Chapter 28 28 Skin Lesions Due to Drugs

Due to a constantly increasing number and use of • Hypercoagulability (Sect. 8.4) drugs, reactions provoked by drugs or their metabo- • Warfarin skin necrosis (Sect. 8.5) lites are very common and may affect internal organs • Contact (Sect. 4.5) as well as the skin. However, it is important to realize • Erythroderma (Sect. 22.5) that food additives, such as preservatives, colorings • Lichenoid lesions (Sect. 24.1.4) and quinine (used in tonic water), and chemicals, in- • (Sect. 26.1.3) haled or absorbed through the skin, may also cause • Eosinophilic (Sect. 26.2.3) adverse skin reactions. • Lymphomatoid drug reactions (Sect. 26.3.5) Adverse reactions to drugs are usually not serious if Skin eruptions caused by drugs can be divided roughly they are recognized and the drug withdrawn, but oc- into two groups: those due to an immunologic (aller- casionally become critical, and even fatal. Skin erup- gic) reaction and those that are nonallergic. Allergic tions are probably the most prevalent and include skin reactions may be categorized as belonging to one a wide spectrum of clinical and histopathologic pat- of the hypersensitivity reactions types I–IV. Best elu- terns. A particular drug, or a metabolite of it, may give cidated are the mechanisms of those related to type I rise to several kinds of eruptions, but usually one kind (urticaria, angioedema), type II (such as drug-induced prevails. Stubb et al. (1994) reported on 1997 consecu- thrombocytopenia), and type III (leukocytoclastic tive patients with drug-related eruptions seen during a ) (described in Sect. 4.3), and the mecha- period of 35 years at the Department of Dermatology nism of delayed hypersensitivity reaction type IV in of the University Central Hospital, Helsinki, Finland. (described in Sect. 4.5). However, Most of the patients were hospitalized and in nearly all the pathways of drug reactions thought to belong to cases the causative drug was verified by oral provoca- delayed hypersensitivity reaction type IV are much tion. Maculopapular exanthemata, urticaria, and fixed more complicated and variable. Naisbitt et al. (2001) eruptions were the most common kinds of lesions. and Pichler et al. (2002) have summarized the possible Antibiotics, antipyretic/antiinflammatory analgesics, occurrences. and drugs acting on the central nervous system were Most drugs are proteins with a low molecular the most common causative drugs. In another large weight (haptens) and are not antigenic until they have study, Hunziker et al. (1997) analyzed the records bound covalently (strongly) to a larger protein, a car- of 1317 hospitalized patients with definite or prob- rier molecule (Sect. 4.1). To be able to bind covalently able drug-induced skin reactions, observed during to the carrier protein, the drug or metabolite must a 20-year period in the divisions of general internal become chemically reactive. It is believed that most medicine in Berne and St. Gallen in Switzerland. The adverse drug reactions that give rise to delayed-type incidence was 2.7%. The reactions comprised maculo- immune-mediated reaction are caused by chemically papular exanthema (91.2%), urticaria (5.9%), and vas- reactive metabolites, generated by the normal process culitis (1.4%). Only six cases (0.5%) of fixed eruption of drug metabolism. This is called drug bioactivation were observed and none of toxic epidermal necrolysis. and usually takes place in hepatocytes, but may also In the previous chapters a number of skin lesions take place in other kinds of cells such as professional that may be provoked by drugs are exemplified and/or antigen presenting cells (i.e., macrophages, dendritic discussed: cells, B cells), and even in epidermal keratinocytes. • Neutrophilic venular vasculitis (Sect. 7.1) T cells recognize small peptide fragments of the • Lymphocytic venular vasculitis (Sect. 7.2) original antigen, presented on a MHC molecule by • Livedo reticularis (Sect. 7.5.4) antigen-presenting cells. The process of presenting • Thrombocytopenia (Sect. 8.3) antigen peptides can take place inside or outside the • Thrombotic- (Sect. 8.3) antigen-presenting cell. Endogenous antigens are 28.1 Acute Allergic Urticaria/Angioedema 215 presented on MHC class I molecules to CD8+ cells, responsible for the conspicuous eosinophilia often whereas exogenous antigens are presented on MHC seen in vesicular and bullous lesions (Pichler 2002). class II molecules to CD4+ cells. It has also been proved that some types of T cells The following are examples of these processes: may attract a large number of neutrophils and even • Reactive drug metabolites generated in the liver that drugs may give rise to drug-specific T cell lines and bound to some intracellular protein are pro- and clones (Britschgi and Pichler 2002). cessed to peptides inside the liver cells. The pro- The final activation of the cellular immune response cess is endogenic and the antigen is consequently is thought to occur via two signals between the anti- presented to cytotoxic CD8+ T cells by MHC class I gen-presenting cell and the lymphocyte. The binding molecules. (receptor–ligand interaction) between the MHC-re- • A drug protein bound to a carrier molecule may es- stricted antigen and the TCR is the first signal. The cape endogenous processing to antigenic peptides second signal occurs through further receptor–ligand in the liver and enter the peripheral circulation. interactions, called costimulatory interactions. How- This exogenous antigen may instead be processed ever, there is probably a third signal, the danger signal, in professional antigen-presenting cells and pre- represented by the cytokine IL-1 in the case of CD4+ sented to CD4+ T cells on MHC class II molecules. cells and of IL-12 in the case of CD8+ cells. Cells that However, it is not known whether drug metabolites are under oxidative stress (see Glossary), cells infected formed in the liver are stable enough to circulate in with virus, necrotic cells, and cells undergoing apop- the periphery. tosis release the third signal. • A circulating drug (stable or reactive hepatic me- From the above and previous discussion it is evi- tabolite) may accumulate inside a specific type of dent that the scenarios of drug eruptions are legion. A cell, e.g. macrophages. Processing may occur in the few are discussed in detail here. cell giving rise to endogenous antigen presented on MHC class I molecules to CD8+ T cells or outside the cell as a cell-surface reaction with antigen pre- 28.1 sentation on MHC class II molecules to CD4+ cells. Acute Allergic Urticaria/Angioedema • Some chemically nonreactive drugs (metabolites) Acute allergic urticaria with or without angioedema may also bind directly and noncovalently to MHC is the second most common skin reaction caused by molecules and may be able to provoke adverse im- drugs. The condition appears at any age, but is most munologic reactions without going through bioac- common in young adults. tivation. The binding is MHC-restricted, but less stable. The diversity of the pathways of T-cell recognition of 28.1.1 drug antigens explains why drugs may activate both Clinical Appearance CD8+ and CD4+ T cells. Also the kind of stimulated T Acute allergic urticaria is characterized by a sudden cell is of importance: and more or less widespread eruption of swellings • CD4+-1 cells secrete IFN-γ, which gives rise to the (wheals) with a white center surrounded by an ery- CD8+ response, and IL-2 secrefion. thematous area and usually associated with severe . • CD4+-2 cells secrete IL-4 and IL-5. These attract eo- The size and form vary from small papules to large sinophils. lesions, which may be rounded, irregular, annular, or • CD4+-3 cells secrete transforming growth factor β serpiginous. The rash is transient and individual ef- (TGF-β) and IL-10. florescences usually disappear within 24 hours. When TGF-β and IL-10 counteract cytokines secreted by angioedema occurs, the face is the most common lo- CD4+-1 and CD4+-2 cells and the cellular immune re- cation. sponse does not appear. This is referred to as the silent immune response and may explain why most individu- als do not develop adverse reactions. 28.1.2 Furthermore, investigations have revealed that, as Histopathologic Appearance compared to maculopapular lesions, vesicular and A typical urticaria wheal below an essentially normal bullous lesions contain a higher number of infiltrating epidermis shows subepidermal edema and small cell CD8+ cells and a higher level of IL-5 secretion. The lat- infiltrates consisting mainly of lymphocytes with an ter, together with the chemokine eotaxin (present in T admixture of both neutrophils and eosinophils. Thin- cells, endothelial cells, and keratinocytes), is probably walled vessels (lymphatics and venules) are dilated 216 28 Skin Lesions Due to Drugs

and some venules are filled with erythrocytes. There Histologic investigation showed marked subepi- is no vasculitis. In angioedema the edema includes the dermal edema and in the upper half of the dermis deep dermis and subcutaneous tissue. sparse to moderate dense perivascular and interstitial cell infiltrates composed of lymphocytes, neutrophils, nuclear fragment, and eosinophils. Vasculitis was not 28.1.3 observed (Fig. 28.1a). Pathogenesis Allergic urticaria is due to a hypersensitivity type I re- Case 2. Urticaria Caused by Methimazole action, in which CD4+-2 T cells are activated. These A 40-year-old woman was given methimazole for cells secrete IL-4 and IL-5, which is followed by pro- hyperthyroidism. Three days later severe itching oc- duction of IgE antibodies, release of histamine from curred all over the body and she presented with ery- mast cells, and activation of eosinophils. The reaction thematous papules in the axilla. A biopsy specimen may be provoked by, for example, drugs, food and was taken from a papule. food additives. Below a subepidermal edema there were sparse Urticaria vasculitis, a type III reaction, is better perivascular and interstitial cell infiltrates composed considered as a variant of neutrophilic venular vas- of lymphocytes, neutrophils and eosinophils. Vasculi- culitis (leukocytoclastic vasculitis) which is described tis was not observed (Fig. 28.1b). in Section 7.1. Drugs may also cause non-allergic ur- ticaria by direct release of histamine from mast cells (pharmacologic reaction). 28.2 Maculopapular Eruptions This group of reactions, also called exanthemata, is the 28.1.4 most common . Examples

Case 1. Urticaria Caused by Penicillin 28.2.1 A 51-year-old woman showed an urticarial reaction Clinical Appearance after treatment with penicillin. A palm-sized area had Eruptions may be morbilliform, scarlatiniform or ru- remained for more than 24 hours; thus urticaria vas- belliform. They are usually discrete and subside when culitis was suggested. the causative drug is withdrawn. However, occasion-

Fig. 28.1 Urticaria. a, b In the upper dermis there are marked edema and sparse diffuse infiltrates of lymphocytes with a slight admixture of neutrophils and eosinophils. Lymphatics are di- lated (arrow) and venules are filled with erythrocytes. H&E 28.3 Fixed Drug Eruptions 217 ally they become widespread and may represent either 28.3.2 the initial phase of erythroderma or toxic necrolysis. Histopathologic Appearance The pattern is variable, but mostly resembles either the dermal or the epidermal pattern of erythema multi- 28.2.2 forme. In inactive hyperpigmented lesions only mac- Histopathologic Appearance rophages containing melanin pigment are observed in The pattern is nonspecific. In the upper dermis there the upper dermis, indicating a previous injury to the are sparse to moderate perivascular infiltrates of lym- basic epidermis. phocytes, histiocyte-like cells, and occasionally eosin- ophils. In the epidermis there are intercellular edema, some lymphocytes, and scattered necrotic keratino- 28.3.3 cytes in the basal part (Yawalkar and Pichler 2001). Pathogenesis A large number of drugs, of which sulfonamides and tetracyclines are the most common, may provoke a 28.2.3 fixed drug eruption (Mahboob and Haroon 1998). Pathogenesis The pathogenesis is not clearly understood. However, Maculopapular eruptions are hypersensitivity type IV investigations have indicated that the phenomenon reactions. The cell infiltrate in the dermis consists of may be due to a localized disturbance of the regula- CD4+ cells and in the dermal–epidermal junction of tion of the activity of memory CD8+ T cells, normally equal numbers of CD4+ and CD8+ cells secreting IFN- homing in the epidermis (Shiohara et al. 2002). γ and IL-5. Both the CD4+ cells and the CD8+ cells contain perforin and granzyme B granules (see Glos- sary), which are cytotoxic. Histiocyte-like cells are 28.3.4 either CD1a+ dendritic cells or CD68+ macrophages Examples (Yawalkar and Pichler 2001). Case 3. Fixed Drug Eruption of Unknown Cause A 34-year-old man had had a frequently recurrent 28.2.4 itching skin lesion for 2 years, always located at the Differential Diagnosis bend of the left arm. He presented with an erythema- The differential diagnosis includes eruption caused by tous plaque that measured 30×15 mm. He returned infectious agents such as morbilli, scarlatina and ru- 2 months later with a new lesion, 10 mm in diameter, bella. at the same location. The patient denied using drugs. Biopsy specimens were taken from both lesions. Both specimens showed the same histologic pat- 28.3 tern. The epidermis was slightly acanthotic, but oth- Fixed Drug Eruptions erwise normal. In addition to marked subepidermal By a fixed drug reaction is meant a sharply demar- edema, dense perivascular cell infiltrates composed cated skin lesion which disappears when the drug is of lymphocytes were observed throughout the dermis. withdrawn and reappears at the same location when Some vessels were dilated and filled with erythrocytes. the drug is given anew. Also extravasated erythrocytes were seen, but no vas- culitis. (Fig. 28.2)

28.3.1 Case 4. Fixed Drug Eruption Caused by Pindolol Clinical Appearance A 66-year-old man for 4 months had experienced An active lesion usually consists of a rounded, ery- several recurrences of a distinct erythematous lesion thematous, and edematous area up to about 50 mm with a large central vesicle, always located on the same in diameter. Some lesions may be vesicular or bullous. area of the scrotum. He had been given, together with Fixed eruptions may also mimic other dermatoses several other drugs, the β-receptor blocking agent pin- such as , erythema multiforme, and pso- dolol. This was suspected to be the culprit. After with- riasis. In inactive periods, the area may show a slight drawal of the drug no recurrences appeared. hyperpigmentation. There may be more than one le- Histologic investigations showed both intraepider- sion, and the eruption is rarely generalized. Prefer- mal and subepidermal vesicles. The latter were stuffed ential sites are the face and genitalia (Mahboob and with eosinophils. Between the vesicles, the dermal Haroon 1998). epidermal interface was totally obscured by densely 218 28 Skin Lesions Due to Drugs

Fig. 28.2 Fixed drug eruption. The epidermis is thickened and acanthotic. There are marked edema and moderate infiltrates of lymphocytes in the papillary dermis. In the rest of the dermis there are dense well-circumscribed infiltrates of lymphocytes. H&E

packed eosinophils. In the dermis there was a rather dense diffuse cell infiltrate consisting of eosinophils and lymphocytes. Veins were dilated and had promi- nent endothelial cells. Vasculitis was not observed (Fig. 28.3). Fig. 28.3 Fixed drug eruption provoked by pindolol. a A cleft between the dermis and epidermis contains a large number of 28.4 eosinophils. b A broad band of densely packed eosinophils ob- Toxic Epidermal Necrolysis and Stevens- scures the dermal–epidermal interface. H&E Johnson Syndrome Toxic epidermal necrolysis (TEN) is the most serious form of drug reaction and Stevens-Johnson syndrome 28.4.1 (SJS) is considered to be a somewhat less severe variant Clinical Appearance of TEN. Lyell (1956) reported on four adult patients Both variants usually start with poorly defined ery- with extensive areas of epidermal necrolysis and called thematous maculae with purpuric centers symmetri- the condition toxic epidermal necrolysis. He regarded cally located on the face and upper trunk. Within a it as closely related to a disease described previously few days the lesions spread all over the body, coalesce in children by Stevens and Johnson. Both variants are and turn into flaccid bullae due to epidermal necro- rare. The estimated incidence ranges from 0.4 to 6 per sis. The necrotic epidermis desquamates in sheets and million persons per year. Conditions in which the im- leaves large denuded areas. In most patients, the mu- munologic status is disturbed, such as erythema- cous membranes and conjunctivae are also affected, tosus and HIV infection, increase the risk of reacting and occasionally even the epithelium of the trachea, with TEN (Roujeau and Stern 1994). bronchi and gastrointestinal tract. The condition is as- 28.4 Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome 219

Fig. 28.4 Drug reaction provoked by furosemide. a The epider- upper dermis there are rather sparse infiltrates of lymphocytes. mis is thickened with elongated and broad rete ridges, which b Close-up of the area indicated (arrows) in a. c, d Other areas in the lower half are disintegrating and contain aggregates of of epidermis with aggregates of apoptotic bodies, in to two of apoptotic bodies (arrows) and lymphocytes. In the papillae and which lymphocytes are attached (arrows). H&E

sociated with a high fever and general illness (Roujeau sions heal without remnants within 3 weeks. However, and Stern 1994). some lesions may heal with scars and ocular sequelae The two disorders merge into each other. A pa- are common (Roujeau and Stern 1994). tient in whom the detached area is less than 10% is considered to have SJS and a patient with more than 30% of detachment to have TEN. In borderline cases 28.4.2 detachment is between 10% and 30%. In SJS atypical Histopathologic Appearance target lesions (i.e., lesions similar to those described In full-blown cases of TEN the epidermis becomes as target lesions in erythema multiforme) may be ob- necrotic. The necrotic epidermis consists of faded served (Bastuji-Garin et al. 1993). Both SJS and TEN shadow cells alternating with areas of necrotic eosin- are life-threatening. If the patient survives, the le- ophilic keratinocytes, and is in large areas separated 220 28 Skin Lesions Due to Drugs

from the dermis. In early lesions numerous apop- tered neutrophils and eosinophils were observed. In totic bodies may be present in the epidermis (Paul et the deeper dermis there were sparse perivascular infil- al. 1996). They sometimes form aggregates to which trates of lymphocytes (Fig. 28.5a,b). one or several lymphocytes may be attached. Inflam- matory cells are sparse both in the epidermis and Case 7. Drug Reaction Provoked by Carbamazepine dermis. In the epidermis there are lymphocytes and A 37-year-old alcoholic woman, who was also suffer- in the dermis histiocytes (macrophages) and lympho- ing from lupus erythematosus, developed generalized cytes; somewhat later neutrophils are added (Paul et al. flaccid bullae after treatment with the anticonvulsant 1996; Paquet and Piérard 1997). carbamazepine. Histologic investigation revealed a subepidermal bulla caused by detachment of a totally necrotic epi- 28.4.3 dermis. The dermis was edematous and contained Pathogenesis dilated thin-walled vessels and sparse lymphocytes The most common causative drugs reported to pro- (Fig. 28.5c,d). voke TEN and SJS are sulfonamides and anticonvul- sants. The conditions are considered to be due to one Case 8. Drug Reaction Provoked by Sulfonamide or several cell-mediated immunologic reactions, the A 28-year-old man had received a sulfonamide on a pathways of which are not fully understood. Immu- previous occasion for prostatitis with good effect. nohistochemical investigations have shown that lym- However, some time later the prostatitis recurred and phocytes in the epidermis mainly consist of CD8+ and he took a single tablet of the same drug. The following those in the dermis mainly of CD4+ T cells (Miyauchi day his whole body was reddened. His condition rap- et al. 1991). Synergistic activity between T cells and idly deteriorated. On hospitalization a few days later histiocytes (macrophages), and abundant deposits of he had vesicles and bullae on the face, neck, palms and TNF-α in the epidermis, have been suggested to be soles, and purulent conjunctivitis. His temperature critical (Paquet et al. 1994; Paquet and Piérard 1997). was 40.7°C. Later large sheets of necrotic epidermis detached from all over the body. The patient died after a short time in spite of intensive care. A biopsy speci- 28.4.4 men was taken from the back. Examples Histologic investigation displayed a totally necrotic epidermis, which was composed of shadow cells al- Case 5. Drug Reaction Provoked by Furosemide ternating with areas of necrotic eosinophilic kera- A 57-year-old man being treated with the diuretic tinocytes, and in large areas was separated from the furosemide consulted for itching erythema that had dermis. The dermis contained a moderate number of rapidly spread all over the body during the previous inflammatory cells composed of lymphocytes, neutro- 24 hours. A biopsy specimen was taken from the glu- phils, and histiocytes (Fig. 28.6). teal area. Investigation showed a thickened and acanthotic epidermis, the lower half of which was edematous and 28.4.4.1 contained numerous apoptotic bodies. Some apoptotic Comment bodies formed aggregates to which scattered lympho- In Case 5 as well as in Case 6 biopsy specimens were cytes were attached (Fig. 28.4). taken on the second day of the eruption. In Case 5 the condition promptly ameliorated and healed after Case 6. Drug Reaction Provoked by withdrawal of the drug, whereas in Case 6 typical TEN A 63-year-old man was given the antiepileptic drug developed. Thus the presence of numerous apoptotic phenytoin after a brain tumor operation and suffered bodies in a more or less preserved epidermis may ap- a widespread and itching maculopapular exanthema pear early in SJS as well as in TEN. associated with a high fever. A biopsy specimen was taken the day after the eruption started. Within a few days TEN developed. The epidermis contained aggregates of apoptotic bodies. The surrounding keratinocytes were faded and disintegrating. At the dermal–epidermal interface, edema and sparse infiltrates of lymphocytes with scat- 28.5 Acute Generalized Exanthematous Pustulosis 221

Fig. 28.5 Toxic epidermal necrolysis. a Provoked by phenytoin. the dermis. In the left corner there are the remains of apoptotic The epidermis contains aggregates of apoptotic bodies (ar- bodies (arrow). d The margin of the lesion shows interface der- rows). The surrounding keratinocytes are faded or disintegrated. matitis with a sparse number of lymphocytes. The dermis is b There is marked subepidermal edema and a moderate number edematous and contains thin-walled dilated vessels and a few of lymphocytes (arrows). c Provoked by carbamazepine. In the lymphocytes. H&E center of the lesion the epidermis is necrotic and detached from

28.4.5 28.5 Differential Diagnosis Acute Generalized Exanthematous • , herpes zoster in advanced stage Pustulosis (Sect. 20). Acute generalized exanthematous pustulosis (AGEP) • The staphylococcal scalded-skin syndrome (Sect. was previously considered as pustular . It 12.5). was differentiated from pustular psoriasis by Baker • Acute graft-versus-host disease may be impossible to and Ryan (1968) and since then has had different differentiate from toxic necrolysis. names such as exanthematous pustular psoriasis, toxic • Phytophotodermatitis also has to be considered pustuloderma, and pustular drug rash (Sidoroff et al. (Sect. 29.4.3). 2001). 222 28 Skin Lesions Due to Drugs

Fig. 28.6 Toxic epidermal necrolysis provoked by sulfonamide. a The lips, nostrils and eyelids are severely affected. The white discoloration is caused by rests of ointment. b The necrotic epi- dermis is detached in large sheets. c Histologic investigation shows that the whole epidermis is necrotic. It consists mainly of shadow cells alternating with smaller areas of necrotic eosino- philic keratinocytes. In the dermis there is a proportionately sparse, mixed cell infiltrate, consisting of lymphocytes, neutro- phils and some histiocytes. H&E

28.5.1 of lymphocytes; occasionally vasculitis has been ob- Clinical Appearance served. In contrast to psoriasis, acanthosis and pap- A generalized eruption of hundreds of small, sterile, illomatosis are usually absent (Roujeau et al. 1991; and non-follicular pustules (less than 5 mm in diam- Sidoroff et al. 2001). eter) suddenly appears on edematous and reddened skin. The lesions are associated with a high fever and massive blood neutrophilia. All symptoms regress 28.5.3 spontaneously within 15 days (Roujeau et al. 1991). Pathogenesis AGEP is a cell-mediated immunologic reaction, mostly provoked by drugs, usually penicillins (Roujeau et al. 28.5.2 1991). It has been possible to isolate drug-specific T Histopathologic Appearance cells from positive patch tests as well as from the pe- There are superficial, neutrophilic and spongiotic pus- ripheral blood of patients with drug-induced AGEP tules in the epidermis, and in the dermis infiltrates (Britschgi and Pichler 2002). Also these drug-specific 28.6 Bullous Skin Lesions due to Photosensitivity Reactions 223

Fig. 28.7 Bullous lesions provoked by nalidixic acid and expo- area between the arrows it is better preserved and displays in- sure to sunlight. a Multiple bullae on the dorsal aspect of the tracellular edema in the basal cells. The floor is composed of feet. b There is a wide subepidermal bulla which in the center the dermis with well-preserved, distinct papillae. Inflammatory cuts through a sweat gland. The roof of the bulla consists mainly cells are sparse. H&E of a shrunken and hyperkeratotic epidermis. However, in the

T cells have been proven to produce large amounts of 28.6.1 IL-8, which is a potent cytokine attracting neutrophils. Example The authors suggested the possibility that a similar mechanism could explain the presence of neutrophils Case 9. Drug Reaction Provoked by Nalidixic Acid in psoriasis, which probably is a cell-mediated immu- in Combination with Intensive Exposure to nologic disease. Sunlight A 55-year-old woman suffered from chronic pyelone- phritis and was treated with nalidixic acid. During a 28.5.4 sun vacation in Spain, bullae appeared on the dorsal Differential Diagnosis aspects of hands and feet. • Pustular psoriasis (Sect. 23.2) A biopsy specimen revealed a wide subepidermal • Intraepidermal IgA pustulosis (Sect. 25.2) bulla, which contained erythrocytes, but no inflam- matory cells. In the central part of the bulla the roof consisted of a shrunken and hyperkeratotic epidermis. 28.6 At the margin where the epithelium was preserved Bullous Skin Lesions due to Photosensitivity and in areas close to the bulla, the basal cells showed Reactions marked intracellular edema. The floor consisted of Only those agents with an absorption spectrum in the dermis with well-preserved papillae and sparse infil- range of sunlight are associated with photosensitivity. trates of lymphocytes (Fig. 28.7). There are two main forms: phototoxicity and photoal- lergy. In phototoxicity, absorption of ultraviolet light produces a reactive drug or metabolite, which by one 28.6.2 of two pathways ultimately gives rise to photosensiti- Differential Diagnosis zation (Svensson et al. 2001). shows a very similar pattern Drug-induced photoallergy is a type IV delayed (Fig. 25.12e,f). Investigation excluded porphyria cu- hypersensitivity reaction. An antigenic drug or its me- tanea tarda as the cause in Case 9 and nalidixic acid tabolite becomes activated after exposure to ultravio- was considered to be the culprit. The only difference let light. Examples of orally administered drugs which between the lesion seen in the patient in Case 9 and a may cause phototoxic or photoallergic bullous reac- lesion of porphyria cutanea tarda may be the intracel- tions are nalidixic acid, chlorpromazine, tetracycline, lular edema observed in the basal cells in the patient thiazides and fluoroquinolone. in Case 9. 224 28 Skin Lesions Due to Drugs

28.7 formation. It inhibits maturation of collagen and is Interstitial Granulomatous Drug Reaction also used in and (Bialy-Golan and Magro et al. (1998) have reported on a series of pa- Brenner 1996). tients with a new clinically and histopathologically well-defined type of cutaneous drug reaction. 28.8.1 Nonallergic Degenerative Lesions Induced by 28.7.1 Penicillamine Clinical Appearance These lesions are dose-dependent and most often seen The lesions consist of nonpruritic erythematous/viola- in patients with diseases which need high doses for a ceous plaques mostly located on the medial aspects of long time, such as Wilson disease and cystinuria, and the arms and thighs and in intertriginous areas. sometimes also in patients with rheumatoid arthritis. They are due to the ability of penicillamine to interfere with the maturation of collagen and elastin (Bialy-Go- 28.7.2 lan and Brenner 1996). Histopathologic Appearance In the upper dermis there are diffuse infiltrations of lymphocytes and histiocytes and piece-meal frag- 28.8.1.1 mentation of collagen and elastic fibers. Lymphocytes Clinical Appearance migrate into the overlying epidermis that shows intra- Besides areas with excessive wrinkling and atrophy, cellular edema. The presenceof atypical (stimulated) lesions similar to pseudoxanthoma elasticum and lymphocytes has been observed in several cases. elastosis perforans serpiginosa may appear, single, to- gether or in different combinations. Pseudoxanthoma elasticum-like lesions consist of pale-yellow waxy pap- 28.7.3 ules and elastosis perforans serpiginosa-like lesions Pathogenesis of raised papules, some with a central keratotic plug, Drugs that have been found to be responsible are, arranged in small annular or serpiginous figures. Pref- among others, calcium channel blockers, angiotensin- erential sites are the back of the neck, axilla and groins converting enzyme inhibitors, beta-blockers and lipid- (Bolognia and Braverman 1992; Iozumi et al. 1997). lowering agents. The pathogenesis is not clear.

28.8.1.2 28.7.4 Histopathologic Appearance Differential Diagnosis Investigation of pseudoxanthoma elasticum-like le- • is located in the mid-dermis; sions in the dermis reveals large, eosinophilic elastic inflammatory cells do not invade the epidermis. fibers, which are rough, unevenly thick, and provided • Lymphoma must be considered if stimulated lym- with oval spike-like projections. In contrast to nor- phocytes are observed. mal elastic fibers they are readily visible in routinely stained sections. In general there is no calcification (Burge and Ryan 1988; Iozumi et al. 1997). After pro- 28.8 tracted treatment with penicillamine, the same kind Skin Lesions Provoked by Penicillamine of changes have also been observed in elastic tissue Because of several different chemical characteristics, of internal organs, for example the wall of the aorta penicillamine has been used in the treatment of very and alveolar septa of the lungs (Burge and Ryan 1988). different kinds of diseases, and may give rise to both al- In lesions similar to elastosis perforans serpiginosa, lergic and nonallergic adverse reactions. For example, in addition to thickened elastic fibers in the dermis, penicillamine may combine with metals and is used there are located in the papillae close to the in Wilson disease (see Glossary) to prevent accumula- epidermis. The abscesses consist of necrotic tissue tion of copper in organs and tissues, and in lead poi- containing degenerated elastic fibers with accentu- soning for detoxification. It may dissociate naturally ated basophilic walls and inflammatory cells. Some of occurring disulfides and macroglobulins such as rheu- them may perforate the epidermis (Meyrick Thomas matoid factor and is used in rheumatoid arthritis, and and Kirby 1985). There may be foreign body granu- in cystinuria (see Glossary) to prevent urinary stone lomas with giant cells. Also in some cases keloid-like 28.9 Bullous Skin Lesions in Acute Drug Intoxication and Coma 225 formations of collagen without elastic fibers have been 28.9 observed (Iozumi et al. 1997). Bullous Skin Lesions in Acute Drug Intoxication and Coma Bullous skin lesions in association with drug intoxi- 28.8.1.3 cation are well known and described clinically (Hol- Example ten 1951-1952; Sorensen 1963; Beveridge and Lawson 1965) as well as histologically (Adebahr 1963; Brehmer- Case 10. Elastosis Perforans Serpiginosa Provoked Andersson and Pedersen 1969; Mandy and Ackerman by Penicillamine1 1970; Arndt et al. 1973; Sanchez Yus et al. 1993). The A 40-year-old man had been treated for many years same types of lesions have also been described in car- with penicillamine for severe cystinuria, known to be bon monoxide intoxication (Achten et al. 1971; Torne present since the age of 17 years. For 5 months he had et al. 1991). Barbiturate is the most common causative observed small bluish-red and circinate infiltrates bi- drug, but other hypnotic and narcotic drugs have also laterally at the dorsal axillary border. He had no sub- been reported to be involved, occasionally in combi- jective symptoms. nation with alcohol. The biopsy specimen included the whole dermis and some subcutaneous tissue. Abnormal elastic fi- bers were observed in the whole dermis. In the middle 28.9.1 and deep part of the dermis the fibers were rough, un- Clinical Appearance even, and provided with spike-like projections. In the In unconscious patients, or in patients who were un- papillary dermis they seemed degenerated and to be conscious shortly before being attended to, well-cir- broken up into smaller pieces. Also there were two ab- cumscribed reddened areas or plaques >10 cm in scesses. One was located in the papillary dermis, and diameter with or without vesicles and/or bullae may the other was intrafollicular (Fig. 28.8). be seen. These are usually, but not always, located on areas exposed to pressure and are often symmetri- cal. Lesions appearing several hours after regaining 28.8.1.4 consciousness have also been observed (Holten 1951- Differential Diagnosis 1952). If the patient survives, the skin lesions heal Pseudoxanthoma elasticum. In this hereditary disease spontaneously. the affected elastic fibers are confined to the middle and lower parts of the dermis, are curled up, and do not have spikes. Older lesions contain calcium (Poon 28.9.2 et al. 2002). Histopathologic Appearance Common to all vesicular/bullous lesions and nonve- sicular lesions are more or less complete necrosis of 28.8.2 sweat glands and sweat gland ducts below the lesional Allergic Skin Reactions Provoked by Penicillamine area. However, in addition to sweat gland necro- Penicillamine may give rise to urticaria and exan- sis, necrosis in the pilosebaceous units has also been thema or autoimmune bullous dermatoses such as observed (Arndt et al. 1973; Sanchez Yus et al. 1993). different variants of and cicatricial pem- Small accumulations of neutrophils, venules with fi- phigoid. These kinds of adverse reactions are seen in brinoid necrosis, and small hemorrhages have been individuals who already have disturbed immunity noted around necrotic sweat glands and hair follicles such as patients with rheumatoid arthritis (Bialy-Go- (see also below). lan and Brenner 1996).

28.9.3 Example

Case 11. Sweat Gland Necrosis in Acute Drug Intoxication A 25-year-old male student was found alone in a dazed condition in his room. Because of bullous skin lesions 1 Courtesy of Dr. Alf Rausing, Microklin AB, Barsebäck, Sweden he was referred to the dermatology department and 226 28 Skin Lesions Due to Drugs

Fig. 28.8 Elastosis perforans serpiginosa-like lesion provoked inflammatory cells. b Close-up shows necrotic tissue with in- by penicillamine. a An is located in a papilla in close flammatory cells and abnormal elastic fibers. Some fibers are contact with the epidermis (arrows). The rete ridge to the left irregular and thick and have dark accentuated walls (arrows); is club-like and contains small hair follicles. There is a narrow others are thinner, lighter, and have minute, plump projections passage between the upper dermis and the abscess. The abscess (arrowheads). H&E contains abnormal elastic fibers and a dense diffuse infiltrate of

hospitalized. Over the right great trochanter was ob- neous tissue and also normal skin. In the affected part served a 5×5 cm large well-defined reddish plaque. there was a large, mainly subepidermal bulla. The floor The surface of the plaque was stuffed with minute of the bulla consisted of dermal papillae, which in vesicles, and also contained a somewhat larger vesicle areas were covered by minimal rests of basal cells. The and a 15×10 mm large bulla (Fig. 28.9a). On the left roof comprised the suprabasal part of the epidermis, trochanter there was an 8×8 cm large reddish plaque which in the central part was disintegrating and without vesicles, and on the medial border of each shrunken. At the dermal-subcutaneous border below foot a 4×4 cm large bulla. Bullae and vesicles con- the bulla several scattered groups of sweat glands and tained clear fluid. A knife biopsy was taken from the ducts were totally or partially necrotic. At different lesion on the right trochanter; it included the bulla levels in the dermis it was possible to identify parts of and normal skin. necrotic ducts, one of which could be followed to the Because of a severe drink problem the patient was floor of the bulla. Beside the bulla there were several regularly taking the tranquillizers meprobamate and vertical, club-shaped or pear-like intraepidermal propiomazine together with disulfiram (a deterrent to vesicles surrounded by normal epithelium. Some of alcohol consumption). He reported that for about two these contained the remnants of a sweat gland duct weeks he had stopped taking disulfiram and a few days at the base. Also a complete acrosyringium with a before he was found, had consumed some alcohol. Af- necrotic duct surrounded by a vesicle was observed. ter that he remembered nothing until he was rescued The bulla and vesicles contained eosinophilic exudate by friends (Brehmer-Andersson and Pedersen 1969). and a moderate number of neutrophils. In addi- The biopsy specimen was cut at ten levels (over 100 tion, there was close to the above-described changes sections) and stained with H&E and according to vG. in the epidermis a longitudinally cut hair follicle, The material included a substantial part of subcuta- which could be followed in its entirety, and showed 28.9 Bullous Skin Lesions in Acute Drug Intoxication and Coma 227

Fig. 28.9 Sweat gland necrosis in acute drug intoxication and dermal papillae. Thearrow indicates an area with tiny remains coma. a A well-demarcated plaque on the right trochanter major of basal cells. d A necrotic sweat gland enters the epidermis. In shows many minute vesicles and also displays a somewhat larger the lower half of the epidermis the necrotic duct is surrounded vesicle and a bulla. b There is a group of totally necrotic sweat by a vesicle and inflammatory cells. To the right there is another glands with a necrotic duct at the top (arrow). c In the left half longitudinal vesicle, which probably also represents an affected of the micrograph there are two longitudinally intraepidermal acrosyringium. H&E (a, d reproduced from Brehmer-Anders- vesicles with the remains of sweat gland ducts at the base. The son and Pedersen 1969, with permission) right half shows a part of the bulla, the floor of which consists of 228 28 Skin Lesions Due to Drugs

Fig. 28.10 Hair follicle necrosis in acute drug intoxication and coma. The micrographs show necrotic areas (arrows) at different levels of the same hair follicle. Necrotic parts are surrounded by edema and infiltrates of neutrophils.a Infundibulum; vG. b Shaft; H&E.c Bulb; H&E

focal necrosis of the root sheath and bulb, and small met, the first question he asked was: “Do you know collections of neutrophils. Just below the hair bulb that drug-intoxicated and comatose patients can get there were two groups of necrotic sweat glands. In the skin lesions due to sweat gland necrosis?” I did not, dermis close to necrotic sweat glands and ducts there and I was skeptical. Could this really be true? When were small areas with infiltrate of neutrophils, venules the slides appeared on my desk I was prepared in my with fibrinoid necrosis and small fresh hemorrhages. mind for sweat gland necrosis, but overlooked the un- These insignificant vascular lesions were judged as expected hair follicle necrosis. reactive. Arterioles were not involved (Fig. 28.9b,c,d and 28.10). 28.9.4 Pathogenesis 28.9.3.1 The mechanism of the phenomenon is not clear and Comment the interpretation of it differs. The most common view I was confronted with Case 11 early in my career as a is a decubitus (pressure) ulcer caused by pressure and dermatopathologist. By chance I did not miss the di- hypoxia during the unconscious state. This is con- agnosis altogether. At the Department for Pathology tradicted by the observations of Holten (1951-1952), I had at my disposal a cubicle at one side of a small who observed lesions appearing even in conscious pa- laboratory. At the other side there was a similar cu- tients, and in unconscious patients lesions sometimes bicle, into which a young colleague from the Depart- so widespread that pressure could not possibly explain ment of Forensic Medicine had just moved. When we them all. References 229

The most significant common finding in histo- References logic investigations of both vesicular/bullous and 1. Achten G, Ledoux-Corbusier M, Thys J-P (1971) Intoxica- nonvesicular lesions is necrosis of sweat gland units. tion à l’oxyde de carbone e lésions cutanées. Ann Dermatol Furthermore, Adebahr (1963), whose investigation Syph 98:421–428 was based on 300 autopsy cases due to barbiturate poi- 2. Adebahr G (1963) Hautveränderungen bei Schlafmittelver- soning, suggested the possibility that the intoxicating giftung. Landarzt 30:1302–1307 drug was excreted via the sweat glands and induced 3. Arndt KA, Mihm MC, Parrish JA (1973) Bullae: a cutane- the damage to the surrounding tissue. The clinical pho- ous sign of a variety of neurologic diseases. J Invest Derma- tograph in Case 11 shows a well-demarcated plaque tol 60:312–320 which is stuffed with minute vesicles and also contains 4. Baker H, Ryan TJ (1968) Generalized pustular psoriasis. A some larger vesicles and a bulla. In accordance with clinical and epidemiological study of 104 cases. Br J Derma- tol 80:771–793 this, the micrographs demonstrate how necrotic sweat 5. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, ducts from underlying necrotic sweat glands can be Roujeau J-C (1993) Clinical classification of cases of toxic followed through the dermis into the epidermis and epidermal necrolysis, Stevens-Johnson syndrome, and ery- become surrounded by a vesicle. These smaller vesi- thema multiforme. Arch Dermatol 129:92–96 cles enlarge, coalesce and form a bulla, which is mainly 6. Beveridge GW, Lawson AAH (1965) Occurrence of bullous subepidermal. However, small remains of basal cells lesions in acute barbiturate intoxication. BMJ 1:835–837 on the dermal papillae at the ends of the bulla, also 7. Bialy-Golan A, Brenner S (1996) Penicillamine-induced observed by Sanchez Yus et al. (1993), indicate that bullous dermatoses. J Am Acad Dermatol 35:732–742 the bulla from the beginning has been intraepidermal. 8. Bolognia JL, Braverman I (1992) Pseudoxanthoma-elasti- These findings strongly indicate the important role of cum-like skin changes induced by penicillamine. Dermatol- the sweat gland units in the development of the vesic- ogy 184:12–18 ular and bullous lesions, and thus highly support the 9. Bouten CV, Oomens CW, Baaijens FP, Bader DL (2003) theory of Adebahr. The etiology of pressure ulcers: skin deep or muscle bound? How then can one explain the fact that even scat- Arch Phys Med Rehabil 84:616–619 tered hair follicle units, which anatomically have 10. Brehmer-Andersson E, Pedersen NB (1969) Sweat gland nothing to do with eccrine sweat duct units, may be necrosis and bullous skin changes in acute drug intoxica- affected? It has long been known that drugs may be tion. Acta Derm Venereol 49:157–162 excreted in the sweat (Brehmer-Andersson and Peder- 11. 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