http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–13 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2015.1015725

REVIEW ARTICLE

Drug-induced skin reactions: a pathologist viewpoint Mahmoud Rezk Abdelwahed Hussein

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Department of Pathology, Faculty of Medicine, Assuit University Hospitals, Assuit University, Assuit, Egypt

Abstract

Keywords

Cutaneous drug reactions are common adverse effects that occur in about 2–3% of the hospitalized patients. They have both immunologic and non-immunologic underlying mechanisms. These reactions are clinically and histologically similar to dermatoses. Their significant clinical indicators include: history of drug intake, atypical clinical features and improvement after cessation of the offending drugs. Their diagnostic histological clues include the presence of mixed histological patterns, apoptotic keratinocytes, eosinophils (dermis and epidermis), papillary dermal edema and extravasations of erythrocytes. However, no single clinical or histological feature is specific of drug eruptions. This work attempts to classify the histomorphologic reactions to various drugs in defined categories for assistance in morphologic diagnosis.

Drug, eruptions, medications, reactions, skin

Introduction Several drugs are associated with adverse skin reactions. They include: antibiotics, non-steroidal anti-inflammatory drugs, anticonvulsants, antihypertensives, biologic and chemotherapeutic agents. After drug intake, the skin eruptions appear within few hour to several months1 and usually affect the trunk and extremities. They include exanthematous, urticarial/ angioedemal reactions2,3, fixed drug reactions, erythroderma and acute generalized exanthematous pustulosis1,4. Other clinical patterns include erythema multiforme/toxic epidermal necrolysis/Stevens-Johnson syndrome overlap, vesiculobullous, eczematous and purpuric drug reactions1. Based on the histological similarity to known skin inflammatory conditions, drug reactions show several histologic patterns including: perivascular, interface, spongiotic, psoriasiform, fibrosing, granulomatous, vasculitic and panniculitis-like inflammatory patterns. About 2% of adverse cutaneous reactions are life threatening mandating rapid diagnosis with withdrawal of the offending drugs. These medical emergencies include vasculitis, Stevens–Johnson syndrome, toxic epidermal necrolysis, drug eruption with eosinophilia and systemic symptoms syndrome and serum sickness-like syndrome5,6. The skin is the largest organ of the body. It contains several immune cells including Langerhans’s cells, dendritic cells, T-lymphocytes, macrophages and mast cells. In normal skin, B cells are almost absent and the lymphocytes are almost of Address for correspondence: Mahmoud Rezk Abdelwahed Hussein, Department of pathology, Faculty of Medicine, Assuit University, Assuit, Egypt. Tel: +093-2581258. Fax: +088-033-272727. E-mail: [email protected]

History Received 22 December 2014 Revised 20 January 2015 Accepted 29 January 2015 Published online 26 June 2015

T-cell type clustered in 1–3 rows around post-capillary venules of the papillary vascular plexus or adjacent to cutaneous appendages. The perivascular T cells are approximately evenly distributed between CD4+ inducer and CD8+ suppressor-cytotoxic T-cell subsets. Intraepidermal, directly subepidermal and other ‘‘free’’ lymphocytes are mostly of the CD8+ suppressor-cytotoxic T-cell subset. Intraepidermally localized T cells represent less than 2% of the total number of lymphocytes present in normal skin. Langerhans’ cells recognize antigens and present them to T-cell lymphocytes7–9. Cutaneous drug eruptions may reflect immunological (hypersensitivity reactions) or non-immunological factors (drug toxicity, overdose, photosensitivity, drug interactions and metabolic alterations)10. The immune response relies on the T cells, T-cell receptors and other as associated molecules such as major histocompatibility complex, cluster designations and co-stimulatory molecules. CD4+ T cells can produce several cytokines. CD8+ T cells contain cytotoxic cytoplasmic granules (T-cell-restricted intracellular antigen, granzyme B and perforin)11–13. T cells are involved in the development of drug reactions. Drugs can be recognized by alpha beta-T cell receptors14. In support, there is a predominant cytotoxic CD8+ T cells close to the keratinocytes with hydropic degeneration and apoptosis (intrinsic, extrinsic or direct mitochondrial inhibition)15. T cells mediate the inflammatory skin reaction through the release of several cytokines such as IL-5, IL-6, TNF-alpha and IFN-gamma. These mediators participate in the inflammatory phenomenon: vasodilatation, dermal edema and recruitment of inflammatory cells including eosinophils. The latter amplify the underlying immune response through the release of further proinflammatory mediators14,16,17.

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Figure 1. Exanthematous, urticarial and erythema multiforme like drug reactions. (A–C) Exanthematous drug reaction. There is focal parakeratosis, basal vacuolopathy (arrow), occasional apoptotic keratinocytes (arrowhead), perivascular, predominantly lymphocytic infiltrate with occasional eosinophils. Stains for fungi (PAS/diastase) are negative for fungal hyphae. (D–F) Urticarial drug reaction. There is subtle perivascular lymphocytic infiltrate with rare apoptotic keratinocytes (arrowhead) and suble basal vacuolopathy (arrow). Stains for fungi (PAS/diastase) are negative for fungal hyphae. (G–I) Erythema multiforme like drug reaction. There is pronounced basal vacuolopathy (arrow), destruction of the basal cell keratinocytes, papillary dermal edema, pigment incontinence, apoptotic keratinocytes and rare eosinophils in the dermis (three different magnifications were used for each photo).

General histological features of drug reactions The general histological clues to cutaneous drug reactions include the presence of multiple discrete foci of inflammation in a given biopsy specimen, overlapping/mixed histological patterns, basal vacuolopathy (vacuolar interface change), apoptotic keratinocytes (epidermis and adnexal epithelium), eosinophils (epidermis and dermis) and signs of acuteness (normal basket-woven cornified layer, telangiectasia of the dermal capillaries and venules with many neutrophils in their lumina, extravasation of erythrocytes and papillary dermal edema). Additional clues include subtle vascular injury (endothelial cell swelling), activated lymphocytes and maturational disturbance of keratinocytes (in chronic long standing drug reactions)18–21. Exanthematous drug reactions Exanthematous (erythematous) eruptions represent about 40% of all the cutaneous drug reactions in the hospitalized patients1,14,22. They occur with almost any medication, shortly after initiation of the offending medications up to a month after the therapy is started. Their clinical presentations include: generalized pruritic erythematous blanchable macules and papules that may progress to erythroderma.

Helpful histologic features to drug etiology include: superficial lymphocytic infiltrate containing eosinophils and sometimes neutrophils, basal vacuolopathy, rare apoptotic keratinocytes and little or no spread of lymphocytes into the papillary dermis and epidermis (Figure 1A–C)4,22. The differential diagnosis include: urticarias, viral exanthemas, connective tissue diseases and arthropod assault reactions. In urticarias, there is papillary dermal edema, both the perivascular and interstitial eosinophils, but usually no or only focal basal vacuolopathy and no apoptotic keratinocytes. In viral exanthemas, there is no or only focal interface changes, and eosinophils are absent. In connective tissue diseases (such as lupus erythematosus and dermatomyositis), epidermal atrophy, focal parakeratosis, basal vacuolopathy and dermal mucin deposition are clue to diagnosis23. In arthropod assault reactions, the infiltrate is denser, usually wedge shaped, rich with eosinophils with accentuation around the eccrine glands18–21. Urticarias- and angioedema-like drug reactions Drug-induced urticarias represent about 5% of all the cutaneous drug reactions2–4. They appear as raised, itchy, red blotches or wheals that are pale in the centre and have

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red base. Histologically, there is a papillary dermal edema with separation of the collagen fibers, dilated lymphatics and perivascular mixed inflammatory cell infiltrate (lymphocytes, eosinophils, neutrophils and mast cells). The presence of neutrophils and deep vascular plexus involvement is a clue to the drug-induced nature of the urticaria (Figure 1D–F)4,19,22. The differential diagnosis include: viral exanthemas, connective tissue diseases and arthropod assault reactions18–21.

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Vacuolar interface dermatitis-like drug reactions Vacuolar interface changes are general histological findings in drug eruptions. Their extent ranges from subtle to extensive basal vacuolopathy with apoptotic keratinocytes. Vacuolar interface dermatitis-like drug reactions include lesions that are histologically indistinguishable from erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis and lupus erythematosus and pityriasis lichenoides acuta18–21. In drug-induced erythema multiforme, sulfonamides and non-steroidal anti-inflammatory drugs are usually implicated. Clinically, drug induced cases of erythema multiforme are indistinguishable from the post-viral and post-herpetic cases. Histologically, there is basal vacuolopathy, apoptotic keratinocytes and lymphocytic tagging of the basal cell keratinocytes and pigment incontinence. Clues to drug etiology

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are: numerous dermal eosinophils and the acrosyringeal accentuation of the necrotic keratinocytes (Figure 1G–I). The latter is related to concentration of the drugs in the sweat with their direct toxic effects on the eccrine ductal epithelium. Sometimes these lesions are severe, with mucous membrane lesions and the clinical picture of the Stevens–Johnson syndrome. In the latter, there is extensive keratinocyte necrosis, with formation of basal or intraepidermal blisters18–21,24. Toxic epidermal necrolysis is a serious cutaneous reaction to drugs with an incidence ranging from 0.4 to 1.2 per million populations and a mortality rate approaching 40%. Sulfonamides, allopurinol and non-steroidal anti-inflammatory drugs are usually implicated. It is a medical emergency characterized by widespread full-thickness epidermal necrosis with involvement of more than 30% of the body surface area. There is severe involvement of the mucous membranes (oropharynx, eyes and genitalia). Histologically, there is a widespread epidermal necrosis, subepidermal blisters, little or no perivascular infiltrate and occasionally scattered dermal eosinophils (Figure 2A–C)1,5,6,25. Drug-induced lupus reactions can be induced by several drugs such as procainamide, isoniazid, hydralazine and quinidine26. Clinically, they resemble skin lesions of lupus erythematosus (systemic, subacute and chronic cutaneous lupus), but with the absence of autoimmune disease or

Figure 2. Toxic epidermal necrolysis, lupus erythematosus and lichenoid drug reactions. (A–C) Toxic epidermal necrolysis drug induced. There is extensive degeneration, necrosis of the epidermis and perivascular lymphocytic infiltrate with rare eosinophils. (D–F) Lupus erythematosus drug induced. The stratum corneum is orthokeratotic. There is band-like lymphocytic infiltrate, basal vacuolopathy (arrow), apoptotic keratinocytes (arrowhead) and rare dermal eosinophils. There is no thickening of the basement membrane. (G–I) Lichenoid drug reaction. There is parakeratosis, apoptotic keratinocytes (arrowhead), dermal elastosis, vague band like and perivascular lymphocytic infiltrate with rare eosinophils (three different magnifications were used for each photo).

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autoantibodies before the administration of the causative drugs. There is a reversal of manifestations within one year of drug cessation. Histologically, there is superficial and deep perivascular and interstitial lymphocytic infiltrate with rare eosinophils, basal vacuolopathy and apoptotic keratinocytes (Figure 2D–F). The differential diagnosis includes lupus erythematosus and graft versus host disease. Clues that favor lupus erythemaosus versus drug-induced lupus reactions include: epidermal atrophy, smudginess of the basement membrane, focal basal vacuolopathy, focal parakeratosis, less frequent apoptotic keratinocytes, dermal mucin deposition and the absence of acrosyringeal accentuation of apoptotic keratinocytes26. Neutrophils may be seen but interstitial infiltrate and eosinophils are absent27–29. In graft versus host disease, there is superficial and deep perivascular lymphocytic infiltrate. Dermal eosinophils are absent18–21. Drug-induced pityriasis lichenoides-like lesions with vacuolar interface changes should be differentiated from pityriasis lichenoides. Features that favor drug etiology are superficial perivascular lymphocytic infiltrate with eosinophils and neutrophils, basal vacuolopathy and apoptotic keratinocytes. No mounds of parakeratosis are noted. In contrast, in pityriasis lichenoides, there is superficial and deep perivascular lymphocytic infiltrate (no eosinophils) and mounds of parakeratosis18–21,30,31. Lichenoid drug reactions Lichenoid drug reactions are so-called due to their resemblance to lichen planus. Historically, lichen planus-like eruptions were reported in troops who took mepacrine in the World War II. They are rare lesions as compared to other drug eruptions32. Clinically, lichenoid drug reactions usually affect elderly with preferential involvement of the trunk and the extensor surfaces of the extremities. The lesions appear as large, dome-shaped scaly papules. They have some eczematous elements and usually leave a pronounced residual pigmentation. Histologically, there is hyperparakeratosis, acanthosis, subepidermal band-like lymphohistiocytic infiltrate with occasional eosinophils that extend to the middermal vascular plexus, basal vacuolopathy and apoptotic keratinocytes. Helpful clues that favor lichenoid drug reactions are: focal thinning of the epidermis, diminished granular layer, focal parakeratosis, abundant transepidermal necrotic keratinocytes, extravasation of the RBCs and deep extension of the lichenoid infiltrate. Additional features are mixed histologic patterns (psoriasiform or eczematous patterns), neutrophils in the lumens of the dilated venules in the papillary dermis and cytoid bodies in the cornified and granular layers (Figure 2G–I)33,34. Multinucleate histiocytic giant cells at dermoepidermal junction, epidermal or adnexal epithelium35 and solar elastosis are sometimes noted18–21,33,36. Lichenoid drug eruptions should be separated from lichen planus. Clinically, lichen planus usually affect middle-aged patients. The lesions appear as flat topped papules that involve the flexor aspects of the forearms, ankles, genetalia and oral mucosa. Histologically, there is repeatable hypergranulosis and the apoptotic keratinocytes are usually confined to the lower one-third of the epidermis.

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Parakeratosis is not a feature. The infiltrate is predominantly superficial band-like lymphocytic infiltrate. No eosinophils or histiocytes are noted. No dermal solar elastosis is noted33,35–38. Variants of lichenoid drug reactions include psoriasiform lichenoid dermatitis and giant cell lichenoid dermatitis35,37,38. The psoriasiform lichenoid drug reactions should be separated from mycosis fungoides. The latter is characterized by the presence of largish-lymphocytes along the basal cell keratinocytes, dense infiltrate of lymphocytes in the dermal papillae, lymphocytes in the epidermis are larger than the dermal lymphocytes, intraepidermal collections of atypical lymphocytes, fibrosis in the papillary dermis (wiry collagen fibers) and predominance of CD4 positive cells36,39. Fixed drug eruptions In fixed drug reactions, the site of the eruption is fixed, i.e. whenever the individual takes the same offending drug the eruptions occur exactly at the same site. They can involve any part of the integument or the mucous membranes, but the hands, feet, tongue, penis and the perianal regions are commonly involved. The causative drugs include: cotrimoxazole, naproxen sodium, dipyrone and dimenhydrinate40. The eruptions usually appear within few hours to few weeks after the intake of the offending drugs. They appear as sharply demarcated, round or oval itchy, red, or violet patches or plaques of erythema and edema. The lesions become dusky violaceous or brown and they fade with time leaving areas of pigmentation. Variants of fixed drug reactions include: pigmenting, generalized, multiple, linear, wandering, nonpigmenting, bullous, neutrophilic, eczematous, urticarial, erythema dyschromicum perstans-like, vulvitis-like, oral, psoriasiform and cellulitis-like fixed drug eruptions41–44. In early lesions of fixed drug reactions, there is interface dermatitis with basal vacuolopathy, lichenoid (lymphocytic) and perivascular infiltrates (lymphocytes, histiocytes, eosinophils, neutrophils and mast cells), pigment incontinence, apoptotic keratinocytes, papillary dermal edema and telangiectasia (Figure 3A–C). In old lesions, there is epidermal hyperplasia, hyperkeratosis, hypergranulosis, pigment incontinence and mild perivascular lymphocytic infiltrate18–21. The differential diagnosis includes erythema multiforme, acute graft-versus-host reaction, lichen planus, lichenoid drug reactions and erythema dyschromicum perstans. Clues that favor fixed drug reactions include: clinical settings, tendency for extension of the polymorphous inflammatory infiltrate (eosinophils and neutrophils) into the deep dermis, presence of numerous melanophages. In erythema multiforme, there is orthokeratosis, necrotic keratinocytes, subepidermal edema but eosinophils are usually absent. In acute graft-versus-host reactions, there is interface dermatitis (lymphocytic infiltrate) and apoptotic keratinocytes at all the levels of epidermis. Involvement of hair follicles and sweat glands is feature. Clinically, patients with fixed drug reactions present with larger plaques with more limited distribution than the papular lesions of lichen planus and lichenoid drug eruptions. Histologically, early lesions of fixed drug eruption lack hyperkeratosis or hypergranulosis. Absence of erythrocytes extravasation and hemosiderin deposition in fixed drug

Drug eruptions

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Figure 3. Fixed drug reactions, leukocytoclastic vasculitis drug induced and psoriasiform-like drug reactions. (A–C) Fixed drug reaction. Sections show focal parakeratosis, lichenoid interface changes with basal vacuolopathy (arrow), apoptotic keratinocytes, perivascular (predominantly lymphocytic with few eosinophils) infiltrates and extravasation of RBCs. (D–F) Drug-induced leukocytoclastic vasculitis. The changes are essentially confined to the small vessels of the superficial and mid dermis. There is swelling/degeneration of the endothelial cells of the blood vessels, perivascular infiltrate (lymphocytes, neutrophils and eosinophils) and leukocytoclasia (arrowhead). No fibrin deposition is seen. (G–I) Psoriasiform drug reaction. The stratum corneum shows hyperparakeratosis. The epidermis shows irregular psoriasiform acanthosis and occasional apoptotic keratinocytes (arrowhead), basal vacuolopathy (arrow) and perivascular inflammatory cell infiltrate (lymphocytes with rare eosinophil). Stains for fungi were performed and they were negative for fungal hyphae (three different magnifications were used for each photo).

reaction help separate fixed drug eruption from erythema dyschromicum perstans18–21,40–44.

vessels in the mid and deep dermis and subcutis. Vasculitis may involve the arterioles and small arteries18–21,45–47.

Drug-induced vasculitis

Psoriasiform drug reactions

Approximately 20% of cases of cutaneous vasculitis represent adverse drug eruptions. Offending drugs include antibiotics, thiazide diuretics, thiouracil, warfarin and coumarin and nonsteroidal anti-inflammatory drugs. Clinically, there are purpuric eruptions. Histologically, the changes are confined to the small vessels of the superficial and mid dermis and are usually associated with additional inflammatory reactions pattern (a histologic clue) such as interface vacuolar, spongiotic and psoriasiform patterns. The vasculitic changes may be histologically similar to leukocytoclastic vasculitis, lymphocytic vasculitis (endothelial swelling and perivascular lymphocytic infiltrate) and granulomatous vasculitis (perivascular aggregates of epithelioid and giant cells). Leukocytoclastic vasculitis drug-induced (necrosis of cutaneous blood vessel walls, leukocytoclasia, neutrophilic infiltration, fibrin deposition and hemorrhage) is the most common histologic type and should be separated from leukocytoclastic vasculitis associated with systemic disease (Figure 3D–F). In the latter, the vasculitic changes usually involve the blood

Several drugs such as lithium, calcium channel blockers, betablockers, biologic therapeutics (such as TNF-alpha inhibitors) and terbinafine can precipitate or exacerbate psoriasiform dermatitis (psoriasis, pustular psoriasis and Acrodermatitis Continua of Hallopeau)48–55. Clinically, psoriasiform drug eruptions present as erythematous plaques surmounted by large dry silvery scales. When compared to psoriasis, these lesions have different nature and distribution and are usually resistant to medications used for psoriasis56. Histologically, there is psoriasiform acanthosis (regular or irregular) and confluent parakeratosis with neutrophilic aggregates57. Other features include: basal vacuolopathy, overlapping/mixed patterns (eczematous and interface), apoptotic keratinocytes and perivascular lymphocytic infiltrate with few dermal eosinophils (Figure 3G–I)18–21,58. The differential diagnosis of psoriasiform drug reactions includes psoriasis, mycosis fungoides and syphilis. Histologic clues to psoriasiform drug etiology include the absence of psoriasiform diathesis (tortuous papillary dermal capillaries

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Figure 4. Pustular, bullous and spongiotic drug reaction. (A–C) Neutrophilic (pustular) drug reaction. There is psoriasiform acanthosis, multiple pustules (intraepidermal, arrowhead), basal vacuolopathy, apoptotic keratinocytes, aggregates of neutrophils and eosinophils (epidermis and dermis) and extravasation of RBCs. (D–F) Bullous drug reaction. There is intraepidermal blister and mild epidermal hyperplasia. Clues to drug etiology include: basket-weave hyperkeratosis, the presence of eosinophils as a predominant component of the inflammatory infiltrate, extension of the infiltrate into the mid and deep dermis, basal vacuolar change, scattered apoptotic keratinocytes (4-E: arrowhead) and extravasation of RBCs. (G–I) Spongiotic drug reaction. There is subtle spongiosis and mild epidermal hyperplasia. Clues to drug etiology include: basal vacuolar changes, rare apoptotic keratinocytes (arrowhead) and the presence of eosinophils in the dermal inflammatory infiltrate (three different magnifications were used for each photo).

and its related suprapapillary epidermal thinning) and the presence of some dermal eosinophils. Histologic clues to syphilis include: psoriasiform dermatitis with numerous dermal plasma cell infiltrate (dermis) together with the presence of epithelioid histiocytes and pallor of the keratinocytes18–21. Drug-induced psoriasiform lichenoid dermatitis should be separated from mycosis fungoides. Histologically, there is acanthosis, papillary dermal fibrosis, lichenoid pattern with some eosinophils and neutrophils in the lumens of the dermal blood vessels. CD4:CD8 ratio is usually 1:1. In mycosis fungoides, there is atypical/largish-lymphocytes along the basal cell keratinocytes, dense infiltrate of lymphocytes in the dermal papillae, lymphocytes in the epidermis are larger than the dermal lymphocytes, intraepidermal collections of atypical lymphocytes, fibrosis in the papillary dermis and prominent CD4 positive cells18–21,36,39. Neutrophilic (pustular) drug reactions Neutrophilic drug reactions include acute generalized exanthematous pustulosis59, Sweet’s syndrome-like drug reactions60, neutrophilic eccrine hidradenitis61, neutrophilc fixed drug reactions62,63, neutrophilic vasculitis64 and eosinophilic

pustular folliculitis65. They follow the intake of several drugs such as adalimumab, hydralazine, carbamazepine and naproxen. Clinically, they resemble neutrophilic dermatoses (pustular psoriasis and subcorneal pustular dermatosis)66. Histologically, there is basal vacuolopathy, apoptotic keratinocytes, aggregates of neutrophils (subcorneal, intraepidermal and subepidermal pustules) and eosinophils (epidermis and dermis; Figure 4A–C)18–21. Acute generalized exanthematous pustulosis is a rare clinical reaction pattern that follow the intake of systemic drugs such as paracetamol, terbinafine and antituberculous drugs59. Histologically, there is papillary dermal edema, eosinophil-exocytosis and apoptotic keratinocytes. Helpful clues that separate this condition from pustular psoriasis include the absence of psoriasiform diathesis (regular acanthosis and vascularized dermal papillae) and the presence of apoptotic keratinocytes and dermal eosinophils. In pustular psoriasis, there is psoriasiform diathesis and the eosinophils are absent. Sweet’s syndrome-like drug reactions is a rare condition that involves the extremities, face, trunk and neck. Neutrophilia and recurrent disease are uncommon. In contrast, in classic Sweet’s syndrome, there is preferential involvement of the head and neck regions. Neutrophilia and recurrent disease are common67,68. Neutrophilic eccrine

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hidradenitis is a rare complication of chemotherapeutics (such as cytarabine). Histologically, there is neutrophilic infiltrate around the eccrine glands and secretory coils18–21,61.

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Vesiculobullous drug reactions Vesiculobullous drug eruptions are noted in 2–5% of the inpatients and more than 1% of the outpatients. The offending drugs include: furosemide, dipeptidyl peptidase-IV inhibitors plus metformin, cephalexin and ciprofloxacin. Clinically, they resemble lesions of idiopathic vesiculobullous dermatitis69–72. Histologically, clues to drug etiology include: basal vacuolopathy, perivascular lymphocytic infiltrate with eosinophils and the presence of apoptotic keratinocytes. The differential diagnosis of bullous drug reactions includes: bullous pemphigoides and its urticarial phase, pemphigus, porphyria cutanea tarda, pseudoporphyria and linear-IgA dermatosis73,74. In urticarial drug reactions (bullous pemphigoides), there is basal vacuolopathy, apoptotic keratinocytes and neutrophils within the dermal venules. There is no clustering of eosinophils at the dermoepidermal junction and eosinophilic spongiosis is not a features (Figure 4D–F). In contrast, in urticarial phase of bullous pemphigoides, there is horizontal clustering of eosinophils at the dermoepidermal junction and in the superficial dermis. Eosinophilic spongiosis is a common finding. Apoptotic keratinocytes and neutrophils are usually absent75,76. Drug-induced pemphigus may follow the intake of penicillamine and captopril. Histologically, it is similar to pemphigus vulgaris and pemphigus foliaceus linearIgA dermatosis and drug-induced linear-IgA dermatosis are histologically indistinguishable. Correlation with the clinical history (intake of medications) and immunofluorescence studies are helpful. Cases with only IgA and no IgG in the basement membrane zone are more likely drug-induced linear-IgA dermatosis18–21,73,74. Drug-induced pseudoporphyria shows, apoptotic keratinocytes, rare dermal eosinophil, less PAS-positive material in vessel walls and less obvious ‘‘festooning’’ (persistence of dermal papillae in the base of the blister). Solar elastosis is not a feature. In porphyria cutanea tarda and pseudoporphyria, PAS-positive material in the vessel walls and ‘‘festooning’’ are more obvious. Apoptotic keratinocytes and dermal eosinophils are absent77. Spongiotic drug reactions Spongiotic drug eruptions represent about 5–10% of drug reactions and can be induced or exacerbated by topical or systemic medications such as vitamin K, imatinib, calcium channel blockers and BCG therapy. Clinically, there is nonspecific dermatitis that is usually widespread and pruritic. Histologically, the lesions may resemble allergic contact dermatitis, seborrheic dermatitis, nummular dermatitis, pityriasis rosea, Id-reactions, photosensitivity dermatitis, atopic dermatitis and erythroderma-like disorders. These drug reactions may have acute, subacute or chronic spongiotic histologic patterns4,18,78–81. Clues to drug-induced spongiotic lesions include: basket-weave hyperkeratosis, the presence of eosinophils as a predominant component of the inflammatory infiltrate, extension of the infiltrate into the mid and deep dermis, the presence of neutrophils (dermis), eosinophils in

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the epidermis and rare or absent scale/serum crust. Other features include: dilated venules filled with neutrophils, disproportionate exocytosis (conspicuous exocytosis of lymphocytes relative to the amount of spongiosis), mild epidermal hyperplasia, basal vacuolar change, scattered necrotic keratinocytes, papillary dermal edema, extravasation of RBCs, mixed patterns (such as overlapping interface and spongiotic dermatitis) and large activated lymphocytes (Figure 4G–I). Eczematous or chronic spongiotic drug reactions may have mycosis fungoides or lymphomatoid/ pseudolymphoma-like patterns18–21,82,83. The differential diagnosis includes acute, subacute and chronic spongiotic dermatitis. Features that favor spongiotic dermatitis over drug-induced spongiotic lesions include: parakeratosis with scale/serum crusts, and less eosinophils. Neutrophils are usually absent in the dermal infiltrate. Eosinophils in the epidermis are rare or absent18–21. Drug-induced photosensitivity reactions Drug-induced photosensitivity reactions refer to eruptions on sun exposed areas84. They represent up to 8% of cutaneous drug reactions and occur when a photosensitizing agent in or on the skin reacts to normally harmless doses of ultraviolet light85–87. Drug-induced photosensitivity reactions include: phototoxic reactions and photoallergic reactions, planus lichenoides reactions, pseudoporphyria, subacute cutaneous lupus erythematosus and photodistributed telangiectasias. Histologically, features common to drug-induced photosensitivity reactions include: apoptotic keratinocytes, basal vacuolopathy, eosinophils (dermis and epidermis), telangiectasia, solar elastosis and dermal stellate myofibroblasts. Drugs that can induce phototoxic drug reactions include antibiotics (tetracyclin), non-steroidal anti-inflammatory drugs (ketoprofen), diuretics (frusemide) and retinoids (isotrentinoin). These reactions are histologically similar to sun burn. In acute lesions, there is perivascular lymphohistiocytic infiltrate with some eosinophils and neutrophils and transepidermal keratinocyte apoptosis. In chronic lesions, there is hyperparakeratosis, hypergranulosis, irregular acanthosis, perivascular lymphocytic infiltrate and pigment incontinence (Figure 5A–C)85–87. Photoallergic drug reactions are less prevalent than phototoxic skin reactions and are associated with the intake of ketoprofen and celecoxib. These reactions are histologically similar to allergic contact dermatitis. Early drug-induced lesions show spongiosis, papillary dermal edema and perivasucalr lymphocytic infiltrate with eosinophils. Late lesions show irregular epidermal hyperplasia, hyperparakeratosis and perivascular lymphocytic infiltrate18–21,85–88. Lesions of photodistributed telangiectasia appear as asymptomatic widely distributed spider-like telangiectasia on the face, V area of the neck and the shoulders. Histologically, there are dilated capillaries without inflammatory infiltrate in the upper dermis18–21,89,90. Folliculitis- and perifolliculitis-like drug reactions Follicular and perifollicular drug reactions include acneiform drug eruptions, drug-induced eosinophilic pustular folliculitis

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Figure 5. Photosensitivity dermatitis like, granulomatous and lymphomatoid drug reactions. (A–C) Drug-induced photosensitivity reaction. There is psoriasiform acanthosis, subtle spongiosis, apoptotic keratinocytes (5-B: arrowhead), basal vacuolopathy, eosinophils (dermis and epidermis), perivascular lymphocytic infiltrate and dermal solar elastosis and dermal stellate myofibroblasts. (D–F) Granulomatous drug reaction. There is dermal lymphohistiocytic infiltrate with giant cells and some eosinophils. There is predominance of lymphocytes over histiocytes. No polarizable foreign bodies are noted. No collagen necrobiosis. Stains for fungi and acid fast bacilli were negative. No dermal mucin deposition is noted. (G–I) Lymphomatoid drug reaction. Sections show perivascular and nodular lymphocytic infiltrate with some eosinophils, basal vacuolopathy and apoptotic keratinocytes (arrowhead). There is no epidermotropism, lymphocytic atypism or wiry bundles of collagen in the papillary dermis (three different magnifications were used for each photo).

and drug-induced alopecia. Acneiform drug eruptions are associated with the intake of antituberculosis drugs, corticosteroids, neuropsychotherapeutic drugs, anabolic steroids, danazol, quinidine, azathioprine and testosterone. Clinically, these lesions resemble acne vulgaris and may be papulopustular, nodular or cystic. While acne vulgaris typically consists of comedones, acneiform drug eruptions usually lack comedones and the eruptions resolve with discontinuation of the therapy. Bacteriology and mycology are negative. Histologically, there is follicular dilatation, erosion of the infundibular epithelium, aggregates of neutrophils and a perifollicular lymphoneutrophilic infiltrate, including foreign body giant cells91,92. Drug-induced eosinophilic pustular folliculitis is associated with the intake of allopurinol, carbamazine, cyclophosphamide and methotrexate. Clinically, there are crops of pruritic follicular papulopustules with a tendency to form annular configurations, mainly on the scalp, face, trunk and extensor surfaces of the arms93,94. Histologically, there is follicular epithelial spongiosis with eosinophil microabscess formation, exocytosis and a perifollicular, perivascular lympho-eosinophilic infiltrate93,94. Drug-induced alopecia is usually associated with the intake of psychotropic drugs, valproic acid, antihypertensive drugs,

anticoagulant and antithyroid drugs and antimitotic agents. Clinically, there is diffuse, non-scarring hair loss that is reversible upon withdrawal of the drug. Histologically, features are those of telogen effluvium with catagen changes in many of the follicles95–97. Granulomatous drug reactions Granulomatous tissue reactions secondary to the administration of systemic medications or to local injection of agents are rare events. Common sites are the inner aspects of the arms, medial thighs, inter-triginous areas and the trunk. Histologically, there is interstitial granulomatous reaction (similar to incomplete form of granuloma annulare) and/or epithelioid cell granulomas98–100. In interstitial granulomatous drug reactions, the patients present with single or multiple erythematous to violaceous, non-pruritic plaques with an annular configuration. Histologically, there is infiltration of the interstitium by mixed inflammatory cells (lymphocytes, eosinophils, neutrophils and histiocytes), piecemeal collagen necrosis (collagen necrobiosis is not prominent), elastic fiber fragmentation, basal vacuolopathy and neutrophils in the lumens of the dilated venules. There is a general predominance of lymphocytes over histiocytes,

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extravasation of erythrocytes and possibly rare apopototic/ keratinocytes. Mucin deposition is usually absent. Histologically, these lesions should be separated from interstitial granuloma annulare. Features that favor the latter include: mucin deposition, prominent collagen necrobiosis and general predominance of histiocytes over lymphocytes. Also, basal vacuolopathy is not a feature18–21. In granulomatous drug reactions with granulomas, the epithelioid cell granulomas are usually seen in close proximity to the eccrine ducts (site of leakage of sweat, a possible cause of granulomas). Features that favor drug etiology include: the presence of basal vacuolopathy, apoptotic keratinocytes and eosinophils (dermis; Figure 5D–F)18–21,68,98–103. Lymphomatoid drug reactions Lymphomatoid drug reactions follow the intake of several drugs such as phenytoin and carbamazepine, angiotensin converting enzyme inhibitors, allopurinol and cyclosporine. The patients present clinically with patches, localized nodules, plaques or noduloplaques. Resolution of these lesions takes longer than for other patterns of drug reactions with some cases persisting for 6 months or more, after cessation of the offending drug. They include B-cell and T-cell pseudolymphomas. Their histologic patterns include nodular, diffuse, band-like and folliculitis-like morphology39. In drug-induced lesions, there is perivascular or lichenoid lymphocytic infiltrate with some eosinophils, basal vacuolopathy and apoptotic keratinocytes (Figure 5G–I). Clinical correlation, molecular analysis (immunohistochemistry and gene re-arrangement studies) are important to separate these conditions from lymphomas18–21,104,105. Lymphomatoid drug reactions should be separated from mycosis fungoides. In mycosis fungoides, there is lichenoid or psoriasiform-lichenoid infiltrate, lymphocytes monopolize, lymphocytes in the epidermis are accompanied by subtle spongiosis, wiry bundles of collagen and elongated mounds of parakeratosis. Narrow grenz zone separating areas of bandlike infiltration in the superficial dermis from the overlying epidermis, and lymphocyte atypia. Under oil examination, excessive gyrate nuclear convolutions often times transecting the nucleus are characteristic of mycosis fungoides. Any skin biopsy with upper dermal interstitial infiltrate of lymphocytes should prompt the consideration of mycosis fungoides. Hyperconvoluted cerebriform lymphocytes assuming a passive pattern of epidermal colonization typically present in epidermal lacunae. One of the most characteristic hallmarks of mycosis fungoides is a narrow grenz zone of uninvolved papillary dermis, which separates the neoplastic band-like infiltrate from the overlying epidermis18–21,106–108. Drug hypersensitivity reactions syndrome/DRESS syndrome Drug hypersensitivity reactions are rare idiosyncratic reactions. It is also known as the DRESS syndrome (drug rash with eosinophilia and systemic symptoms) is characterized by fever, widespread exantheme and organ toxicity. It can occur weeks to months after the intake of certain drugs such as allopurinol. A blood eosinophilia is often present. Patients with DRESS present with maculopapular eruptions, toxic

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epidermal necrolysis, Stevens–Johnson syndrome and facial edema. The histological features are largely non-specific and include apoptotic keratinocytes, basal vacuolopathy and papillary dermal edema. Associated patterns include lichenoid, mycosis fungoides-like pattern with activated lymphocytes, leukocytoclastic vasculitis and pseudolymphomatous pattern107,109. Final diagnosis is based on clinical criteria and specific laboratory values as indicated by the diagnostic score published by Kardaun and colleagues18–21,109. Drug-induced scleroderma-like skin lesions/fibrosing dermatitis Drug-induced sclerodermoid reactions may be associated with occupational exposure to polyvinyl chloride and following the intake of certain drugs such as bleomycin, valporic acid, Taxane, Methysergide and paclitaxel. Clinically, the patients present with skin fibrosis. Histologically, early lesions demonstrate an interstitial mononuclear inflammatory cell infiltrate. Late lesions exhibit full-layer dermal fibrosis with thickened collagen bundles (homogenized collagen), and perivascular monocytic cell infiltration including plasma cells, atrophy of the adnexal structures, loss of fat cushions around the eccrine secretary coils and dermal perivascular inflammatory cell infiltrate. Fibrosis may result from the stimulation of fibroblasts by cytokines such as TGF-b and platelet-derived growth factor18–21,110–115. Other forms drug reactions Other drug reactions include: halogenodermas, chemotherapy-induced interface dermatitis, pigmentary alterations, panniculitis, erythema nodosum, skin ulceration, Acni, hair gain (hirsutism), sweat gland necrosis, hypertrichosis, hemorrhagic infarction of the skin and Sweat gland necrosis in drug-induced comas18–21. Halogenodermas include iododerma, bromoderma and fluoroderma. They result from the ingestion of iodides, bromides and fluorides, respectively. Clinically, they present as verrucous plaques. Histologically, there is pseudoepitheliomatous hyperplasia with intraepidermal and some dermal abscesses containing few eosinophils and degenerated epithelial cells18–21,116–118. In chemotherapy-induced interface dermatitis, there is basal vacuolopathy, maturation arrest, keratinocyte pleomorphism, dyskeratosis and acanthosis. Clinical presentations include erythema, fissuring and ulceration on the palms, soles, as well as fingers and toes beginning with dysesthesia followed by edema and erythema. Histological changes include basal vacuolopathy, apoptotic keratinocytes and mild spongiosis, papillary dermal edema, dilated blood vessels and a sparse superficial perivascular lymphocytic infiltrate18–21,119,120. Pigmentary alterations (hypopigmentation and hyperpigmentation) may follow the intake of certain drugs such as minocycline, antimalarials drugs and phenytoin. This may result from increased or decreased melanin pigment production, deposition of lipofuscin or drug related materials in the dermis. In drug-induced persistent pigmented purpuric dermatosis, there is perivascular or lichenoid infiltrate with some eosinophils, vacuolar alterations and apoptotic keratinocytes.

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M. R. A. Hussein

Alteration of the dermal collagen is not a feature. This condition should be separated from persistent pigmented purpuric dermatosis. In the latter, there is perivascular and interstitial, sometimes lichenoid, infiltrate, lymphocytes, erythrocytes and siderophages. There is no changes in the epidermis basal vacuolopathy and dermal eosinophils are not a feature121,122. Panniculitis may result from the injection of some drugs. Erythema nodosum is a specific pattern of panniculitis sometimes associated with drug ingestion. Both erythema nodosum and drug-induced erythema nodosum are similar histologically. However, scant eosinophils are normal constituent of the septal inflammation and cannot be interpreted as an indication of underlying drug etiology18–21,123. Ulceration is an extremely rare complication of drugs. Allopurinol has been incriminated in the formation of a foot ulcer, resulting from a peripheral neuropathy124. Nicorandil, a potassium-channel activator used for treatment of ischemic heart disease, has been recently implicated as having a drug side effect of recurrent aphthous-like ulceration125. Drugs are important etiological factors in erythroderma (exfoliative dermatitis). It presents clinically as a generalized confluent erythematous rash, that may be associated with desquamation (exfoliative dermatitis), or systemic manifestations (fever, anorexia and lymphadenopathy)126,127. Nail changes occur after the intake of a large number of drugs. These changes include Beau’s lines (horizontal notches in the nail plate), brittle nails, onycholysis (separation of the nail plate from the nail bed), onychomadesis (separation of the nail plate from the matrix area, with progression to shedding) and paronychia (erythematous and tender nail folds)128,129. Key references Crowson AN, Brown TJ, Magro CM. Progress in the understanding of the pathology and pathogenesis of cutaneous drug eruptions: implications for management. American Journal of Clinical Dermatology 2003;4(6):407–428. PubMed PMID: 12762833. Epub 2003/05/24. eng. Weyers W, Metze D. Histopathology of drug eruptions – general criteria, common patterns, and differential diagnosis. Dermatology Practical & Conceptual 2011;1(1):33–47. PubMed PMID: 24396718. Pubmed Central PMCID: 3881081. Naim M, Weyers W, Metze D. Histopathologic features of exanthematous drug eruptions of the macular and papular type. The American Journal of Dermatopathology 2011 Oct;33(7):695–704. PubMed PMID: 21785331. Epub 2011/ 07/26. eng. Turk BG, Gunaydin A, Ertam I, Ozturk G. Adverse cutaneous drug reactions among hospitalized patients: five year surveillance. Cutaneous and Ocular Toxicology 2013 Mar;32(1):41–45. PubMed PMID: 22812902. Gerson D, Sriganeshan V, Alexis JB. Cutaneous drug eruptions: a 5-year experience. Journal of the American Academy of Dermatology 2008 Dec;59(6):995–999. PubMed PMID: 19022101. Research questions –

What are the key cytokines involved in the development of drug reactions?

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Compare and contrast the role of T-cells and macrophages in the pathogenesis of drug reactions? Compare and contrast the role of apoptotic and proapoptotic molecules in the development of drug reactions? What are the epigenetic mechanisms involved in the pathogenesis of drug reactions?

The main messages of the article  





Cutaneous drug reactions are common complications in the hospitalized patients. Important clinical clues to drug reaction include: history of drug intake, atypical clinical features and improvement after cessation of the offending drugs. The general histological clues to cutaneous drug reactions include: the presence of multiple discrete foci of inflammation in a given biopsy specimen, overlapping/ mixed histological patterns, basal vacuolopathy (vacuolar interface change), apoptotic keratinocytes (epidermis and adnexal epithelium), eosinophils (epidermis and dermis), and signs of acuteness. On histology, drug reactions can resemble any dermatoses. Important histologic clue include mixed histological patterns, apoptotic keratinocytes, eosinophils (dermis and epidermis), papillary dermal edema and extravasations of erythrocytes.

Conclusions Drug eruptions are manifestations of intolerance to drugtherapy. With an ever-increasing number of medications available for use, the list of drugs that is responsible for cutaneous drug eruptions also grows. These lesions include a wide spectrum of clinical and histological phenotypes. Common variants are exanthematous, urticarial and fixed drug reactions. Life-threatening drug reactions include exfoliative dermatitis, Stevens–Johnson syndrome and toxic epidermal necrolysis. The presence of perivascular and interstitial infiltrate of neutrophils and eosinophils together with basal vacuolopathy and apoptotic keratinocytes are important histologic features of drug eruptions. Sometimes, the clinical and histologic features of drug eruptions are difficult to place into one of the distinct histological or clinical patterns. In sum, an inflammatory pattern that does not correspond to any well-defined disease entity should raise the possibility of drug eruptions. Multiple choice questions The following histologic findings favor the diagnosis of lichen planus: – Dermal lichenoid infiltrate (true) – Basal vacuolopathy (true) – Periodic hypergranulosis (true) – Dermal eosinophils (false) In drug reactions, the histologic features of acuteness include: – Telangiectasia of the dermal capillaries (true) – Parakeratosis (false) – Extravasation of erythrocytes (true) – Papillary dermal edema (true)

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DOI: 10.3109/15569527.2015.1015725

Histologic clues to drug etiology in exanthematous skin eruptions include: – Dense deep dermal infiltrate (perivascular and periadnexal distribution) (false) – Occasional dermal eosinophils in the papillary dermis (true) – Basal vacuolopathy (true) – Rare apoptotic keratinocytes (true) Lymphomatoid drug reactions are characterized by: – Dense dermal lymphocytic infiltrate (perivascular, nodular, lichenoid or diffuse patterns) with some eosinophils (true) – Apoptotic keratinocytes (true) – Disproportionate spongiosis (false) – Lymphocyte atypia (hyperconvoluted cerebriform lymphocytes with excessive gyrate nuclear convolutions often times transecting the nucleus) (false) Clinical and histologic findings that favor the diagnosis of psoriasiform drug reactions over psoriasis includes – History of drug intake (true) – Irregular psoriasiform acanthosis (true) – Features of the psoriasiform diathesis (tortuous papillary dermal capillaries and suprapapillary epidermal thinning) (false) – Basal vacuolopathy and some dermal eosinophils (true)

Declaration of interest The author reports no conflicts of interest. The author alone is responsible for the content and writing of this article.

References 1. Turk BG, Gunaydin A, Ertam I, Ozturk G. Adverse cutaneous drug reactions among hospitalized patients: five year surveillance. Cutan Ocul Toxicol 2013;32:41–45. 2. Cousin F, Phillips K, Larbre JP, et al. Drug-induced urticaria. Ann Dermatol Venereol 2001;128:1166–1173. 3. Cousin F, Philips K, Favier B, et al. Drug-induced urticaria. Eur J Dermatol 2001;11:181–187. 4. Crowson AN, Brown TJ, Magro CM. Progress in the understanding of the pathology and pathogenesis of cutaneous drug eruptions: implications for management. Am J Clin Dermatol 2003;4:407–428. 5. Wolf R, Matz H, Marcos B, Orion E. Drug rash with eosinophilia and systemic symptoms vs toxic epidermal necrolysis: the dilemma of classification. Clin Dermatol 2005;23:311–314. 6. Wolf R, Orion E, Marcos B, Matz H. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol 2005;23: 171–181. 7. Bos JD, Zonneveld I, Das PK, et al. The skin immune system (SIS): distribution and immunophenotype of lymphocyte subpopulations in normal human skin. J Invest Dermatol 1987;88: 569–573. 8. Kanitakis J. Anatomy, histology and immunohistochemistry of normal human skin. Eur J Dermatol 2002;12:390–399 (quiz 400–401). 9. Hussein MR. Dendritic cells and melanoma tumorigenesis: an insight. Cancer Biol Ther 2005;4:501–505. 10. McKenna JK, Leiferman KM. Dermatologic drug reactions. Immunol Allergy Clin North Am 2004;24:399–423. 11. Hussein MR. Tumour-infiltrating lymphocytes and melanoma tumorigenesis: an insight. Br J Dermatol 2005;153:18–21. 12. Hussein MR. Tumour-associated macrophages and melanoma tumourigenesis: integrating the complexity. Int J Exp Pathol 2006; 87:163–176.

Drug eruptions

11

13. Hussein MR. Cutaneous pseudolymphomas: inflammatory reactive proliferations. Expert Rev Hematol 2013;6:713–733. 14. Pichler WJ, Yawalkar N, Britschgi M, et al. Cellular and molecular pathophysiology of cutaneous drug reactions. Am J Clin Dermatol 2002;3:229–238. 15. Au JS, Navarro VJ, Rossi S. Drug-induced liver injury – its pathophysiology and evolving diagnostic tools [Review]. Aliment Pharmacol Ther 2011;34:11–20. 16. Yawalkar N, Egli F, Hari Y, et al. Infiltration of cytotoxic T cells in drug-induced cutaneous eruptions. Clin Exp Allergy 2000;30: 847–855. 17. Yawalkar N, Pichler WJ. Immunohistology of drug-induced exanthema: clues to pathogenesis. Curr Opin Allergy Clin Immunol 2001;1:299–303. 18. Crowson AN, Magro CM. Recent advances in the pathology of cutaneous drug eruptions. Dermatol Clin 1999;17:537–560, viii. 19. Justiniano H, Berlingeri-Ramos AC, Sanchez JL. Pattern analysis of drug-induced skin diseases. Am J Dermatopathol 2008;30: 352–369. 20. Gerson D, Sriganeshan V, Alexis JB. Cutaneous drug eruptions: a 5-year experience. J Am Acad Dermatol 2008;59:995–999. 21. Weyers W, Metze D. Histopathology of drug eruptions – general criteria, common patterns, and differential diagnosis. Dermatol Pract Concept 2011;1:33–47. 22. Naim M, Weyers W, Metze D. Histopathologic features of exanthematous drug eruptions of the macular and papular type. Am J Dermatopathol 2011;33:695–704. 23. Crowson AN, Magro C. The cutaneous pathology of lupus erythematosus: a review. J Cutan Pathol 2001;28:1–23. 24. Zohdi-Mofid M, Horn TD. Acrosyringeal concentration of necrotic keratinocytes in erythema multiforme: a clue to drug etiology. Clinicopathologic review of 29 cases. J Cutan Pathol 1997;24:235–240. 25. Wolkenstein PE, Roujeau JC, Revuz J. Drug-induced toxic epidermal necrolysis. Clin Dermatol 1998;16:399–408. 26. Callen JP. Drug-induced subacute cutaneous lupus erythematosus. Lupus 2010;19:1107–1111. 27. Harnett DT, Chandra-Sekhar HB, Hamilton SF. Drug-induced lupus erythematosus presenting with cardiac tamponade: a case report and literature review. Can J Cardiol 2014;30:247. e11–247.e12. 28. Pretel M, Marques L, Espana A. Drug-induced lupus erythematosus. Acta Dermo-Sifiliograficas 2014;105:18–30. 29. Wagner G, Sachse MM. Drug-induced subacute cutaneous lupus erythematosus: repeated occurrence following treatment with terbinafine. Hautarzt 2014;65:548–552. [in German]. 30. Stosiek N, Peters KP, von den Driesch P. Pityriasis-lichenoides-etvarioliformis-acuta-like drug exanthema caused by astemizole. Hautarzt 1993;44:235–237. [in German]. 31. Machan M, Loren R, Fraga G, Liu D. Pityriasis lichenoides et varioliformis acuta associated with subcutaneous immunoglobulin administration. J Am Acad Dermatol 2012;67:e151–e152. 32. ATYPICAL lichen planus and mepacrine. Lancet 1945;2: 711–713. 33. Van den Haute V, Antoine JL, Lachapelle JM. Histopathological discriminant criteria between lichenoid drug eruption and idiopathic lichen planus: retrospective study on selected samples. Dermatologica 1989;179:10–13. 34. Halevy S, Shai A. Lichenoid drug eruptions. J Am Acad Dermatol 1993;29:249–255. 35. Khelifa-Hamdani E, Touati-Serraj M, Perriard J, et al. Giant cell lichenoid dermatitis in a patient with baboon syndrome. J Cutan Pathol 2008;35:17–19. 36. Clark SH, Duvic M, Prieto VG. Mycosis fungoides-like reaction in a patient treated with Gleevec. J Cutan Pathol 2003;30: 279–281. 37. Cordoba S, Fraga J, Bartolome B, et al. Giant cell lichenoid dermatitis within herpes zoster scars in a bone marrow recipient. J Cutan Pathol 2000;27:255–257. 38. Hussein MR, Aboulhagag NM, Atta HS, Atta SM. Evaluation of the profile of the immune cell infiltrate in lichen planus, discoid lupus erythematosus, and chronic dermatitis. Pathology 2008;40: 682–693. 39. Hussein MR. Atypical lymphoid proliferations: the pathologist’s viewpoint. Expert Rev Hematol 2013;6:139–153.

Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by University of Otago on 07/28/15 For personal use only.

12

M. R. A. Hussein

40. Ozkaya-Bayazit E, Bayazit H, Ozarmagan G. Drug related clinical pattern in fixed drug eruption. Eur J Dermatol 2000;10:288–291. 41. Ghislain PD, Ghislain E. Fixed drug eruption due to fluconazole: a third case. J Am Acad Dermatol 2002;46:467. 42. Ozkaya-Bayazit E. Specific site involvement in fixed drug eruption. J Am Acad Dermatol 2003;49:1003–1007. 43. Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol 1998;37:833–838. 44. Fischer G. Vulvar fixed drug eruption. A report of 13 cases. J Reprod Med 2007;52:81–86. 45. Mullick FG, McAllister Jr HA, Wagner BM, Fenoglio Jr JJ. Drug related vasculitis. Clinicopathologic correlations in 30 patients. Hum Pathol 1979;10:313–325. 46. Brandi G, Venturi M, Dika E, et al. Cutaneous leukocytoclastic vasculitis due to erlotinib: just an adverse event or also a putative marker of drug efficacy? Cutan Ocul Toxicol 2013;32:336–338. 47. Radic M, Kaliterna MD, Radic J. Drug-induced vasculitis: a clinical and pathological review. Neth J Med 2012;70:12–17. 48. Whittam LR, Wakelin SH, Barker JN. Generalized pustular psoriasis or drug-induced toxic pustuloderma? The use of patch testing. Clin Exp Dermatol 2000;25:122–124. 49. Nishiwaki F, Matsumura Y, Morita N, et al. Acrodermatitis continua of Hallopeau due to oral terbinafine. Br J Dermatol 2007; 157:1073–1074. 50. Wachter T, Murach WM, Brocker EB, Schon MP. Recalcitrant lithium-induced psoriasis in a suicidal patient alleviated by tumour necrosis factor-alpha inhibition. Br J Dermatol 2007;157:627–629. 51. Kim GK, Del Rosso JQ. Drug-provoked psoriasis: is it drug induced or drug aggravated?: understanding pathophysiology and clinical relevance. J Clin Aesthet Dermatol 2010;3:32–38. 52. Park JJ, Choi YD, Lee JB, et al. Psoriasiform drug eruption induced by anti-tuberculosis medication: potential role of plasmacytoid dendritic cells. Acta Dermato-Venereol 2010;90:305–306. 53. Serra D, Goncalo M, Mariano A, Figueiredo A. Pustular psoriasis and drug-induced pustulosis. G Ital Dermatol Venereol 2011;146: 155–158. 54. Biswas S, Myszor M, De Silva A. Management of psoriasis in patients treated with anti-TNF-alpha therapy for inflammatory bowel disease. J Crohn’s Colitis 2013;7:e708–e709. 55. Brauchli YB, Jick SS, Curtin F, Meier CR. Association between beta-blockers, other antihypertensive drugs and psoriasis: population-based case-control study. Br J Dermatol 2008;158: 1299–1307. 56. Tsankov N, Kazandjieva J, Drenovska K. Drugs in exacerbation and provocation of psoriasis. Clin Dermatol 1998;16:333–351. 57. Yamamoto M, Ikeda M, Kodama H, Sano S. Transition of psoriasiform drug eruption to psoriasis de novo evidenced by histopathology. J Dermatol 2008;35:732–736. 58. Katoulis AC, Bozi E, Kanelleas A, et al. Psoriasiform fixed drug eruption caused by nimesulide. Clin Exp Dermatol 2009;34: e360–e361. 59. Llamas-Velasco M, Godoy A, Sanchez-Perez J, et al. Acute generalized exanthematous pustulosis with histopathologic findings of lymphomatoid drug reaction. Am J Dermatopathol 2013; 35:690–691. 60. Lund JJ, Stratman EJ, Jose D, et al. Drug-induced bullous sweet syndrome with multiple autoimmune features. Autoimmune Dis 2011;2011:176749. 61. Bhanu P, Santosh KV, Gondi S, et al. Neutrophilic eccrine hidradenitis: a new culprit-carbamazepine. Indian J Pharmacol 2013;45:91–92. 62. Ozkaya E, Buyukbabani N. Neutrophilic fixed drug eruption caused by naproxen: a real entity or a stage in the histopathologic evolution of the disease? J Am Acad Dermatol 2005;53:178–179. 63. Agnew KL, Oliver GF. Neutrophilic fixed drug eruption. Aust J Dermatol 2001;42:200–202. 64. Wood BA, Leboit PE. An ‘inflammatory’ variant of solar purpura: a simulant of leukocytoclastic vasculitis and neutrophilic dermatoses. Pathology 2013;45:484–488. 65. Katoh M, Nomura T, Miyachi Y, Kabashima K. Eosinophilic pustular folliculitis: a review of the Japanese published works. J Dermatol 2013;40:15–20. 66. Sauder MB, Glassman SJ. Palmoplantar subcorneal pustular dermatosis following adalimumab therapy for rheumatoid arthritis. Int J Dermatol 2013;52:624–628.

Cutan Ocul Toxicol, Early Online: 1–13

67. Grelle JL, Halloush RA, Khasawneh FA. Azathioprine-induced acute febrile neutrophilic dermatosis (Sweet’s syndrome). BMJ Case Rep 2013;2013. doi: 10.1136/bcr-2013-200405. 68. Anzalone CL, Cohen PR. Acute febrile neutrophilic dermatosis (Sweet’s syndrome). Curr Opin Hematol 2013;20:26–35. 69. Ma HJ, Hu R, Jia CY, et al. Case of drug-induced bullous pemphigoid by levofloxacin. J Dermatol 2012;39:1086–1087. 70. Skandalis K, Spirova M, Gaitanis G, et al. Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin. J Eur Acad Dermatol Venereol 2012;26:249–253. 71. Liu LF, Yan JL, Wang JY, et al. Purulent bullous epidermal necrolysis: a potential new clinical pattern of drug eruption. Exp Ther Med 2013;5:1040–1042. 72. Jain SP, Jain PA. Bullous fixed drug eruption to ciprofloxacin: a case report. J Clin Diagn Res 2013;7:744–745. 73. Kuechle MK, Stegemeir E, Maynard B, et al. Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature. J Am Acad Dermatol 1994;30:187–192. 74. Chanal J, Ingen-Housz-Oro S, Ortonne N, et al. Linear IgA bullous dermatosis: comparison between drug-induced and spontaneous forms. Br J Dermatol 2013;169:1041–1048. 75. Czechowicz RT, Reid CM, Warren LJ, et al. Bullous pemphigoid induced by cephalexin. Aust J Dermatol 2001;42:132–135. 76. Vassileva S. Drug-induced pemphigoid: bullous and cicatricial. Clin Dermatol 1998;16:379–387. 77. Breier F, Feldmann R, Pelzl M, Gschnait F. Pseudoporphyria cutanea tarda induced by furosemide in a patient undergoing peritoneal dialysis. Dermatology 1998;197:271–273. 78. Lowther C, Miedler JD, Cockerell CJ. Id-like reaction to BCG therapy for bladder cancer. Cutis 2013;91:145–146, 51. 79. Brazzelli V, Prestinari F, Roveda E, et al. Pityriasis rosea-like eruption during treatment with imatinib mesylate: description of 3 cases. J Am Acad Dermatol 2005;53:S240–S243. 80. Cabanas R, Caballero MT, Lopez-Serrano MC, et al. Delayed hypersensitivity to enoxaparin. J Invest Allergol Clin Immunol 1998;8:383–384. 81. Lemlich G, Green M, Phelps R, et al. Cutaneous reactions to vitamin K1 injections. J Am Acad Dermatol 1993;28:345–347. 82. Magro CM, Crowson AN, Kovatich AJ, Burns F. Druginduced reversible lymphoid dyscrasia: a clonal lymphomatoid dermatitis of memory and activated T cells. Hum Pathol 2003;34: 119–129. 83. Summers EM, Bingham CS, Dahle KW, et al. Chronic eczematous eruptions in the aging: further support for an association with exposure to calcium channel blockers. JAMA Dermatol 2013;149: 814–818. 84. Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Saf 2002;25: 345–372. 85. Glatz M, Hofbauer GF. Phototoxic and photoallergic cutaneous drug reactions. Chem Immunol Allergy 2012;97:167–179. 86. Mokos ZB, Lipozencic J. Photoallergic drug reactions. Acta Med Croatica 2011;65:107–110 [in Croatian]. 87. Stein KR, Scheinfeld NS. Drug-induced photoallergic and phototoxic reactions. Exp Opin Drug Saf 2007;6:431–443. 88. Yazici AC, Baz K, Ikizoglu G, et al. Celecoxib-induced photoallergic drug eruption. Int J Dermatol 2004;43:459–461. 89. Byun JW, Bang CI, Yang BH, et al. Photodistributed telangiectasia induced by amlodipine. Ann Dermatol 2011;23:S30–S32. 90. Vaccaro M, Borgia F, Barbuzza O, Guarneri B. Photodistributed eruptive telangiectasia: an uncommon adverse drug reaction to venlafaxine. Br J Dermatol 2007;157:822–824. 91. Kunzle N, Venetz JP, Pascual M, et al. Sirolimus-induced acneiform eruption. Dermatology 2005;211:366–369. 92. Galimont-Collen AF, Vos LE, Lavrijsen AP, et al. Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer 2007;43:845–851. 93. Ooi CG, Walker P, Sidhu SK, et al. Allopurinol induced generalized eosinophilic pustular folliculitis. Aust J Dermatol 2006;47:270–273. 94. Laing ME, Laing TA, Mulligan NJ, Keane FM. Eosinophilic pustular folliculitis induced by chemotherapy. J Am Acad Dermatol 2006;54:729–730.

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DOI: 10.3109/15569527.2015.1015725

95. van den Bemt PM, Brodie-Meijer CC, Krijnen RM, Nieboer C. Drug induced alopecia. Ned Tijdschr Geneeskd 1999;143: 990–994 [in Dutch]. 96. Roudier-Pujol C, Jan V. Drug-induced alopecia. Ann Dermatol Venereol 2000;127:1S26–1S28. 97. Mangalvedhekar SS, Gogtay NJ, Manjula S, et al. Phenytoin associated alopecia: drug induced lupus. J Assoc Physicians India 2001;49:929–930. 98. Magro CM, Crowson AN, Schapiro BL. The interstitial granulomatous drug reaction: a distinctive clinical and pathological entity. J Cutan Pathol 1998;25:72–78. 99. Perrin C, Lacour JP, Castanet J, Michiels JF. Interstitial granulomatous drug reaction with a histological pattern of interstitial granulomatous dermatitis. Am J Dermatopathol 2001;23:295–298. 100. Deng A, Harvey V, Sina B, et al. Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor alpha inhibitors. Arch Dermatol 2006;142:198–202. 101. Lee MW, Choi JH, Sung KJ, et al. Interstitial and granulomatous drug reaction presenting as erythema nodosum-like lesions. Acta Dermato-venereol 2002;82:473–474. 102. Lim AC, Hart K, Murrell D. A granuloma annulare-like eruption associated with the use of amlodipine. Aust J Dermatol 2002;43: 24–27. 103. Inaoka M, Kano Y, Horie C, Shiohara T. Cutaneous granulomatous reaction after herpes zoster in drug-induced hypersensitivity syndrome. Am J Dermatopathol 2011;33:872–874. 104. Mutasim DF. Lymphomatoid drug eruption mimicking digitate dermatosis: cross reactivity between two drugs that suppress angiotensin II function. Am J Dermatopathol 2003;25:331–334. 105. Welsh JP, Ko C, Hsu WT. Lymphomatoid drug reaction secondary to methylphenidate hydrochloride. Cutis 2008;81:61–64. 106. Okun MM, Henner M, Paulson C. A quinine-induced drug reaction of photosensitive distribution with histological features mimicking mycosis fungoides. Clin Exp Dermatol 1994;19: 246–248. 107. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg 1996;15:250–257. 108. Shalin SC, Brantley J, Diwan AH. Follicular mucinosis and mycosis-fungoides-like drug eruption due to leuprolide acetate: a case report and review. J Cutan Pathol 2012;39:1022–1025. 109. Chiou CC, Yang LC, Hung SI, et al. Clinicopathological features and prognosis of drug rash with eosinophilia and systemic symptoms: a study of 30 cases in Taiwan. J Eur Acad Dermatol Venereol 2008;22:1044–1049. 110. Ferzli GT, El-Tal Ael K, Kibbi AG, Mikati MA. Localized morphea: a rare adverse effect of valproic acid. Pediatr Neurol 2003;29:253–255. 111. Kluger N, Girard C, Bessis D, Guillot B. Methysergide-induced scleroderma-like changes of the legs. Br J Dermatol 2005;153: 224–225.

Drug eruptions

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112. Kupfer I, Balguerie X, Courville P, et al. Scleroderma-like cutaneous lesions induced by paclitaxel: a case study. J Am Acad Dermatol 2003;48:279–281. 113. Kano Y, Sakuma K, Shiohara T. Sclerodermoid graft-versus-host disease-like lesions occurring after drug-induced hypersensitivity syndrome. Br J Dermatol 2007;156:1061–1063. 114. Itoh M, Yanaba K, Kobayashi T, Nakagawa H. Taxane-induced scleroderma. Br J Dermatol 2007;156:363–367. 115. Konishi Y, Sato H, Sato N, et al. Scleroderma-like cutaneous lesions induced by paclitaxel and carboplatin for ovarian carcinoma, not a single course of carboplatin, but re-induced and worsened by previously administrated paclitaxel. J Obstet Gynaecol Res 2010;36:693–696. 116. Cordoliani F, Rybojad M, Morel P, Puissant A. Halogenoderma and monoclonal gammopathy. J Am Acad Dermatol 1991; 25:1099. doi: http://dx.doi.org/10.1016/S0190-9622(08)80455-0. 117. Zevin S, Hershko C, Rosenmann E. Halogenoderma of the forearm caused by 2-chlorodeoxyadenosine treatment. Am J Hematol 1996;53:209–210. 118. Alagheband M, Engineer L. Lithium and halogenoderma. Arch Dermatol 2000;136:126–127. 119. Fitzpatrick JE. New histopathologic findings in drug eruptions. Dermatol Clin 1992;10:19–36. 120. Hueso L, Sanmartin O, Nagore E, et al. Chemotherapy-induced acral erythema: a clinical and histopathologic study of 44 cases. Actas Dermo-sifiliogr 2008;99:281–290 [in Spanish]. 121. Nishioka K, Katayama I, Masuzawa M, et al. Drug-induced chronic pigmented purpura. J Dermatol 1989;16:220–222. 122. Leong KW, Lee TC, Goh AS. Imatinib mesylate causes hypopigmentation in the skin. Cancer 2004;100:2486–2487 (author reply 7–8). 123. Biedermann L, Kerl K, Rogler G, Hofbauer GF. Drug-induced erythema nodosum after the administration of certolizumab in Crohn’s disease. Inflamm Bowel Dis 2013;19:E4–E6. 124. Bouloc A, Reygagne P, Lecoz P, Dubertret L. Perforating foot ulceration with allopurinol therapy. Clin Exp Dermatol 1996;21: 351–352. 125. Shotts RH, Scully C, Avery CM, Porter SR. Nicorandil-induced severe oral ulceration: a newly recognized drug reaction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87: 706–707. 126. Smith EV, Shipley DR. Severe exfoliative dermatitis caused by strontium ranelate: two cases of a new drug reaction. Age Ageing 2010;39:401–403. 127. Igawa K, Konishi M, Moriyama Y, et al. Erythroderma as drug eruption induced by intravesical mitomycin C therapy. J Eur Acad Dermatol Venereol 2015;29:613–614. 128. Piraccini BM, Alessandrini A. Drug-related nail disease. Clin Dermatol 2013;31:618–626. 129. Chang P. Drug reactions with involvement of the proximal nail fold. Skinmed 2013;11:265–268.