe skin lesions, many patients with PNP develop life-threatening bronchiolitis obliterans. PNP is generally resistant to conventional therapies (i.e., those used to treat PV); rarely, a patient’s disease may ameliorate or even remit following ablation or removal of underlying neoplasms. BULLOUS PEMPHIGOID Bullous pemphigoid (BP) is a polymorphic autoimmune subepidermal blistering disease usually seen in the elderly. Initial lesions may consist of urticarial plaques; most patients eventually display tense blisters on either normal-appearing or erythematous skin (Fig. 73-2). The lesions are usually distributed over the lower abdomen, groin, and flexor surface of the extremities; oral mucosal lesions are found in some patients. Pruritus may be nonexistent or severe. As lesions evolve, tense blisters tend to rupture and be replaced by erosions with or without surmounting crust. Nontraumatized blisters heal without scarring. The major histocompatibility complex class II allele HLA-DQβ1*0301 is prevalent in patients with BP. Despite isolated reports, several studies have shown that patients with BP do not have a higher incidence of malignancy than appropriately age- and gender-matched controls. Biopsies of early lesional skin demonstrate subepidermal blisters and histologic features that roughly correlate with the clinical character of the particular lesion under study. Lesions on normal-appearing skin generally contain a sparse perivascular leukocytic infiltrate with some eosinophils; conversely, biopsies of inflammatory lesions typically show an eosinophil-rich infiltrate at sites of vesicle formation and in perivascular areas. In addition to eosinophils, cell-rich lesions also contain mononuclear cells and neutrophils. It is not possible to distinguish BP from other subepidermal blistering diseases by routine histologic studies alone. Direct immunofluorescence microscopy of normal-appearing perilesional skin from patients with BP shows linear deposits of IgG and/ or C3 in the epidermal basement membrane. The sera of ~70% of these patients contain circulating IgG autoantibodies that bind the epidermal basement membrane of normal human skin in indirect immunofluorescence microscopy. IgG from an even higher percentage of patients reacts with the epidermal side of 1 M NaCl split skin (an alternative immunofluorescence microscopy test substrate used to distinguish circulating IgG autoantibodies to the basement membrane in patients with BP from those in patients with similar, yet different, subepidermal blistering diseases; see below). In BP, circulating autoantibodies recognize 230- and 180-kDa hemidesmosome-associated proteins in basal keratinocytes (i.e., BPAG1 and BPAG2, respectively). Autoantibodies to BPAG2 are thought to deposit in situ, activate complement, produce dermal mast-cell degranulation, and generate granulocyte-rich infiltrates that cause tissue damage and blister formation. BP may persist for months to years, with exacerbations or remissions. Extensive involvement may result in widespread erosions and compromise cutaneous integrity; elderly and/or debilitated patients may die. The mainstay of treatment is systemic glucocorticoids. Local or minimal disease can sometimes be controlled with topical glucocorticoids alone; more extensive lesions generally respond to systemic glucocorticoids either alone or in combination with immunosuppressive agents. Patients usually respond to prednisone (0.75–1 mg/kg per day). In some instances, azathioprine (2–2.5 mg/kg per day), mycophenolate mofetil (20–35 mg/kg per day), or cyclophosphamide (1–2 mg/kg per day) are necessary adjuncts. PEMPHIGOID GESTATIONIS Pemphigoid gestationis (PG), also known as herpes gestationis, is a rare, nonviral, subepidermal blistering disease of pregnancy and the puerperium. PG may begin during any trimester of pregnancy or present shortly after delivery. Lesions are usually distributed over the abdomen, trunk, and extremities; mucous membrane lesions are rare. Skin lesions in these patients may be quite polymorphic and consist of erythematous urticarial papules and plaques, vesiculopapules, and/or frank bullae. Lesions are almost always extremely pruritic. Severe exacerbations of PG frequently follow delivery, typically within 24–48 h. PG tends to recur in subsequent pregnancies, often beginning earlier during such gestations. Brief flare-ups of disease may occur with resumption of menses and may develop in patients later exposed to oral contraceptives. Occasionally, infants of affected mothers have transient skin lesions. Figure 73-2 Bullous pemphigoid with tense vesicles and bullae on erythematous, urticarial bases. (Courtesy of the Yale Resident’s Slide Collection; with permission.) 373 CHAPTER 73 Immunologically Mediated Skin Diseases Biopsies of early lesional skin show teardrop-shaped subepidermal vesicles forming in dermal papillae in association with an eosinophilrich leukocytic infiltrate. Differentiation of PG from other subepidermal bullous diseases by light microscopy is difficult. However, direct immunofluorescence microscopy of perilesional skin from PG patients reveals the immunopathologic hallmark of this disorder: linear deposits of C3 in the epidermal basement membrane. These deposits develop as a consequence of complement activation produced by low-titer IgG anti–basement membrane autoantibodies directed against BPAG2, the same hemidesmosome-associated protein that is targeted by autoantibodies in patients with BP—a subepidermal bullous disease that resembles PG clinically, histologically, and immunopathologically. The goals of therapy in patients with PG are to prevent the development of new lesions, relieve intense pruritus, and care for erosions at sites of blister formation. Many patients require treatment with moderate doses of daily glucocorticoids (i.e., 20–40 mg of prednisone) at some point in their course. Mild cases (or brief flare-ups) may be controlled by vigorous use of potent topical glucocorticoids. Infants born of mothers with PG appear to be at increased risk of being born slightly premature or “small for dates.” Current evidence suggests that there is no difference in the incidence of uncomplicated live births between PG patients treated with systemic glucocorticoids and those managed more conservatively. If systemic glucocorticoids are administered, newborns are at risk for development of reversible adrenal insufficiency. DERMATITIS HERPETIFORMIS Dermatitis herpetiformis (DH) is an intensely pruritic, papulovesicular skin disease characterized by lesions symmetrically distributed over extensor surfaces (i.e., elbows, knees, buttocks, back, scalp, and posterior neck) (see Fig. 70-8). Primary lesions in this disorder consist of papules, papulovesicles, or urticarial plaques. Because pruritus is prominent, patients may present with excoriations and crusted papules but no observable primary lesions. Patients sometimes report that their pruritus has a distinctive burning or stinging component; the onset of such local symptoms reliably heralds the development of distinct clinical lesions 12–24 h later. Almost all DH patients have associated, usually subclinical, gluten-sensitive enteropathy (Chap. 349), and >90% express the HLA-B8/DRw3 and HLA-DQw2 haplotypes. DH may present at any age, including in childhood; onset in the second to fourth decades is most common. The disease is typically chronic. Biopsy of early lesional skin reveals neutrophil-rich infiltrates within dermal papillae. Neutrophils, fibrin, edema, and microvesicle formation at these sites are characteristic of early disease. Older lesions may demonstrate nonspecific features of a subepidermal bulla or an excoriated papule. Because the clinical and histologic features of this disease can be variable and resemble those of other subepidermal blistering disorders, the diagnosis is confirmed by direct immunofluorescence microscopy of normal-appearing perilesional skin. Such studies demonstrate granular deposits of IgA (with or without complement components) in the papillary dermis and along the epidermal basement membrane zone. IgA deposits in the skin are unaffected by control of disease with medication; however, these immunoreactants diminish in intensity or disappear in patients maintained for long periods on a strict gluten-free diet (see below). Patients with DH have granular deposits of IgA in their epidermal basement membrane zone and should be distinguished from individuals with linear IgA deposits at this site (see below). Although most DH patients do not report overt gastrointestinal symptoms or have laboratory evidence of malabsorption, biopsies of the small bowel usually reveal blunting of intestinal villi and a lymphocytic infiltrate in the lamina propria. As is true for patients with celiac disease, this gastrointestinal abnormality can be reversed by a glutenfree diet. Moreover, if maintained, this diet alone may control the skin disease and eventuate in clearance of IgA deposits from these patients’ epidermal basement membrane zones. Subsequent gluten exposure in such patients alters the morphology of their small bowel, elicits a flareup of their skin disease, and is associated with the reappearance of IgA in their epidermal basement membrane zones. As in patients with celiac disease, dietary gluten sensitivity in patients with DH is associated with IgA endomysial autoantibodies that target tissue transglutaminase. Studies indicate that patients with DH also have high-avidity IgA autoantibodies to epidermal transglutaminase 3 and that the latter is co-localized with granular deposits of IgA in the papillary dermis of DH patients. Patients with DH also have an increased incidence of thyroid abnormalities, achlorhydria, atrophic gastritis, and autoantibodies to gastric parietal cells. These associations likely relate to the high frequency of the HLA-B8/DRw3 haplotype in these patients, because this marker is commonly linked to autoimmune disorders. The mainstay of treatment of DH is dapsone, a sulfone. Patients respond rapidly (24–48 h) to dapsone (50–200 mg/d), but require careful pretreatment evaluation and close follow-up to ensure that complications are avoided or controlled. All patients taking dapsone at >100 mg/d will have some hemolysis and methemoglobinemia, which are expected pharmacologic side effects of this agent. Gluten restriction can control DH and lessen dapsone requirements; this diet must rigidly exclude gluten to be of maximal benefit. Many months of dietary restriction may be necessary before a beneficial result is achieved. Good dietary counseling by a trained dietitian is essential. LINEAR IgA DISEASE Linear IgA disease, once considered a variant form of DH, is actually a separate and distinct entity. Clinically, patients with linear IgA disease may resemble individuals with DH, BP, or other subepidermal blistering diseases. Lesions typically consist of papulovesicles, bullae, and/or urticarial plaques that develop predominantly on central or flexural sites. Oral mucosal involvement occurs in some patients. Severe pruritus resembles that seen in patients with DH. Patients with linear IgA disease do not have an increased frequency of the HLA-B8/DRw3 haplotype or an associated enteropathy and therefore are not candidates for treatment with a gluten-free diet. Histologic alterations in early lesions may be virtually indistinguishable from those in DH. However, direct immunofluorescence microscopy of normal-appearing perilesional skin reveals a linear band of IgA (and often C3) in the epidermal basement membrane zone. Most patients with linear IgA disease have circulating IgA basement membrane autoantibodies directed against neoepitopes in the proteolytically processed extracellular domain of BPAG2. These patients generally respond to treatment with dapsone (50–200 mg/d). EPIDERMOLYSIS BULLOSA ACQUISITA Epidermolysis bullosa acquisita (EBA) is a rare, noninherited, polymorphic, chronic, subepidermal blistering disease. (The inherited form is discussed in Chap. 427.) Patients with classic or noninflammatory EBA have blisters on noninflamed skin, atrophic scars, milia, nail dystrophy, and oral lesions. Because lesions generally occur at sites exposed to minor trauma, classic EBA is considered a mechanobullous disease. Other patients with EBA have widespread inflammatory scarring and bullous lesions that resemble severe BP. Inflammatory EBA may evolve into the classic, noninflammatory form of this disease. Rarely, patients present with lesions that predominate on mucous membranes. The HLA-DR2 haplotype is found with increased frequency in EBA patients. Studies suggest that EBA is sometimes associated with inflammatory bowel disease (especially Crohn’s disease). The histology of lesional skin varies with the character of the lesion being studied. Noninflammatory bullae are subepidermal, feature a sparse leukocytic infiltrate, and resemble the lesions in patients with porphyria cutanea tarda. Inflammatory lesions consist of neutrophilrich subepidermal blisters. EBA patients have continuous deposits of IgG (and frequently C3) in a linear pattern within the epidermal basement membrane zone. Ultrastructurally, these immunoreactants are found in the sublamina densa region in association with anchoring fibrils. Approximately 50% of EBA patients have demonstrable circulating IgG basement membrane autoantibodies directed against type VII collagen—the collagen species that makes up anchoring fibrils. Such IgG autoantibodies bind the dermal side of 1 M NaCl split skin (in contrast to IgG autoantibodies in patients with BP). Studies have shown that passive transfer of experimental or clinical IgG against type 374 PART 2 Cardinal Manifestations and Presentation of Diseases VII collagen can produce lesions in mice that clinically, histologically, and immunopathologically resemble those in patients with inflammatory EBA. Treatment of EBA is generally unsatisfactory. Some patients with inflammatory EBA may respond to systemic glucocorticoids, either alone or in combination with immunosuppressive agents. Other patients (especially those with neutrophil-rich inflammatory lesions) may respond to dapsone. The chronic, noninflammatory form of EBA is largely resistant to treatment, although some patients may respond to cyclosporine, azathioprine, or IVIg. MUCOUS MEMBRANE PEMPHIGOID Mucous membrane pemphigoid (MMP) is a rare, acquired, subepithelial immunobullous disease characterized by erosive lesions of mucous membranes and skin that result in scarring of at least some sites of involvement. Common sites include the oral mucosa (especially the gingiva) and conjunctiva; other sites that may be affected include the nasopharyngeal, laryngeal, esophageal, and anogenital mucosa. Skin lesions (present in about one-third of patients) tend to predominate on the scalp, face, and upper trunk and generally consist of a few scattered erosions or tense blisters on an erythematous or urticarial base. MMP is typically a chronic and progressive disorder. Serious complications may arise as a consequence of ocular, laryngeal, esophageal, or anogenital lesions. Erosive conjunctivitis may result in shortened fornices, symblepharon, ankyloblepharon, entropion, corneal opacities, and (in severe cases) blindness. Similarly, erosive lesions of the larynx may cause hoarseness, pain, and tissue loss that, if unrecognized and untreated, may eventuate in complete destruction of the airway. Esophageal lesions may result in stenosis and/or strictures that could place patients at risk for aspiration. Strictures may also complicate anogenital involvement. Biopsies of lesional tissue generally show subepithelial vesiculobullae and a mononuclear leukocytic infiltrate. Neutrophils and eosinophils may be seen in biopsies of early lesions; older lesions may demonstrate a scant leukocytic infiltrate and fibrosis. Direct immunofluorescence microscopy of perilesional tissue typically reveals deposits of IgG, IgA, and/or C3 in the epidermal basement membrane. Because many patients with MMP exhibit no evidence of circulating basement membrane autoantibodies, testing of perilesional skin is important diagnostically. Although MMP was once thought to be a single nosologic entity, it is now largely regarded as a disease phenotype that may develop as a consequence of an autoimmune reaction to a variety of molecules in the epidermal basement membrane (e.g., BPAG2, laminin-332, type VII collagen, and other antigens yet to be completely defined). Studies suggest that MMP patients with autoantibodies to laminin-332 have an increased relative risk for cancer. Treatment of MMP is largely dependent upon the sites of involvement. Due to potentially severe complications, patients with ocular, laryngeal, esophageal, and/or anogenital involvement require aggressive systemic treatment with dapsone, prednisone, or the latter in combination with another immunosuppressive agent (e.g., azathioprine, mycophenolate mofetil, cyclophosphamide, or rituximab) or IVIg. Less threatening forms of the disease may be managed with topical or intralesional glucocorticoids. AUTOIMMUNE SYSTEMIC DISEASES WITH PROMINENT CUTANEOUS FEATURES DERMATOMYOSITIS The cutaneous manifestations of dermatomyositis (Chap. 388) are often distinctive but at times may resemble those of systemic lupus erythematosus (SLE) (Chap. 378), scleroderma (Chap. 382), or other overlapping connective tissue diseases (Chap. 382). The extent and severity of cutaneous disease may or may not correlate with the extent and severity of the myositis. The cutaneous manifestations of dermatomyositis are similar, whether the disease appears in children or in the elderly, except that calcification of subcutaneous tissue is a common late sequela in childhood dermatomyositis. The cutaneous signs of dermatomyositis may precede or follow the development of myositis by weeks to years. Cases lacking muscle involvement (i.e., dermatomyositis sine myositis) have also been reported. The most common manifestation is a purple-red discoloration of the upper eyelids, sometimes associated with scaling (“heliotrope” erythema; Fig. 73-3) and periorbital edema. Erythema on the cheeks and nose in a “butterfly” distribution may resemble the malar eruption of SLE. Erythematous or violaceous scaling patches are common on the upper anterior chest, posterior neck, scalp, and the extensor surfaces of the arms, legs, and hands. Erythema and scaling may be particularly prominent over the elbows, knees, and dorsal interphalangeal joints. Approximately one-third of patients have violaceous, flat-topped papules over the dorsal interphalangeal joints that are pathognomonic of dermatomyositis (Gottron’s papules). Thin violaceous papules and plaques on the elbows and knees of patients with dermatomyositis are referred to as Gottron’s sign (Fig. 73-4). These lesions can be contrasted with the erythema and scaling on the dorsum of the fingers that spares the skin over the interphalangeal joints of some SLE patients. Periungual telangiectasia may be prominent in patients with dermatomyositis. Lacy or reticulated erythema may be associated with fine scaling on the extensor and lateral surfaces of the thighs and upper arms. Other patients, particularly those with long-standing disease, develop areas of hypopigmentation, hyperpigmentation, mild atrophy, and telangiectasia known as poikiloderma. Poikiloderma is rare in both SLE and scleroderma and thus can serve as a clinical sign that distinguishes dermatomyositis from these two diseases. Cutaneous changes may Figure 73-3 Dermatomyositis. Periorbital violaceous erythema characterizes the classic heliotrope rash. (Courtesy of James Krell, MD; with permission.) Figure 73-4 Gottron’s papules. Dermatomyositis often involves the hands as erythematous flat-topped papules over the knuckles. Periungual telangiectases are also evident. 375 CHAPTER 73 Immunologically Mediated Skin Diseases be similar in dermatomyositis and various overlap syndromes where thickening and binding down of the skin of the hands (sclerodactyly) as well as Raynaud’s phenomenon can be seen. However, the presence of severe muscle disease, Gottron’s papules, heliotrope erythema, and poikiloderma serves to distinguish patients with dermatomyositis. Skin biopsy of the erythematous, scaling lesions of dermatomyositis may reveal only mild nonspecific inflammation but sometimes may show changes indistinguishable from those found in SLE, including epidermal atrophy, hydropic degeneration of basal keratinocytes, edema of the upper dermis, and a mild mononuclear cell infiltrate. Direct immunofluorescence microscopy of lesional skin is usually negative, although granular deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone have been described in some patients. Treatment should be directed at the systemic disease. Topical glucocorticoids are sometimes useful; patients should avoid exposure to ultraviolet irradiation and aggressively use photoprotective measures, including broad-spectrum sunscreens. LUPUS ERYTHEMATOSUS The cutaneous manifestations of lupus erythematosus (LE) (Chap. 378) can be divided into acute, subacute, and chronic or discoid types. Acute cutaneous LE is characterized by erythema of the nose and malar eminences in a “butterfly” distribution (Fig. 73-5A). The erythema is often sudden in onset, accompanied by edema and fine scale, and correlated with systemic involvement. Patients may have widespread involvement of the face as well as erythema and scaling of the extensor surfaces of the extremities and upper chest (Fig. 73-5B). These acute lesions, while sometimes evanescent, usually last for days and are often associated with exacerbations of systemic disease. Skin biopsy of acute lesions may show only a sparse dermal infiltrate of mononuclear cells and dermal edema. In some instances, cellular infiltrates around blood vessels and hair follicles are notable, as is hydropic degeneration of basal cells of the epidermis. Direct immunofluorescence microscopy of lesional skin frequently reveals deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone. Treatment is aimed at control of systemic disease. Photoprotection is very important in this as well as in other forms of LE. Subacute cutaneous lupus erythematosus (SCLE) is characterized by a widespread photosensitive, nonscarring eruption. In most patients, renal and central nervous system involvement is mild or absent. SCLE may present as a papulosquamous eruption that resembles psoriasis or as annular polycyclic lesions that resemble those seen in erythema multiforme. In the papulosquamous form, discrete erythematous papules arise on the back, chest, shoulders, extensor surfaces of the arms, and dorsum of the hands; lesions are uncommon on the central face and the flexor surfaces of the arms as well as below the waist. These slightly scaling papules tend to merge into large plaques, some with a reticulate appearance. The annular form involves the same areas and presents with erythematous papules that evolve into oval, circular, or polycyclic lesions. The lesions of SCLE are more widespread but have less tendency for scarring than lesions of discoid LE. Skin biopsy reveals a dense mononuclear cell infiltrate around hair follicles and blood vessels in the superficial dermis, combined with hydropic degeneration of basal cells in the epidermis. Direct immunofluorescence microscopy of lesional skin reveals deposits of immunoglobulin(s) in the epidermal basement membrane zone in about one-half of these cases. A particulate pattern of IgG deposition throughout the epidermis has been associated with SCLE. Most SCLE patients have anti-Ro autoantibodies. Local therapy alone is usually unsuccessful. Most patients require treatment with aminoquinoline antimalarial drugs. Low-dose therapy with oral glucocorticoids is sometimes necessary. Photoprotective measures against both ultraviolet B and ultraviolet A wavelengths are very important. Discoid lupus erythematosus (DLE, also called chronic cutaneous LE) is characterized by discrete lesions, most often found on the face, scalp, and/or external ears. The lesions are erythematous papules or plaques with a thick, adherent scale that occludes hair follicles (follicular plugging). When the scale is removed, its underside shows small excrescences that correlate with the openings of hair follicles (so-called “carpet tacking”), a finding relatively specific for DLE. Longstanding lesions develop central atrophy, scarring, and hypopigmentation but frequently have erythematous, sometimes raised borders (Fig. 73-6). These lesions persist for years and tend to expand slowly. Up to 15% of patients with DLE eventually meet the American College of Rheumatology criteria for SLE. However, typical discoid lesions are frequently seen in patients with SLE. Biopsy of DLE lesions shows hyperkeratosis, follicular plugging, atrophy of the epidermis, hydropic degeneration of basal keratinocytes, and a mononuclear cell infiltrate adjacent to epidermal, adnexal, and microvascular basement membranes. Direct immunofluorescence microscopy demonstrates immunoglobulin(s) and complement deposits at the basement membrane zone in ~90% of cases. Treatment is focused on control of local cutaneous disease and consists mainly of photoprotection and topical or intralesional glucocorticoids. If local therapy is ineffective, use of aminoquinoline antimalarial agents may be indicated. SCLERODERMA AND MORPHEA The skin changes of scleroderma (Chap. 382) usually begin on the hands, feet, and face, with episodes of recurrent nonpitting edema. Sclerosis of the skin commences distally on the fingers (sclerodactyly) and spreads proximally, usually accompanied by resorption of bone of the fingertips, which may have punched out ulcers, stellate scars, or areas of hemorrhage (Fig. 73-7). The fingers may actually shrink and Figure 73-5 Acute cutaneous lupus erythematosus (LE). A. Acute cutaneous LE on the face, showing prominent, scaly, malar erythema. Involvement of other sun-exposed sites is also common. B. Acute cutaneous LE on the upper chest, demonstrating brightly erythematous and slightly edematous papules and plaques. (B, Courtesy of Robert Swerlick, MD; with permission.) 376 PART 2 Cardinal Manifestations and Presentation of Diseases become sausage-shaped, and, because the fingernails are usually unaffected, they may curve over the end of the fingertips. Periungual telangiectases are usually present, but periungual erythema is rare. In advanced cases, the extremities show contractures and calcinosis cutis. Facial involvement includes a smooth, unwrinkled brow, taut skin over the nose, shrinkage of tissue around the mouth, and perioral radial furrowing (Fig. 73-8). Matlike telangiectases are often present, particularly on the face and hands. Involved skin feels indurated, smooth, and bound to underlying structures; hyper- and hypopigmentation are common as well. Raynaud’s phenomenon (i.e., cold-induced blanching, cyanosis, and reactive hyperemia) is documented in almost all patients and can precede development of scleroderma by many years. Linear scleroderma is a limited form of disease that presents in a linear, bandlike distribution and tends to involve deep as well as superficial layers of skin. The combination of calcinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia has been termed the CREST syndrome. Centromere antibodies have been reported in a very high percentage of patients with the CREST syndrome but in only a small minority of patients with scleroderma. Skin biopsy reveals thickening of the dermis and homogenization of collagen bundles. Direct immunofluorescence microscopy of lesional skin is usually negative. Morphea is characterized by localized thickening and sclerosis of skin; it dominates on the trunk. This disorder may affect children or adults. Morphea begins as erythematous or flesh-colored plaques that become sclerotic, develop central hypopigmentation, and have an erythematous border. In most cases, patients have one or a few lesions, and the disease is termed localized morphea. In some patients, widespread cutaneous lesions may occur without systemic involvement (generalized morphea). Many adults with generalized morphea have concomitant rheumatic or other autoimmune disorders. Skin biopsy of morphea is indistinguishable from that of scleroderma. Scleroderma and morphea are usually quite resistant to therapy. For this reason, physical therapy to prevent joint contractures and to maintain function is employed and is often helpful. Treatment options for early, rapidly progressive disease include phototherapy (UVA1 or PUVA) or methotrexate (15–20 mg/week) alone or in combination with daily glucocorticoids. Diffuse fasciitis with eosinophilia is a clinical entity that can sometimes be confused with scleroderma. There is usually a sudden onset of swelling, induration, and erythema of the extremities, frequently following significant physical exertion. The proximal portions of the extremities (upper arms, forearms, thighs, calves) are more often involved than are the hands and feet. While the skin is indurated, it usually displays a woody, dimpled, or “pseudocellulite” appearance rather than being bound down as in scleroderma; contractures may occur early secondary to fascial involvement. The latter may also cause muscle groups to be separated and veins to appear depressed (i.e., the “groove sign”). These skin findings are accompanied by peripheralblood eosinophilia, increased erythrocyte sedimentation rate, and sometimes hypergammaglobulinemia. Deep biopsy of affected areas of skin reveals inflammation and thickening of the deep fascia overlying muscle. An inflammatory infiltrate composed of eosinophils and mononuclear cells is usually found. Patients with eosinophilic fasciitis appear to be at increased risk for developing bone marrow failure or other hematologic abnormalities. While the ultimate course of eosinophilic fasciitis is uncertain, many patients respond favorably to treatment with prednisone in doses of 40–60 mg/d. The eosinophilia-myalgia syndrome, a disorder with epidemic numbers of cases reported in 1989 and linked to ingestion of l-tryptophan manufactured by a single company in Japan, is a multisystem disorder characterized by debilitating myalgias and absolute eosinophilia in association with varying combinations of arthralgias, pulmonary symptoms, and peripheral edema. In a later phase (3–6 months after initial symptoms), these patients often develop localized sclerodermatous skin changes, weight loss, and/or neuropathy (Chap. 382). The precise cause of this syndrome, which may resemble other sclerotic skin conditions, is unknown. However, the implicated lots of l-tryptophan contained the contaminant 1,1-ethylidene bis[tryptophan]. This contaminant may be pathogenic or may be a marker for another substance that provokes the disorder. Figure 73-7 Scleroderma showing acral sclerosis and focal digital ulcers. Figure 73-8 Scleroderma often eventuates in development of an Figure 73-6 Discoid (chronic cutaneous) lupus erythematosus. expressionless, masklike facies. Violaceous, hyperpigmented, atrophic plaques, often with evidence of follicular plugging that may result in scarring, are typical. 377 CHAPTER 74 Cutaneous Drug Reactions Cutaneous Drug Reactions Kanade Shinkai, Robert S. Stern, Bruce U. Wintroub Cutaneous reactions are among the most frequent adverse reactions to drugs. Most are benign, but a few can be life threatening. Prompt recognition of severe reactions, drug withdrawal, and appropriate therapeutic interventions can minimize toxicity. This chapter focuses on adverse cutaneous reactions to systemic medications; it covers their incidence, patterns, and pathogenesis and provides some practical guidelines on treatment, assessment of causality, and future use of drugs. USE OF PRESCRIPTION DRUGS IN THE UNITED STATES In the United States, more than 3 billion prescriptions for over 60,000 drug products, which include more than 2000 different active agents, are dispensed annually. Hospital inpatients alone annually receive about 120 million courses of drug therapy, and half of adult Americans receive prescription drugs on a regular outpatient basis. Many patients use over-the-counter medicines that may cause adverse cutaneous reactions. INCIDENCE OF CUTANEOUS REACTIONS Several large cohort studies established that acute cutaneous reaction to drugs affected about 3% of hospital inpatients. Reactions usually occur a few days to 4 weeks after initiation of therapy. Many drugs of common use are associated with a 1–2% rate of rashes during premarketing clinical trials. The risk is often higher when medications are used in general, unselected populations. The rate may reach 3–7% for amoxicillin, sulfamethoxazole, many anticonvulsants, and anti-HIV agents. In addition to acute eruptions, a variety of skin diseases can be induced or exacerbated by prolonged use of drugs (e.g., pruritus, pigmentation, nail or hair disorders, psoriasis, bullous pemphigoid, photosensitivity, and even cutaneous neoplasms). These drug reactions are not frequent, but neither their incidence nor their impact on public health has been evaluated. In a series of 48,005 inpatients over a 20-year period, morbilliform rash (91%) and urticaria (6%) were the most frequent skin reactions. Severe reactions are actually too rare to be detected in such cohorts. Although rare, severe cutaneous reactions to drugs have an important impact on health because of significant sequelae, including mortality. Adverse drug rashes are responsible for hospitalization, increase the duration of hospital stay, and are life threatening. Some populations are at increased risk of drug reactions, including patients with collagen vascular diseases, bone marrow graft recipients, and those with acute Epstein-Barr virus infection. The pathophysiology underlying this association is unknown, but may be related to immunocompromise or immune dysregulation. Risk of drug allergy, including severe hypersensitivity reactions, is increased with HIV infection; individuals with advanced HIV disease 

Figure 74-9 Toxic epidermal necrolysis. (Photo credit: Lindy Peta Fox, MD, and Jubin Ryu, MD, PhD.) Table 74-2 Clinical and Laborat ory Findings Associated with More Serious Drug-Induced Cuta neous Clinical Findings Cutaneous Generalized erythema Facial edema Skin pain Palpable purpura Target lesions Skin necrosis Blisters or epidermal detachment Positive Nikolsky's sign Mucous membrane erosions Urticaria Swelling of tongue General High fever (temperature >40°C [>104°F]) Enlarged lymph nodes Arthralgias or arthritis Shortness of breath, wheezing, hypotension Laboratory Results Eosinophil count >1000/μL Lymphocytosis with atypical lymphocytes Abnormal liver or kidney function tests Source: Adapted from JC Roujeau, RS Stern: N Engl J Med 331:1272, 1994. 384 PART 2 Cardinal Manifestations and Presentation of Diseases The decision to continue or discontinue any medication will depend on the severity of the reaction, the severity of the primary disease, the degree of suspicion of causality, and the feasibility of an alternative safer treatment. In any potentially fatal drug reaction, elimination of all possible suspect drugs or unnecessary medications should be attempted. Some rashes may resolve when “treating through” a benign drug-related eruption. The decision to treat through an eruption should, however, remain the exception and withdrawal of every suspect drug the general rule. On the other hand, drugs that are not suspected and are important for the patient (e.g., antihypertensive agents) generally should not be quickly withdrawn. This approach prevents reluctance to future use of these agents. RECOMMENDATION FOR FUTURE USE OF DRUGS The aims are (1) to prevent the recurrence of the drug eruption and (2) not to compromise future treatments by contraindicating otherwise useful medications. Begin with thorough assessment of drug causality. Drug causality is evaluated based on timing of the reaction, evaluation of other possible causes, effect of drug withdrawal or continuation, and knowledge of medications that have been associated with the observed reaction. Combination of these criteria leads to considering the causality as definite, probable, possible, or unlikely. The RegiSCAR group has proposed a useful algorithm called Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) to determine drug causality in SJS/ TEN. A drug with a “definite” or “probable” causality should be contraindicated, a warning card or medical alert tag (e.g., wristband) should be given to the patient, and the drugs should be listed in the patient’s medical chart as an allergy. A drug with a “possible” causality may be submitted to further investigations depending on the expected need for future treatment. A drug with “unlikely” causality or that has been continued when the reaction improved or was reintroduced without a reaction can be administered safely. The usefulness of laboratory tests to determine causality is still debated. Many in vitro immunologic assays have been developed, but the predictive value of these tests has not been validated in any large series of affected patients; these tests exist primarily for research and not clinical purposes. In some cases, diagnostic rechallenge may be appropriate, even for drugs with high rates of adverse reactions. Desensitization is often successful in HIV-infected patients with morbilliform eruptions to sulfonamides but is not recommended in HIV-infected patients who manifested erythroderma or a bullous reaction in response to their earlier sulfonamide exposure. In patients with history suggesting immediate IgE-mediated reactions to penicillin, skin-prick testing with penicillins or cephalosporins has proved useful for identifying patients at risk of anaphylactic reactions to these agents. However, skin tests themselves carry a small risk of anaphylaxis. Negative skin tests do not totally rule out IgE-mediated reactivity, but the risk of anaphylaxis in response to penicillin administration in patients with negative skin tests is about 1%. In contrast, two-thirds of patients with a positive skin test experience an allergic response upon rechallenge. For patients with delayed-type hypersensitivity, the clinical utility of skin tests is more questionable. At least one of a combination of several tests (prick, patch, and intradermal) is positive in 50–70% of patients with a reaction “definitely” attributed to a single medication. This low sensitivity corresponds to the observation that readministration of drugs with negative skin testing resulted in eruptions in 17% of cases. CROSS-SENSITIVITY Because of the possibility of cross-sensitivity among chemically related drugs, many physicians recommend avoidance of not only the medication that induced the reaction but also all drugs of the same pharmacologic class. Table 74-3 Clinical Feat ures of Severe Cuta neous Drug React ions Diagnosis Mucosal Lesions Typical Skin Lesions Frequent Signs and Symptoms Alternative Causes Not Related to Drugs Stevens-Johnson syndrome Erosions usually at two or more sites Small blisters on dusky purpuric macules or atypical targets; rare areas of confluence; detachment ≤10% of body surface area Most cases involve fever 10–20% cause not determined Toxic epidermal necrolysisa Erosions usually at two or more sites Individual lesions like those seen in Stevens-Johnson syndrome; confluent erythema; outer layer of epidermis separates readily from basal layer with lateral pressure; large sheet of necrotic epidermis; total detachment of >30% of body surface area Nearly all cases involve fever, "acute skin failure," leukopenia 10–20% cause not determined Hypersensitivity syndrome Infrequent Severe exanthematous rash (may become purpuric), exfoliative dermatitis, facial edema 30–50% of cases involve fever, lymphadenopathy, hepatitis, nephritis, myocarditis, eosinophilia, atypical lymphocytes Cutaneous lymphoma Acute generalized exanthematous pustulosis About 20% erosions (mouth, tongue) Initially nonfollicular, small pustules overlying edematous erythema, sometimes leading to superficial erosions Fever, burning, pruritus, facial swelling, leukocytosis, hypocalcemia Infection Serum sickness or reactions resembling serum sickness Absent Morbilliform lesions, sometimes with urticarial plaques (typically polycyclic) Fever, arthralgias Infection Anticoagulant-induced necrosis Infrequent Erythema then purpura and necrosis, especially of fatty areas Pain in affected areas Disseminated intravascular coagulopathy, septicemia Angioedema Often involved Urticaria or swelling of central part of face Respiratory distress, cardiovascular collapse Insect stings, foods aOverlap of Stevens-Johnson syndrome and toxic epidermal necrolysis have features of both and attachment of 10–30% of body surface area may occur. Source: Adapted from JC Roujeau, RS Stern: N Engl J Med 331:1272, 1994. 385 CHAPTER 75 Photosensitivity and Other Reactions to Light Photosensitivity and Other Reactions to Light Alexander G. Marneros, David R. Bickers SOLAR RADIATION Sunlight is the most visible and obvious source of comfort in the environment. The sun provides the beneficial effects of warmth and vitamin D synthesis. However, acute and chronic sun exposure also has pathologic consequences. Few effects of sun exposure beyond those affecting the skin have been identified, but cutaneous exposure to sunlight is the major cause of human skin cancer and can have immunosuppressive effects as well. The sun’s energy reaching the earth’s surface is limited to components of the ultraviolet (UV) spectrum, the visible spectrum, and portions of the infrared spectrum. The cutoff at the short end of the UV spectrum at ~290 nm is due primarily to stratospheric ozone—formed by highly energetic ionizing radiation—that prevents penetration to the earth’s surface of the shorter, more energetic, potentially more harmful wavelengths of solar radiation. Indeed, concern about destruction of the ozone layer by chlorofluorocarbons released into the atmosphere has led to international agreements to reduce production of those chemicals. Measurements of solar flux showed a twentyfold regional variation in the amount of energy at 300 nm that reaches the earth’s surface. This variability relates to seasonal effects, the path that sunlight traverses through ozone and air, the altitude (a 4% increase for each 300 m of elevation), the latitude (increasing intensity with decreasing latitude), and the amount of cloud cover, fog, and pollution. The major components of the photobiologic action spectrum that are capable of affecting human skin include the UV and visible wavelengths between 290 and 700 nm. In addition, the wavelengths beyond 700 nm in the infrared spectrum primarily emit heat and in certain circumstances may exacerbate the pathologic effects of energy in the UV and visible spectra. The UV spectrum reaching the earth represents

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