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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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). 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.


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InternalMed_Harrison. 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).


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InternalMed_Harrison. 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 I. Primary cutaneous disorders A. Peripheral vascular disease (Chap. 302) 1. 2. B. Livedoid vasculopathy in the setting of venous hypertensionb


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InternalMed_Harrison. I. Primary cutaneous disorders A. Peripheral vascular disease (Chap. 302) 1. 2. 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. A. 1. 2. Hemoglobinopathies (Chap. 127) 3. Cryoglobulinemia,c cryofibrinogenemia 4. 5. 6. Antiphospholipid syndrome (Chap. 141) 7. Neuropathice (Chap. 417) 8. 9. Kaposi's sarcoma, acral angiodermatitis 10. B. Hands and feet 1. Raynaud's phenomenon (Chap. 302) 2. C. Generalized 1. Pyoderma gangrenosum, but most commonly legs 2. Calciphylaxis (Chap. 424) 3. Infections, e.g., dimorphic fungi, leishmaniasis 4. D. Face, especially perioral, and anogenital 1. Chronic herpes simplexf III. A. Behçet's syndrome (Chap. 387) B. Erythema multiforme major, Stevens-Johnson syndrome, TEN C.


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InternalMed_Harrison. D. Face, especially perioral, and anogenital 1. Chronic herpes simplexf III. 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. F. 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.


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InternalMed_Harrison. Abbreviation: TEN, toxic epidermal necrolysis. (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). 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


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InternalMed_Harrison. CHAPTER 72 Skin Manifestations of Internal Disease lesions. immunologically Mediated Skin Diseases Kim B. Yancey, Thomas J. Lawley A number of immunologically mediated skin diseases and immuno-logically mediated systemic disorders with cutaneous manifestations 73 PART 2 Cardinal Manifestations and Presentation of Diseases 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


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InternalMed_Harrison. 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 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.


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InternalMed_Harrison. 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. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. FIguRE 73-1 Pemphigus vulgaris. A. Flaccid bullae are easily ruptured, resulting in multiple erosions and crusted plaques.


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InternalMed_Harrison. 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.) 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 371 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


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InternalMed_Harrison. 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 treatment-resistant disease.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 160kDa 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 372 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 ageand gender-matched controls.


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InternalMed_Harrison. 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. PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 73-2 Bullous pemphigoid with tense vesicles and bullae on erythematous, urticarial bases. (Courtesy of the Yale Resident’s Slide Collection; with permission.)


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InternalMed_Harrison. 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 230and 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 auto-antibodies in patients with BP—a subepidermal bullous disease that resembles PG clinically, histologically, and immunopathologically.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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).


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InternalMed_Harrison. 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 gluten-free 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 associ-373 ated with IgA endomysial autoantibodies that target tissue transglutaminase. Studies indicate that patients with DH also have high-avidity IgA


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InternalMed_Harrison. gluten sensitivity in patients with DH is associ-373 ated 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,


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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).


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InternalMed_Harrison. 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).


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InternalMed_Harrison. 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 VII collagen can produce lesions in mice


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InternalMed_Harrison. 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 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.


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InternalMed_Harrison. 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,


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases 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


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InternalMed_Harrison. FIguRE 73-3 Dermatomyositis. Periorbital violaceous erythema characterizes the classic heliotrope rash. (Courtesy of James Krell, MD; with permission.) 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. FIguRE 73-4 Gottron’s papules. Dermatomyositis often involves the hands as erythematous flat-topped papules over the knuckles. Periungual telangiectases are also evident. 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


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InternalMed_Harrison. 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.) correlated with systemic involvement. Patients may have widespread 375 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 73-6 Discoid (chronic cutaneous) lupus erythematosus. Violaceous, hyperpigmented, atrophic plaques, often with evidence of follicular plugging that may result in scarring, are typical.


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InternalMed_Harrison. 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; hyperand 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 FIguRE 73-7 Scleroderma showing acral sclerosis and focal digi-tal ulcers. FIguRE 73-8 Scleroderma often eventuates in development of an expressionless, masklike facies.


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InternalMed_Harrison. FIguRE 73-7 Scleroderma showing acral sclerosis and focal digi-tal ulcers. FIguRE 73-8 Scleroderma often eventuates in development of an expressionless, masklike facies. 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.


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InternalMed_Harrison. 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 peripheral-blood 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. Cutaneous Drug Reactions Evidence suggests an immunologic basis for most acute drug eruptions. Drug reactions may result from immediate release of preformed


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InternalMed_Harrison. Cutaneous Drug Reactions Evidence suggests an immunologic basis for most acute drug eruptions. Drug reactions may result from immediate release of preformed Kanade Shinkai, Robert S. Stern, Bruce U. Wintroub mediators (e.g., urticaria, anaphylaxis), antibody-mediated reactions, 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.


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InternalMed_Harrison. 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. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 (e.g., CD4 T lymphocyte count <200 cells/μL) have a fortyto fiftyfold


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InternalMed_Harrison. drug allergy, including severe hypersensitivity reactions, is increased with HIV infection; individuals with advanced HIV disease (e.g., CD4 T lymphocyte count <200 cells/μL) have a fortyto fiftyfold increased risk of adverse reactions to sulfamethoxazole (Chap. 226).


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InternalMed_Harrison. Adverse cutaneous responses to drugs can arise as a result of immunologic or nonimmunologic mechanisms. Examples of responses that arise from nonimmunologic mechanisms are pigmentary changes related to dermal accumulation of medications or their metabolites; alteration of hair follicles by antimetabolites and signaling inhibitors; and lipodystrophy associated with metabolic effects of anti-HIV medications. These side effects are mostly toxic, predictable, and sometimes can be avoided in part by simple preventive measures.


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InternalMed_Harrison. immune complex deposition, and antigen-specific responses. Drug-specific T cell clones can be derived from the blood or from skin lesions of patients with a variety of drug allergies, strongly suggesting that these T cells play a role in drug allergy in an antigen-specific manner. Specific clones were obtained with penicillin G, amoxicillin, cephalosporins, sulfamethoxazole, phenobarbital, carbamazepine, and lamotrigine (medications that are frequently a cause of drug eruptions). Both CD4 and CD8 clones have been obtained; however, their specific roles in the manifestations of allergy have not been elucidated. Drug presentation to T cells was major histocompatibility complex (MHC)-restricted and may involve drug-peptide complex recognition by specific T cell receptors (TCRs).


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InternalMed_Harrison. Once a drug has induced an immune response, the final phenotype of the reaction probably depends on the nature of effectors: cytotoxic (CD8+) T cells in blistering and certain hypersensitivity reactions, chemokines for reactions mediated by neutrophils or eosinophils, and collaboration with B cells for production of specific antibodies for urticarial reaction. Immunologic reactions have recently been classified into further subtypes that provide a useful framework for designating adverse drug reactions based on involvement of specific immune pathways (Table 74-1).


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InternalMed_Harrison. Immediate Reactions Immediate reactions depend on the release of mediators of inflammation by tissue mast cells or circulating basophils. These mediators include histamine, leukotrienes, prostaglandins, bradykinins, platelet-activating factor, enzymes, and proteoglycans. Drugs can trigger mediator release either directly (“anaphylactoid” reaction) or through IgE-specific antibodies. These reactions usually manifest in the skin and gastrointestinal, respiratory, and cardiovascular systems (Chap. 376). Primary symptoms and signs include pruritus, urticaria, nausea, vomiting, abdominal cramps, bronchospasm, laryngeal edema, and, occasionally, anaphylactic shock with hypotension and death. They occur within minutes of drug exposure. Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, and radiocontrast media are frequent causes of direct mast cell degranulation or anaphylactoid reactions, which can occur on first exposure. Penicillins and muscle relaxants used in general


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InternalMed_Harrison. aspirin, and radiocontrast media are frequent causes of direct mast cell degranulation or anaphylactoid reactions, which can occur on first exposure. Penicillins and muscle relaxants used in general anesthesia are the most frequent causes of IgE-dependent reactions to drugs, which require prior sensitization. Release of mediators is triggered when polyvalent drug protein conjugates cross-link IgE molecules fixed to sensitized cells. Certain routes of administration favor different clinical patterns (e.g., gastrointestinal effects from oral route, circulatory effects from intravenous route).


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InternalMed_Harrison. Immune Complex–Dependent Reactions Serum sickness is produced by tissue deposition of circulating immune complexes with consumption of complement. It is characterized by fever, arthritis, nephritis, neuritis, edema, and a urticarial, papular, or purpuric rash (Chap. 385). First described following administration of nonhuman sera, it currently occurs in the setting of monoclonal antibodies and other similar medications. In classic serum sickness, symptoms develop 6 days or more after exposure to a drug, the latent period representing the time needed to synthesize antibody. Cutaneous or systemic vasculitis, a relatively rare complication of drugs, may also be a result of immune complex deposition (Chap. 385). Cephalosporin and other medications, including monoclonal antibodies such as infliximab, rituximab, and omalizumab, may be associated with clinically similar “serum sickness–like” reactions. The mechanism of this reaction is unknown but is unrelated to complement activation and


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InternalMed_Harrison. rituximab, and omalizumab, may be associated with clinically similar “serum sickness–like” reactions. The mechanism of this reaction is unknown but is unrelated to complement activation and immune complex formation.


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InternalMed_Harrison. Delayed Hypersensitivity While not completely understood, delayed hypersensitivity directed by drug-specific T cells is an important mechanism underlying the most common drug eruptions, i.e., morbilliform eruptions, and also rare and severe forms such as drug-induced hypersensitivity syndrome (DIHS) (also known PART 2 Cardinal Manifestations and Presentation of Diseases Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor. as drug rash with eosinophilia and systemic symptoms [DRESS]), acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (Table 74-1). Drug-specific T cells have been detected in these types of drug eruptions. For example, drug-specific cytotoxic T cells have been detected in the skin lesions of fixed drug eruptions and of TEN. In TEN, skin lesions contain T lymphocytes reactive to autologous lymphocytes and keratinocytes in a drug-specific, HLA-restricted, and perforin/ granzyme-mediated pathway.


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InternalMed_Harrison. The mechanism(s) by which medications result in T cell activation is unknown. Two hypotheses prevail: first, that the antigens driving these reactions may be the native drug itself or components of the drug covalently complexed with endogenous proteins, presented in association with HLA molecules to T cells through the classical antigen presentation pathway, or alternatively, through direct interaction of the drug/metabolite with the T cell receptor or peptide-loaded HLA (e.g., the pharmacologic interaction of drugs with immune receptors, or p-i hypothesis). Recent x-ray crystallography data characterizing binding between specific HLA molecules to particular drugs known to cause hypersensitivity reactions demonstrates unique alterations to the MHC peptide-binding groove, suggesting a molecular basis for T cell activation and the development of hypersensitivity reactions.


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InternalMed_Harrison. Genetic determinants may predispose individuals to severe responses to drugs. Polymorphisms in cytochrome P450 enzymes, drug acetylation, methylation (such as thiopurine methyltransferase activity and azathioprine), and other forms of metabolism (such as glucose-6-phosphate dehydrogenase) may increase susceptibility to drug toxicity or underdosing, highlighting a role for differential pharmacokinetic or pharmacodynamic effects.


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InternalMed_Harrison. Associations between drug hypersensitivities and HLA haplotypes also suggest a key role for immune mechanisms. Hypersensitivity to the anti-HIV medication abacavir is strongly associated with HLAB*57:01 (Chap. 226). In Taiwan, within a homogeneous Han Chinese population, a 100% association was observed between SJS/TEN (but not DIHS) related to carbamazepine and HLA-B*15:02. In the same population, another 100% association was found between SJS, TEN, or DIHS related to allopurinol and HLA-B*58:01. These associations are drug and phenotype specific; that is, HLA-specific T cell stimulation by medications leads to distinct reactions and may explain why the reaction patterns are so clinically diverse. However, the strong associations found in Taiwan have not been observed in other countries with more heterogeneous populations.


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InternalMed_Harrison. Recognition of the HLA associations with drug hypersensitiv ity has been acknowledged by recommendations to screen high-risk populations. Genetic screening for HLA-B*57:01 to prevent abacavir hypersensitivity, which carries a 100% negative predictive value when patch test confirmed and 55% positive predictive value generalizable across races, is becoming the clinical standard of care worldwide (number needed to treat = 13). The U.S. Food and Drug Administration recently mandated new labeling of carbamazepine recommending HLA-B*15:02 screening of Asian individuals prior to receiving a new prescription of the medication. The American College of Rheumatology has recommended HLA-B*58:01 screening of Han Chinese patients prescribed allopurinol. To date, screening for a single HLA (but not multiple HLA haplotypes) in specific populations has been determined to be cost-effective.


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InternalMed_Harrison. Several investigators have proposed that specific HLA haplotypes associated with drug hypersensitivity indeed play a pathogenic role; stimulation of carbamazepine-specific cytotoxic T lymphocytes (CTL) in the context of HLA-B*15:02 results in production of a putative mediator of keratinocyte necrosis in TEN. Other studies have identified CTLs reactive to carbamazepine that use highly restricted V-alpha and V-beta TCR repertoires in patients with carbamazepine hypersensitivity that are not found in carbamazepine-tolerant individuals. Although not yet clinically available, some investigators have suggested combined genetic testing for specific HLA haplotypes and functional screening for TCR repertoire to best identify patients at risk.


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InternalMed_Harrison. NONIMMuNE CuTANEOuS REACTIONS Exacerbation or Induction of Dermatologic Diseases A variety of drugs can exacerbate preexisting diseases or sometimes induce a disease that may or may not disappear after withdrawal of the inducing medication. For example, NSAIDs, lithium, beta blockers, tumor necrosis factor (TNF) α cytokine antagonists, interferon (IFN) α, and angiotensinconverting enzyme (ACE) inhibitors can exacerbate plaque psoriasis, whereas antimalarials and withdrawal of systemic glucocorticoids can worsen pustular psoriasis. The situation of TNF-α inhibitors is unusual, as this class of medications is used to treat psoriasis; however, in other cases, they may induce psoriasis (especially palmar-plantar) in patients being treated for other conditions. Acne may be induced by glucocorticoids, androgens, lithium, and antidepressants. Follicular papular or pustular eruptions of the face and trunk, sometimes mimicking acne, frequently occur with epidermal growth factor (EGF) receptor


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InternalMed_Harrison. androgens, lithium, and antidepressants. Follicular papular or pustular eruptions of the face and trunk, sometimes mimicking acne, frequently occur with epidermal growth factor (EGF) receptor antagonists. In the case of EGF-receptor antagonists, the severity of the eruption correlates with a better anticancer effect. It may be secondarily impetiginized and often spares areas of prior or active radiation. Tetracycline antibiotics, topical corticosteroids, and topical anti-acne treatments (such as benzoyl peroxide and clindamycin lotion) are helpful.


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InternalMed_Harrison. Several medications induce or exacerbate autoimmune disease. Interleukin (IL) 2, IFN-α, and anti-TNF-α are associated with new-onset systemic lupus erythematosus (SLE). Drug-induced lupus is classically marked by antinuclear and antihistone antibodies and, in some cases, anti-double-stranded DNA (D-penicillamine, anti-TNF-α) or p-ANCA (minocycline) antibodies. Minocycline and thiazide diuretics may exacerbate subacute SLE; pemphigus can be induced by D-penicillamine and ACE inhibitors. Furosemide is associated with drug-induced bullous pemphigoid. Vancomycin is associated with linear IgA bullous dermatitis, a transient blistering disorder.


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InternalMed_Harrison. Other medications may cause highly selective cutaneous reactions. Gadolinium contrast has been associated with nephrogenic systemic fibrosis, a condition of sclerosing skin with rare internal organ involvement; advanced renal compromise may be an important risk factor. Granulocyte colony-stimulating factor may induce various neutrophilic dermatoses, including Sweet syndrome and pyoderma gangrenosum. Both systemic and topical glucocorticoids cause a variety of atrophic skin changes, including atrophy and striae, and, in sufficiently high doses, can impede wound healing. The hypothesis that a drug may be responsible should always be considered, especially in cases with atypical clinical presentation. Resolution of the cutaneous reaction may be delayed upon discontinuation of the medication (e.g., lichenoid drug eruptions may take years to resolve).


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InternalMed_Harrison. Photosensitivity Eruptions Photosensitivity eruptions are usually most marked in sun-exposed areas but may extend to sun-protected areas. The mechanism is almost always phototoxicity. Phototoxic reactions resemble sunburn and can occur with first exposure to a drug. Blistering may occur in drug-related pseudoporphyria, most commonly with NSAIDs (Fig. 74-1). The severity of the reactions depends on the tissue level of the drug, its efficiency as a photosensitizer, and the extent of exposure to the activating wavelengths of ultraviolet (UV) light (Chap. 75). Common orally administered photosensitizing drugs include fluoroquinolones and tetracycline antibiotics. Other drugs less frequently encountered are chlorpromazine, thiazides, and NSAIDs. Voriconazole may result in severe photosensitivity, accelerated photo-induced aging, and cutaneous carcinogenesis in organ transplant recipients.


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InternalMed_Harrison. Because UV-A and visible light, which trigger these reactions, are not easily absorbed by nonopaque sunscreens and are transmitted through window glass, photosensitivity reactions may be difficult to block. Photosensitivity reactions abate with removal of either the drug or UV radiation, use of sunscreens that block UV-A light, and treating the reaction as one would a sunburn. Rarely, individuals develop persistent reactivity to light, necessitating long-term avoidance of sun 379 exposure.


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InternalMed_Harrison. Pigmentation Changes Drugs, either systemic or topical, may cause a variety of pigmentary changes in the skin. Oral contraceptives may induce melasma. Long-term minocycline, pefloxacin, and amiodarone may cause blue-gray pigmentation. Phenothiazine, gold, and bismuth result in gray-brown pigmentation of sun-exposed areas. Numerous cancer chemotherapeutic agents may be associated with characteristic patterns of pigmentation (e.g., bleomycin, busulfan, daunorubicin, cyclophosphamide, hydroxyurea, and methotrexate). Clofazimine causes a drug-induced lipofuscinosis with characteristic red-brown coloration. Hyperpigmentation of the face, mucous membranes, and pretibial and subungual areas occurs with antimalarials. Quinacrine causes generalized, cutaneous yellow discoloration. Pigmentation changes may also occur in mucous membranes (busulfan, bismuth), conjunctiva (chlorpromazine, thioridazine, imipramine, clomipramine), nails (zidovudine, doxorubicin, cyclophosphamide, bleomycin,


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InternalMed_Harrison. changes may also occur in mucous membranes (busulfan, bismuth), conjunctiva (chlorpromazine, thioridazine, imipramine, clomipramine), nails (zidovudine, doxorubicin, cyclophosphamide, bleomycin, fluorouracil, hydroxyurea), hair, and teeth (tetracyclines).


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InternalMed_Harrison. Warfarin Necrosis of Skin This rare reaction (0.01–0.1%) usually occurs between the third and tenth days of therapy with warfarin, usually in women. Common sites are breasts, thighs, and buttocks (Fig. 74-2). Lesions are sharply demarcated, indurated, and erythematous or purpuric and may progress to form large, hemorrhagic bullae with eventual necrosis and slow-healing eschar formation. These lesions can be life threatening.


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InternalMed_Harrison. Development of the syndrome is unrelated to drug dose, and the course is not altered by discontinuation of the drug after onset of the eruption. Warfarin anticoagulation in heterozygous protein C deficiency causes a precipitous fall in circulating levels of protein C, permitting hypercoagulability and thrombosis in the cutaneous microvasculature, with consequent areas of necrosis. Heparin-induced necrosis may have clinically similar features but is probably due to heparin-induced platelet aggregation with subsequent occlusion of blood vessels; it can affect areas adjacent to the injection site or more distant sites if infused. Warfarin-induced cutaneous necrosis is treated with vitamin K, heparin, surgical debridement, and intensive wound care. Treatment with protein C concentrates may also be helpful. Newer agents such as dabigatran etexilate may avoid warfarin necrosis in high-risk patients.


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InternalMed_Harrison. Drug-Induced Hair Disorders • dRUg-INdUCEd HAIR LOSS Medications may affect hair follicles at two different phases of their growth cycle: anagen (growth) or telogen (resting). Anagen effluvium occurs within days of drug administration, especially with antimetabolite or other chemotherapeutic drugs. In contrast, in telogen effluvium, the delay is 2 to 4 months following initiation of a new medication. Both present as diffuse nonscarring alopecia most often reversible after discontinuation FIguRE 74-1 Pseudoporphyria due to nonsteroidal anti-inflammatory drugs. FIguRE 74-2 Warfarin necrosis.


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InternalMed_Harrison. FIguRE 74-1 Pseudoporphyria due to nonsteroidal anti-inflammatory drugs. FIguRE 74-2 Warfarin necrosis. 380 of the responsible agent. The prevalence and severity of alopecia depend on the drug as well as on an individual’s predisposition. A considerable number of drugs have been reported to induce hair loss. These include antineoplastic agents (alkylating agents, bleomycin, vinca alkaloids, platinum compounds), anticonvulsants (carbamazepine, valproate), antihypertensive drugs (beta blockers), antidepressants, antithyroid drugs, IFNs (especially IFN-α), oral contraceptives, and cholesterol-lowering agents.


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InternalMed_Harrison. dRUg-INdUCEd HAIR gROwTH Medications may also cause hair growth. Hirsutism is an excessive growth of terminal hair with masculine hair growth pattern in a female, most often on the face and trunk, due to androgenic stimulation of hormone-sensitive hair follicles (anabolic steroids, oral contraceptives, testosterone, corticotropin). Hypertrichosis is a distinct pattern of hair growth, not in a masculine pattern, typically located on the forehead and temporal regions of the face. Drugs responsible for hypertrichosis include anti-inflammatory drugs, glucocorticoids, vasodilators (diazoxide, minoxidil), diuretics (acetazolamide), anticonvulsants (phenytoin), immunosuppressive agents (cyclosporine A), psoralens, and zidovudine.


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InternalMed_Harrison. Changes in hair color or structure are uncommon adverse effects from medications. Hair discoloration may occur with chloroquine, IFN-α, chemotherapeutic agents, and tyrosine kinase inhibitors. Changes in hair structure have been observed in patients given epidermal growth factor receptor (EGFR) inhibitors, tyrosine kinase inhibitors (Fig. 74-3), and acitretin. Drug-Induced Nail Disorders Drug-related nail disorders usually involve all 20 nails and need months to resolve after withdrawal of the offending agent. The pathogenesis is most often toxic. Drug-induced nail changes include Beau’s line (transverse depression of the nail plate), onycholysis (detachment of the distal part of the nail plate), onychomadesis (detachment of the proximal part of the nail plate), pigmentation, and paronychia (inflammation of periungual skin).


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InternalMed_Harrison. ONYCHOLYSIS Onycholysis occurs with tetracyclines, fluoroquinolones, phenothiazines, and psoralens, as well as in persons taking NSAIDs, captopril, retinoids, sodium valproate, and many chemotherapeutic agents such as anthracyclines or taxanes including paclitaxel and docetaxel. The risk of onycholysis in patients receiving cytotoxic drugs, tetracyclines, quinolones, phenothiazines, and psoralens can be increased by exposure to sunlight. ONYCHOMAdESIS Onychomadesis is caused by temporary arrest of nail matrix mitotic activity. Common drugs reported to induce onychomadesis include carbamazepine, lithium, retinoids, and chemotherapeutic agents such as cyclophosphamide and vincristine. PARONYCHIA Paronychia and multiple pyogenic granuloma (Fig. 74-4) with progressive and painful periungual abscess of fingers and toes PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 74-3 Dysmorphic eyelashes in association with erlotinib.


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 74-3 Dysmorphic eyelashes in association with erlotinib. FIguRE 74-4 Pyogenic granuloma in association with isotretinoin. are side effects of systemic retinoids, lamivudine, indinavir, and anti-EGFR monoclonal antibodies (cetuximab, gefitinib). NAIL dISCOLORATION Some drugs—including anthracyclines, taxanes, fluorouracil, psoralens, and zidovudine—may induce nail bed hyper-pigmentation through melanocyte stimulation. It appears to be reversible and dose-dependent. Toxic Erythema of Chemotherapy and Other Chemotherapy Reactions


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InternalMed_Harrison. Toxic Erythema of Chemotherapy and Other Chemotherapy Reactions Because many agents used in cancer chemotherapy inhibit cell division, rapidly proliferating elements of the skin, including hair, mucous membranes, and appendages, are sensitive to their effects. A broad spectrum of chemotherapy-related skin toxicities have been reported, including neutrophilic eccrine hidradenitis, sterile cellulitis, exfoliative dermatitis, and flexural erythema; although previously designated as distinct skin eruptions, recent nomenclature classifies these under the unifying diagnosis of toxic erythema of chemotherapy (TEC). Acral erythema, marked by dysesthesia and an erythematous, edematous eruption of the palms and soles, is caused by cytarabine, doxorubicin, methotrexate, hydroxyurea, and fluorouracil and may be alleviated by pyridoxine supplementation.


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InternalMed_Harrison. The recent introduction of many new monoclonal antibody and small molecular signaling inhibitors for the treatment of cancer has been accompanied by numerous reports of skin and hair toxicity; only the most common of these are mentioned here. Cetuximab and other EGFR antagonists induce follicular eruptions and nail toxicity after a mean interval of 10 days in a majority of patients. Xerosis, eczematous eruptions, acneiform eruptions, and pruritus are common. Erlotinib is associated with marked hair textural changes (Fig. 74-3). Sorafenib, a tyrosine kinase inhibitor, may result in follicular eruptions and bullous palmoplantar eruptions with dysesthesia (Fig. 74-5). BRAF inhibitors are associated with photosensitivity, dyskeratotic (Grover’s-like) rash, hyperkeratotic benign cutaneous neoplasms, and keratoacanthoma-like squamous cell carcinomas. Rash, pruritus, and vitiliginous depigmentation have been reported in association with ipilimumab (anti-CTLA4) treatment.


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InternalMed_Harrison. IMMuNE CuTANEOuS REACTIONS: COMMON Maculopapular Eruptions Morbilliform or maculopapular eruptions (Fig. 74-6) are the most common of all drug-induced reactions, often start on the trunk or intertriginous areas, and consist of erythematous macules and papules that are symmetric and confluent. Involvement of mucous membranes is unusual; the eruption may be associated with moderate to severe pruritus and fever. Diagnosis is rarely assisted by laboratory testing. Skin biopsy often shows nonspecific inflammatory changes. A viral exanthem is the principal differential diagnostic consideration, especially in children, and graft-versus-host disease is also a consideration in the proper clinical setting. Absence of enanthems; absence of ear, nose, throat, and upper respiratory tract symptoms; and polymorphism of the skin lesions support a drug rather than a viral eruption. Certain medications carry very high rates of morbilliform eruption, including nevirapine and lamotrigine, even in the


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InternalMed_Harrison. and polymorphism of the skin lesions support a drug rather than a viral eruption. Certain medications carry very high rates of morbilliform eruption, including nevirapine and lamotrigine, even in the absence of hypersensitivity reactions. Lamotrigine morbilliform rash is associated with higher starting doses, rapid dose escalation, concomitant use of valproate (which increases lamotrigine levels and half-life) and use in children, especially with seizure disorder.


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InternalMed_Harrison. FIguRE 74-5 Sorafenib-associated hand-foot syndrome. Maculopapular reactions usually develop within 1 week of initiation of therapy and last less than 2 weeks. Occasionally, these eruptions resolve despite continued use of the responsible drug. Because the eruption may also worsen, the suspect drug should be discontinued unless it is essential; it is important to note that the rash may continue to progress for a few days to up to one week following medication discontinuation. Oral antihistamines and emollients may help relieve pruritus. Short courses of potent topical glucocorticoids can reduce inflammation and symptoms. Systemic glucocorticoid treatment is rarely indicated.


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InternalMed_Harrison. Pruritus Pruritus is associated with almost all drug eruptions and, in some cases, may represent the only symptom of the adverse cutaneous reaction. It is usually alleviated by antihistamines such as hydroxyzine or diphenhydramine. Pruritus stemming from specific medications may require distinct treatment; opiate-related pruritus may require selective opiate antagonists to gain relief. Pruritus is a common complication of antimalarial therapy, occurring in up to 50% of black patients receiving chloroquine, and may be severe enough to lead to discontinuation of treatment. It is much rarer in Caucasians taking chloroquine. Intense pruritus, sometimes accompanied by an eczematous rash, may occur in 20% of patients receiving IFN and ribavirin for hepatitis C; addition of the protease inhibitor telaprevir may increase 381 this occurrence to 50% of treated patients. FIguRE 74-6 Morbilliform drug eruption.


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InternalMed_Harrison. FIguRE 74-6 Morbilliform drug eruption. urticaria/Angioedema/Anaphylaxis Urticaria, the second most frequent type of cutaneous reaction to drugs, is characterized by pruritic, red wheals of varying size rarely lasting more than 24 h. It has been observed in association with nearly all drugs, most frequently ACE inhibitors, aspirin, NSAIDs, penicillin, and blood products. However, medications account for no more than 10–20% of acute urticaria cases. Deep edema within dermal and subcutaneous tissues is known as angioedema and may involve respiratory and gastrointestinal mucous membranes as well. Urticaria and angioedema may be part of a life-threatening anaphylactic reaction.


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InternalMed_Harrison. Drug-induced urticaria may be caused by three mechanisms: an IgE-dependent mechanism, circulating immune complexes (serum sickness), and nonimmunologic activation of effector pathways. IgE-dependent urticarial reactions usually occur within 36 h of drug exposure but can occur within minutes. Immune complex–induced urticaria associated with serum sickness–like reactions usually occurs 6–12 days after first exposure. In this syndrome, the urticarial eruption (typically polycyclic plaques) may be accompanied by fever, hematuria, arthralgias, hepatic dysfunction, and neurologic symptoms. Certain drugs, such as NSAIDs, ACE inhibitors, angiotensin II antagonists, radiographic dye, and opiates, may induce urticarial reactions, angioedema, and anaphylaxis in the absence of drug-specific antibody through direct mast-cell degranulation.


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InternalMed_Harrison. Radiocontrast agents are a common cause of urticaria and, in rare cases, can cause anaphylaxis. High-osmolality radiocontrast media were about five times more likely to induce urticaria (1%) or anaphylaxis than were newer low-osmolality media. About one-third of those with mild reactions to previous exposure react on reexposure. Pretreatment with prednisone and diphenhydramine reduces reaction rates. Persons with a reaction to a high-osmolality contrast media may be given low-osmolality media if later contrast studies are required.


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InternalMed_Harrison. The treatment of urticaria or angioedema depends on the severity of the reaction. In severe cases with respiratory or cardiovascular compromise, epinephrine is the mainstay of therapy, but its effect is reduced in patients using beta blockers. Treatment with intravenous systemic glucocorticoids is helpful. For patients with urticaria without symptoms of angioedema or anaphylaxis, drug withdrawal and oral antihistamines are usually sufficient. Future drug avoidance is recommended; rechallenge, especially in individuals with severe reactions, should only occur in an intensive care setting. Anaphylactoid Reactions Vancomycin is associated with red man syndrome, a histamine-related anaphylactoid reaction characterized by flushing, diffuse maculopapular eruption, and hypotension. In rare cases, cardiac arrest may be associated with rapid IV infusion of the medication.


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InternalMed_Harrison. Irritant/Allergic Contact Dermatitis Patients using topical medications may develop an irritant or allergic contact dermatitis to the medication itself or to a preservative or other component of the formulation. Reactions to chlorhexidine, neomycin sulfate, and polymyxin B are common. Allergic contact dermatitis to topical glucocorticoids may also occur and is paradoxically partially masked by the anti-inflammatory nature of the medication itself; typically this allergy is selective for one of the four classes of glucocorticoid types, as subdivided by allergenic properties. Patch testing can be useful to determine whether a patient is steroid allergic. Desoximetasone is rarely allergenic.


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InternalMed_Harrison. Fixed Drug Eruptions These less common reactions are characterized by one or more sharply demarcated, dull red to brown lesions, sometimes with central bulla (Fig. 74-7). Hyperpigmentation often results after resolution of the acute inflammation. With rechallenge, the lesion recurs in the same (e.g., fixed) location. Lesions often involve the lips, hands, legs, face, genitalia, and oral mucosa and cause a burning sensation. Most patients have multiple lesions. Fixed drug eruptions have been associated with pseudoephedrine (frequently a nonpigmented reaction), phenolphthalein (in laxatives), sulfonamides, tetracyclines, NSAIDs, and barbiturates. FIguRE 74-7 Fixed drug eruption. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. FIguRE 74-7 Fixed drug eruption. PART 2 Cardinal Manifestations and Presentation of Diseases IMMuNE CuTANEOuS REACTIONS: RARE AND SEVERE Vasculitis Cutaneous small-vessel vasculitis often presents as palpable purpuric lesions that may be generalized or limited to the lower extremities or other dependent areas (Chap. 385). Pustular lesions and hemorrhagic blisters also occur. Vasculitis may involve other organs, including the liver, kidney, brain, and joints. Drugs are implicated as a cause of 10–15% of all cases of small-vessel vasculitides. Infection, malignancy, and collagen vascular disease are responsible for the majority of non-drug-related cases.


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InternalMed_Harrison. Propylthiouracil induces a cutaneous vasculitis that is accompanied by leukopenia and splenomegaly. Direct immunofluorescent changes in these lesions suggest immune-complex deposition. Common drugs implicated in vasculitis include allopurinol, thiazides, sulfonamides, antimicrobials, and NSAIDs. The presence of eosinophils in the perivascular infiltrate of skin biopsy suggests a drug etiology.


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InternalMed_Harrison. Pustular Eruptions AGEP is a rare reaction pattern (3–5 cases per million per year) that is often associated with exposure to drugs (Fig. 74-8). Usually beginning on the face or intertriginous areas, small nonfollicular pustules overlying erythematous and edematous skin may coalesce and lead to superficial erosion. Differentiating this eruption from TEN in its initial stages may be difficult. A skin biopsy is important and shows neutrophil collections and sparse necrotic keratinocytes in the upper part of the epidermis instead of the full-thickness epidermal necrosis that characterizes TEN. Fever and leukocytosis are common, and eosinophilia occurs in one-third of cases. Acute pustular psoriasis is the principal differential diagnostic consideration. DIHS with pustular features must also be clinically considered, although the timing for the onset of DIHS is distinct (much later onset). AGEP often begins within a few days of initiating drug treatment, most notably antibiotics, but may


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InternalMed_Harrison. be clinically considered, although the timing for the onset of DIHS is distinct (much later onset). AGEP often begins within a few days of initiating drug treatment, most notably antibiotics, but may occur as late as 7–14 days after initiation of treatment. A broad range of drug classes (anticonvulsants, mercury, radiocontrast dye) and infections (viral, Mycoplasma) are also associated with AGEP. Patch testing with the responsible drug results in a localized pustular eruption.


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InternalMed_Harrison. FIguRE 74-8 Acute generalized exanthematous pustulosis.


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InternalMed_Harrison. Drug-induced Hypersensitivity Syndrome Drug-induced hypersensitivity syndrome (DIHS) is a multiorgan drug reaction previously known as DRESS (drug reaction with eosinophilia and systemic symptoms); since eosinophilia is not always present, the term DIHS is now preferred. Allopurinol is the most common cause. Although less frequently prescribed, abacavir has been reported to cause DIHS with an incidence as high as 4–8%. It presents as a widespread erythematous eruption that may become purpuric, pustular, or lichenoid and is accompanied by many of the following features: fever, facial edema, lymphadenopathy, leukocytosis (often with atypical lymphocytes and eosinophilia), hepatitis, myositis (including myocarditis), and sometimes nephritis (with proteinuria) or pneumonitis. Distinct patterns of timing of onset and organ involvement may exist; e.g., allopurinol classically induces DIHS with renal involvement. Cardiac and lung involvement is more common with minocycline; gastrointestinal


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InternalMed_Harrison. of timing of onset and organ involvement may exist; e.g., allopurinol classically induces DIHS with renal involvement. Cardiac and lung involvement is more common with minocycline; gastrointestinal involvement is almost exclusively seen with abacavir, and some medications typically lack eosinophilia (abacavir, dapsone, lamotrigine). The cutaneous reaction usually begins 2–8 weeks after the drug is started and lasts longer than mild eruptions after drug cessation. Signs and symptoms may persist for several weeks, especially those associated with hepatitis. The eruption recurs with rechallenge, and cross-reactions among aromatic anticonvulsants, including phenytoin, carbamazepine, and barbiturates, are frequent. Other drugs causing this syndrome include sulfonamides and other antibiotics. Hypersensitivity to reactive drug metabolites, hydroxylamine for sulfamethoxazole, and arene oxide for aromatic anticonvulsants may be involved in the pathogenesis of DIHS. Reactivation of herpes


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InternalMed_Harrison. Hypersensitivity to reactive drug metabolites, hydroxylamine for sulfamethoxazole, and arene oxide for aromatic anticonvulsants may be involved in the pathogenesis of DIHS. Reactivation of herpes viruses, especially herpesvirus 6 and Epstein-Barr virus (EBV), has been frequently reported in this syndrome, although the causal role of viral infection has been debated. Recent research suggests that inciting drugs may reactivate quiescent herpes viruses, resulting in expansion of viral-specific CD8+ T lymphocytes with subsequent end-organ damage. Viral reactivation may be associated with a worse clinical prognosis. Mortality rates as high as 10% have been reported; mortality is highest in association with hepatitis. Systemic glucocorticoids (prednisone, 1–2 mg/kg daily) should be started with slow taper over 8–12 weeks. A steroid-sparing agent, such as mycophenolate mofetil, may be indicated in cases of rapid recurrence upon steroid taper. In all cases, rapid withdrawal of the suspected


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InternalMed_Harrison. slow taper over 8–12 weeks. A steroid-sparing agent, such as mycophenolate mofetil, may be indicated in cases of rapid recurrence upon steroid taper. In all cases, rapid withdrawal of the suspected drug is required. Given the severe long-term complications of myocarditis, patients should undergo cardiac evaluation if heart involvement is suspected by hypotension or arrhythmia. Patients should be closely monitored for resolution of organ dysfunction and for development of late-onset autoimmune thyroiditis (up to 6 months).


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InternalMed_Harrison. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis SJS and TEN are characterized by blisters and mucosal/epidermal detachment resulting from full-thickness epidermal necrosis in the absence of substantial dermal inflammation (Fig. 74-9). The term Stevens-Johnson syndrome describes cases with blisters developing on target lesions, dusky or purpuric macules in which mucosal involvement is significant, and total body surface area blistering and eventual detachment in <10% of cases. The term Stevens-Johnson syndrome/toxic epidermal necrolysis overlap is used to describe cases with 10–30% detachment, and TEN is used to describe cases with >30% detachment.