Severe Adverse Cutaneous Reactions to Drugs/Mastocytosis

[Guest guest]

A reference for Mastocytosis is included in this study below. It's a

long read, but well worth it. It is stated that immunization is also

included in these types of reactions.

131.. Horan RF, Schneider LC, Sheffer AL. Allergic skin disorders and

mastocytosis. JAMA 1992;268:2858-2868.[CrossRef][Medline]

Some more info,

Mast Cells- The Central Cell of Allergic Reactions

When IgE is produced, it seeks cells containing receptors for the

back of the antibody molecule (called the Fc portion). There are two

major types of receptors for IgE on cells. One, called a low affinity

receptor, is found on a variety of cells including lymphocytes and

eosinophils. The other, a high affinity receptor, is found primarily

on mast cells. Mast cells are found in or near a variety of organs

and tissues including nose, lungs, gut, skin and even blood vessels.

They contain large granules which house molecules such as

histamine ,serotonin and tryptase. They normally function as part of

the host defense system.Once the mast cells are " armed " by the

allergen-specific IgE molecules binding to the high affinity

receptors, the " immune gun is cocked " . Subsequent exposure to the

specific allergen (i.e. pollen, dander, etc.) causes pairs of IgE

molecules to become crosslinked. This " pulls the trigger " on the mast

cell, causing its granules to release their contents as well as

activating to form new molecules. The histamine causes itching,

increase in vascular permeability, smooth muscle constriction and

reflexes such as sneezing, coughing and gastrointestinal motility

increases. Crosslinking also activates mast cells to begin to

synthesize and secrete molecules that can attract inflammatory cells

(such as eosinophils) and further the allergic reaction itself. One

such mechanism is activation of biochemical pathways that metabolize

a component of cell membranes called arachadonic acid. Arachadonic

acid can be metabolized down two major pathways by two different

enzyme systems - cyclooxygenase and lipooxygenase. The end products

of these pathways are called prostaglandins and leukotrienes. Both

prostaglandins and leukotrienes are capable of enhancing the

inflammation characteristic of this part of the allergic reaction.

While the immediate hypersensitivity of histamine release typically

occurs in minutes, the inflammatory response take several hours (3-

24) and is referred to as a late phase allergic response. The

affected organs define the specific signs and symptoms of allergic

disease in a particular patient. Why all allergic patients do not

have rhinitis, asthma, atopic dermatitis and anaphylaxis together is

not understood but is the subject of great interest and research.

http://content.nejm.org/cgi/content/full/331/19/1272

Severe Adverse Cutaneous Reactions to Drugs

Claude Roujeau, and S. Stern

Medline Citation

Although the rate of acute severe adverse cutaneous reactions to

medications is low, these reactions can affect anyone who takes

medications and can result in death or disability1. Even a small

number of cases associated with a particular drug may alter the

recommendations for its use2,3,4. Prompt differentiation of severe

adverse cutaneous reactions from less serious skin disorders may be

difficult. Rapid recognition of severe reactions is essential. Prompt

withdrawal of the offending drug is often the most important action

to minimize morbidity.

Adverse cutaneous reactions to drugs are frequent, affecting 2 to 3

percent of hospitalized patients5. Many commonly used drugs have

reaction rates above 1 percent5. Fortunately, most adverse cutaneous

reactions are not severe, and few are fatal.

Complications of drug therapy are the most common type of adverse

event in hospitalized patients, accounting for 19 percent of such

events6. Cutaneous or allergic reactions to drugs are responsible for

approximately 3 percent of all disabling injuries during

hospitalization6. The reported percentage of cutaneous drug reactions

that physicians diagnose as potentially serious varies greatly but is

probably about 2 percent7,8. We estimate that about 1 of every 1000

hospitalized patients has a serious cutaneous drug reaction. Each

year thousands of outpatients have cutaneous reactions that may

result in substantial morbidity or death unless promptly recognized

and treated. Not all serious adverse reactions to drugs with a

prominent cutaneous component develop rapidly. For example, the

distinctive cutaneous changes of eosinophilia-myalgia syndrome cause

great morbidity but usually occur after prolonged exposure9.

In this article, we shall emphasize the clinical recognition,

epidemiology, pathophysiology, and treatment of acute, serious

cutaneous adverse reactions. Table 1 presents the key clinical

features of the reactions we shall discuss.

Recognition

Drug eruptions are most often morbilliform or exanthematous (Figure 1)

5,6,7. They usually fade in a few days but may worsen. In rare

instances in which no alternative therapy is available, a drug may be

continued in spite of a morbilliform eruption. Unfortunately, a

morbilliform eruption is often the initial presentation of more

serious reactions including toxic epidermal necrolysis,

hypersensitivity syndrome, and serum sickness. Table 2 lists clinical

features that should alert the physician that a reaction is serious.

When a drug reaction is suspected, the presence of urticaria,

blisters, mucosal involvement, facial edema, ulcers, palpable or

extensive purpura, fever, or lymphadenopathy almost always

necessitates discontinuation of the drug.

A Morbilliform Drug Eruption with Numerous Erythematous

Macules and Papules That Vary in Size and Are Symmetrically

Distributed.

Most lesions are faint, but some may be slightly

infiltrated and resemble urticaria. This exanthematous eruption often

starts on the trunk, as in this patient. It may also begin on areas

subjected to pressure. The rash may become confluent.

Several algorithms have been proposed for the assessment of adverse

drug reactions,10,11,12 but none have proved to be both sensitive and

specific. The following criteria and Table 1 and Table 3 provide

guidelines for formulating a differential diagnosis. First,

alternative causes should be excluded, especially infections, since

many infectious illnesses are difficult to distinguish clinically

from the adverse effects of drugs used to treat infections. Second,

the interval between the introduction of a drug and the onset of a

reaction should be examined. Third, any improvement after drug

withdrawal should be noted. Fourth, the physician should determine

whether similar reactions have been associated with the same

compound. Fifth, any reaction on readministration of the drug should

be noted.

A skin biopsy is often critical for an accurate diagnosis, but biopsy

does not help in establishing whether the disease is drug-induced. In

vivo tests include readministration of the drug (rechallenge) and

skin tests. Reactions after rechallenge may be worse. Rechallenge

should not be performed after a serious reaction.

Skin tests and in vitro tests (such as the radioallergosorbent test)

help diagnose IgE-mediated type I hypersensitivity reactions,

especially to penicillin13. In other types of eruptions, skin testing

has low sensitivity and specificity14. In vitro testing of cellular

proliferative responses to drugs is usually not helpful15. Although

still investigational, in vitro studies of enhanced toxic effects of

drugs or drug metabolites on cells may someday aid in the diagnosis

and understanding of the pathogenesis of some types of

reactions16,17.

s- Syndrome and Toxic Epidermal Necrolysis

s- syndrome and toxic epidermal necrolysis are two

related mucocutaneous disorders with high rates of morbidity and

mortality (Table 1)1,18,19. Although the nosology and specific

diagnostic criteria for these disorders remain controversial, we

believe certain clinical features help define these conditions20

Clinical Features

In 1922, s and described children with febrile erosive

stomatitis, severe ocular involvement, and a disseminated cutaneous

eruption of discrete dark-red macules, sometimes with a necrotic

center. This became known as s- syndrome21. In 1956,

Lyell introduced the term " toxic epidermal necrolysis " to describe

patients with extensive loss of epidermis due to necrosis that leaves

the skin surface looking scalded22. In severe cases, s-

syndrome can include extensive areas of epidermal necrolysis. In most

cases of toxic epidermal necrolysis, the discrete red macules

typically seen with s- syndrome occur around larger

necrolytic areas. The similarities between the histopathological

findings and the drugs responsible suggest that these two conditions

are part of a single spectrum18,19,23,24. The term s-

syndrome is also frequently used as a synonym for erythema multiforme

major, resulting in confusion. In our opinion, the two are different

conditions that are usually clinically distinguishable20. Patients

with erythema multiforme major have typical target lesions,

predominantly on the extremities (Figure 2). Erythema multiforme

major usually occurs after infections, especially herpes simplex and

mycoplasma, and has a benign course25. Patients with widely

distributed purpuric macules and blisters (Figure 3) and prominent

involvement of the trunk and face (Figure 4) are likely to have

s- syndrome, which is usually drug-

induced.

Patients may present with a clinical picture of s-

syndrome that evolves to one of toxic epidermal necrolysis within a

few days. Fever and influenza-like symptoms unexplained by infectious

illness often precede the mucocutaneous lesions of these two

conditions by one to three days. Burning and pain occur. Initially,

these eruptions are symmetrically distributed on the face and upper

trunk, areas that usually remain the most severely affected20. The

rash spreads rapidly and is usually maximal within four days,

sometimes within hours. The initial skin lesions are usually poorly

defined macules with darker purpuric centers that coalesce.

Although precise diagnostic boundaries between the two disorders have

not been established, cases with limited areas of epidermal

detachment are usually labeled s- syndrome and those

with extensive detachment toxic epidermal necrolysis. We classify

cases with detachment of less than 10 percent of the epidermis as

s- syndrome and those with more than 30 percent as toxic

epidermal necrolysis20. In cases with detachment of 10 to 30 percent

of the epidermis we consider the two syndromes to overlap20. In toxic

epidermal necrolysis, sheet-like loss of epidermis and raised flaccid

blisters, which spread with pressure, often occur, and Nikolsky's

sign (i.e., dislodgment of epidermis by lateral pressure) is positive

on erythematous areas. With trauma, full-thickness epidermal

detachment (Figure 6) yields exposed, red, sometimes oozing dermis.

In other areas, pale necrotic epidermis may remain (Figure 7).

About 90 percent of patients with each disorder have mucosal lesions,

including painful erosions and crusts on any surface (Figure 8)18.

Impaired alimentation, photophobia, and painful micturition often

result. The epithelium of the trachea, bronchi, or gastrointestinal

tract may be involved26,27,28. Often overlooked, these lesions may

cause substantial morbidity. About 85 percent of patients have

conjunctival lesions18,29,30. These range from hyperemia to extensive

pseudomembrane formation29,30,31. Synechiae between eyelids and

conjunctiva often occur. Keratitis and corneal erosions are less

frequent. Fever is usually higher in toxic epidermal necrolysis

(temperature, >38 °C) than in s- syndrome, and asthenia,

skin pain, and anxiety are often extreme.

The complications of toxic epidermal necrolysis and extensive thermal

burns are similar. The severity is proportional to the extent of skin

necrosis. Massive transepidermal fluid losses (3 to 4 liters daily in

adults with half their body-surface area involved) occur with

associated electrolyte imbalance18. Prerenal azotemia is common.

Bacterial colonization of the skin and decreased immune

responsiveness increase the likelihood of sepsis. A hypercatabolic

state, sometimes with inhibition of insulin secretion or insulin

resistance, is common. Diffuse interstitial pneumonitis, which may

lead to the adult respiratory distress syndrome, sometimes develops.

Even if the diagnosis of s- syndrome or toxic epidermal

necrolysis is clinically evident, a skin biopsy helps confirm the

diagnosis, thus usually excluding bullous diseases not related to

drug therapy. Early on, there is full-thickness epidermal necrosis

and detachment, with an only slightly altered underlying dermis

(Figure 6). The use of frozen sections allows a rapid diagnosis.

Immunofluorescence studies only help exclude other bullous diseases.

Anemia and lymphopenia are frequent, but eosinophilia is rare.

Neutropenia suggests a poor prognosis32.

The regrowth of epidermis may begin within days but usually takes

about three weeks, the typical length of the hospitalization33. Areas

subject to pressure and periorificial areas often heal last. Ocular

sequelae affect about 35 percent of patients who survive toxic

epidermal necrolysis and a smaller percentage of those with s-

syndrome18,30. A Sjogren-like sicca syndrome with a

deficiency of mucin in tears, inturned eyelashes, proliferation of

squamous metaplasia, and neovascularization of conjunctiva and

cornea, symblepharon, punctate keratitis, and corneal scarring may

develop30. Persistent photophobia, burning eyes, visual impairment,

and even blindness may result. Other possible sequelae include

scarring, irregular pigmentation, eruptive nevi, persistent erosions

of the mucous membranes, phimosis, vaginal synechiae, and abnormal

regrowth of nails18.

Differential Diagnosis

Skin disorders involving desquamation, exfoliation, or blistering are

sometimes misdiagnosed as s- syndrome or toxic epidermal

necrolysis. Exfoliative dermatitis is characterized by generalized

erythema and scaling (Figure 9)34. When the scales separate in large

sheets, especially on the palms and soles, desquamation may be

clinically confused with full-thickness epidermal detachment (Figure

10).

In infants, staphylococcal scalded skin syndrome may resemble toxic

epidermal necrolysis. Specific staphylococcal exotoxins cause

extensive subcorneal separation of the stratum corneum (Figure 6 and

Figure 11)35. Acute exanthematous pustulosis is drug-induced and

resembles pustular psoriasis36. The subcorneal aseptic pustules are

usually distinctive and may coalesce to produce extensive superficial

exfoliation (Figure 12). The mucous membranes are infrequently

involved. Subcorneal skin separation (Figure 6) and the absence of

necrosis in both conditions facilitate their pathological and

clinical diagnosis.

Paraneoplastic pemphigus of acute onset may be confused with toxic

epidermal necrolysis37. Direct immunofluorescence microscopy can be

used to distinguish these disorders. Thermal burns, phototoxic

reactions, and pressure blisters occurring in comatose patients may

resemble toxic epidermal necrolysis, even on pathological analysis.

The pattern of the blisters and the clinical history facilitate

proper diagnosis.

Epidemiologic Features

Although infrequent, toxic epidermal necrolysis and s-

syndrome occur in all ages, all races, and both sexes, with an

incidence ranging from 0.4 to 1.2 and 1.2 to 6 per million person-

years, respectively1,3,19,38,39,40.

Most cases of toxic epidermal necrolysis are drug-induced. Fewer than

5 percent of patients report no drug use3,19. A strong association

with specific medications is observed in about 80 percent of the

cases. Other occasional reported causes include chemicals, mycoplasma

pneumonia, viral infections, and immunization41,42. That there is a

less frequent clear-cut relation of drugs to s- syndrome

(in about 50 percent of cases) probably reflects the common confusion

between this syndrome (Figure 3 and Figure 4) and erythema multiforme

major (Figure 2).

Drug-induced s- syndrome and toxic epidermal necrolysis

typically begin one to three weeks after the initiation of therapy

but occur more rapidly with rechallenge18. More than 100 different

compounds have been implicated in both

syndromes3,18,19,33,38,39,40,42,43. Table 4 lists frequently

implicated drugs. For all drugs, the reported reaction rates are

relatively low. The drugs with the highest estimated incidence

include co-trimoxazole (trimethoprim-sulfamethoxazole; 1 to 3

reactions per 100,000 users),3,39,40 a long-acting combination of

sulfadoxine and pyrimethamine (Fansidar-R; 10 reactions per 100,000

users),4,23,44 and carbamazepine (14 reactions per 100,000 users)45.

These estimates, which were based on retrospective series or

spontaneous reports, may substantially underestimate the true

incidence.

Patients often have underlying diseases. A role for infection as a

cofactor has been postulated, but there is little supporting

evidence43. Conditions that alter immunologic function, including

systemic lupus erythematosus, may increase risk46. The HLA phenotype

B12 is associated with a threefold increase in risk47.

Toxic epidermal necrolysis has been described in an animal model of

cutaneous acute graft-versus-host disease (GVHD)48. Toxic epidermal

necrolysis has developed in humans a few weeks after bone marrow

transplantation49,50. In transplant recipients cutaneous necrolysis

is most often related to acute GVHD, but in some cases it is drug-

induced50,51. Ocular lesions are rare in acute GVHD and frequent in

drug-induced toxic epidermal necrolysis18,50,51. Whether drug-induced

or related to acute GVHD, epidermal necrolysis after bone marrow

transplantation suggests a very poor prognosis49,50,51.

Patients with the acquired immunodeficiency syndrome have a higher

incidence of many drug-induced skin rashes, including s-

syndrome and toxic epidermal necrolysis, with a combined incidence of

1 per 1000 person-years52,53,54,55. Sulfonamides are the most

frequently implicated agent. The risk of reactions to sulfonamides is

10 to 100 times higher among persons infected with the human

immunodeficiency virus (HIV) than among other persons. This high risk

reflects more frequent drug use and greater susceptibility54,55.

Pathophysiology

Patients with s- syndrome or toxic epidermal necrolysis

induced by sulfonamides or anticonvulsant agents often have an

alteration in the detoxification of reactive drug metabolites56,57.

The recurrence of s- syndrome and toxic epidermal

necrolysis within 48 hours of rechallenge (although the initial

reaction occurs about 14 days after treatment is begun) argues

against a direct toxic effect and is more consistent with immunologic

mechanisms18.

The immunopathologic pattern of early lesions suggests a cell-

mediated cytotoxic reaction against epidermal cells58,59,60,61. The

epidermis is infiltrated by activated lymphocytes, mainly CD8 cells,

and macrophages58,59,60,61. An immune reaction against drug-reactive

metabolites produced in excess may be responsible. Because

infiltrating cells are present in only moderate numbers, it is

unlikely that these cells are the principal cause of epidermal

necrosis. Cytokines, released by activated mononuclear cells and

keratinocytes, may contribute to local cell death, fever, and

malaise.

Prognosis and Treatment

Mortality rates are below 5 percent for s- syndrome but

about 30 percent for toxic epidermal necrolysis18,19. Sepsis is the

principal cause of death. More extensive epidermal detachment,

increased age, increased blood urea nitrogen concentrations, and

visceral involvement indicate a poorer prognosis. The prognosis does

not appear to be affected by the type and dose of the responsible

drug or the presence of HIV infection.

The physician is responsible for the early recognition of the

reaction, the withdrawal of all potentially responsible drugs, and

the initiation of intravenous-fluid replacement. Although some drugs

are clearly more often responsible than others (Table 4), all drugs,

especially those introduced within one month of the reaction, should

be considered suspect. Patients with widespread skin involvement

should be transferred to an intensive care unit or burn unit. During

transfer, pain control, fluid replacement, aseptic handling, and

avoidance of any adhesive material are important. The main principles

of therapy are the same as for thermal burns, including aggressive

fluid replacement, nutritional support, and antibacterial

treatment62,63.

Many interventions meant to halt the progression of toxic epidermal

necrolysis have been tried, each in a few patients. A positive

result, usually defined as one that halts the spread of necrolysis,

has typically been noted after several previous " ineffective "

treatments. However, in untreated patients, the average duration of

progression is less than four days. Therefore, the results of these

uncontrolled studies cannot be interpreted. Short courses of

corticosteroids early in the disease have been advocated,64 but their

effectiveness has never been demonstrated in controlled trials. Toxic

epidermal necrolysis can develop in patients who are receiving high-

dose corticosteroids3,65. Retrospective studies demonstrate no

benefit of corticosteroids or higher rates of morbidity and mortality

in corticosteroid-treated patients66,67,68. We recommend against

their use. Case reports claiming that plasmapheresis, cyclosporine,

cyclophosphamide, and monoclonal antibodies directed against

cytokines are helpful should be regarded with skepticism59,69,70.

Because these disorders progress so rapidly, many cases have evolved

fully before the patients are hospitalized, thus limiting the

practical value of such treatments. Therefore, therapies that reduce

morbidity associated with skin loss or accelerate regrowth of the

skin are the most promising.

Hypersensitivity Syndrome

A variety of hypersensitivity responses are responsible for most

cutaneous reactions to drugs. The term " hypersensitivity syndrome "

refers to a specific severe idiosyncratic reaction. The syndrome

typically includes skin rash and fever, often with hepatitis,

arthralgias, lymphadenopathy, or hematologic abnormalities (Table 1,

Table 2, and Table 3). Perhaps because of its relatively late onset,

slow evolution, and clinical similarity to many infectious illnesses,

the diagnosis of hypersensitivity syndrome may be delayed.

The aromatic antiepileptic agents (phenytoin, carbamazepine, and

phenobarbital) -- with an estimated incidence of 1 reaction per 5000

patients and perhaps a higher rate among black patients -- and

sulfonamides are the most frequent causes of hypersensitivity

syndrome56,57,71,72,73,74,75,76. Other drugs, especially allopurinol,

gold salts, dapsone, and sorbinil, are also associated with the

syndrome77,78,79,80. Hypersensitivity syndrome may be difficult to

distinguish from serum sickness or drug-induced vasculitis.

Laboratory findings often help distinguish these clinically similar

conditions from each other and from infectious diseases (Table 2).

The hypersensitivity syndrome typically develops two to six weeks

after a drug is first used, later than most other serious skin

reactions (Table 3). With antiepileptic drugs, fever and rash are the

most frequent presenting symptoms (in 87 percent of cases).

Lymphadenopathy (in about 75 percent) is frequent and usually due to

benign lymphoid hyperplasia17. Atypical lymphoid hyperplasia and

pseudolymphoma occasionally occur81. Some of these cases resolve with

withdrawal of the drug, but in some cases lymphoma eventually

develops82. Hepatitis (51 percent); interstitial nephritis (11

percent); hematologic abnormalities, especially eosinophilia (30

percent); and mononucleosis-like atypical lymphocytosis are also

common17. Involvement of the heart, lung, thyroid, and brain is less

frequent17,83. Severe cases of hepatitis may be life-threatening84.

A genetically determined inability to detoxify the toxic arene oxide

metabolic products of anticonvulsant agents has been observed in

patients with the hypersensitivity syndrome, but the syndrome also

occurs in patients without this abnormality17,85. Cells from the

parents of affected patients have a degree of in vitro sensitivity to

these toxic metabolites that is intermediate between that of affected

patients and that of controls17. Positive tests have been noted in

multiple family members86. Cross-sensitivity between the various

aromatic antiepileptic drugs is well documented, making it difficult

to select alternative anticonvulsant therapy87,88.

Rashes of all types are reported with carbamazepine or phenytoin

therapy73,89. Most of these rashes are morbilliform (Figure 1) and

will abate even if the drug is continued. Unfortunately, the

hypersensitivity syndrome often initially presents as a morbilliform

eruption indistinguishable from less serious reactions (Figure 1).

The reaction may become indurated and infiltrated (Figure 13). Any

cutaneous reaction associated with aromatic anticonvulsant agents

that includes facial swelling, exfoliative dermatitis (Figure 9),

fever, lymphadenopathy, eosinophilia, arthritis, hepatitis, or

bullous or purpuric skin lesions or begins more than two weeks after

therapy is initiated is especially worrisome.

Sulfonamide-induced hypersensitivity syndrome and that induced by

antiepileptic agents are clinically indistinguishable16,57. Slow N-

acetylation of sulfonamide and increased susceptibility of patients'

leukocytes in vitro to toxic hydroxylamine metabolites are associated

with greater susceptibility, but only a small percentage of people

who acetylate sulfonamides slowly have reactions to these

drugs16,57,90.

Recovery is usually total, but rash and hepatitis may persist for

weeks. Treatment with corticosteroids has been widely advocated, but

controlled studies are lacking91. We have observed dramatic

improvements in symptoms and laboratory measurements in patients

given systemic corticosteroids ( 0.5 mg per kilogram of body

weight). Relapses of rash and hepatitis may occur as corticosteroids

are tapered. Transient hypothyroidism may also develop92.

Vasculitis and Serum Sickness

Vasculitis characterized by inflammation and necrosis of blood-vessel

walls has many causes93. Drug-induced vasculitis typically involves

small vessels and is a subtype of hypersensitivity vasculitis,94

which also includes cutaneous leukocytoclastic vasculitis and serum

sickness94.

In 1905, von Pirquet and Schick described serum sickness in children

treated with horse serum containing diphtheria antitoxin95. More

recently, serum sickness has been noted in patients treated with

horse antithymocyte globulins or human diploid-cell rabies

vaccine95,96,97. Serum sickness is a type III hypersensitivity

reaction mediated by the deposition of immune complexes in small

vessels, activation of complement, and recruitment of granulocytes.

Drug-induced vasculitis is believed to result from antibodies

directed against drug-related haptens, but this has not been

proved98. Alternative proposed mechanisms include direct drug

toxicity against vessel walls, autoantibodies reacting with

endothelial cells, and cell-mediated cytotoxic reactions against

vessels93,99,100,101.

Clinical Presentation

Serum sickness has distinctive skin findings. Typically, erythema

first occurs on the sides of the fingers, toes, and hands, before a

more widespread eruption that is most often morbilliform (in two

thirds of patients), sometimes with urticaria95,96,97. Urticaria is

seldom seen alone. About half the cases of serum sickness have

visceral involvement. Rash, fever, constitutional symptoms,

arthralgia, and arthritis are the most frequent clinical

findings95,96.

The clinical hallmark of cutaneous vasculitis is palpable purpuric

papules, classically located on the lower extremities, although any

site may be involved (Figure 14)93,102,103. Hemorrhagic blisters,

urticaria, ulcers, nodules, Raynaud's disease, and digital necrosis

may also occur. The same vasculitic process may also affect the

kidney, liver, gastrointestinal tract, or nervous system and can be

life-threatening. Histologically, small dermal vessels exhibit

fibrinoid necrosis, infiltration by polymorphonuclear leukocytes, and

nuclear dust103. The results of direct immunofluorescence are often

positive, with deposits of IgM and C3 complement on capillary

walls103.

In serum sickness, serum C3 and C4 complement levels are markedly

decreased96. Serum sickness begins 8 to 14 days after the initial

exposure to a foreign protein. Other kinds of drug-induced vasculitis

typically develop 7 to 21 days after a new drug is begun, but the

interval can be longer99. When otherwise unexplained palpable purpura

develops in a patient, any drug the patient is taking, especially

those introduced within the preceding two months, should be

considered suspect. Withdrawing the drug usually leads to rapid

resolution. Systemic corticosteroids may benefit some patients.

Differential Diagnosis

Drug-induced hypersensitivity vasculitis may be difficult to

distinguish from other types of vasculitis. Schonlein-Henoch purpura

usually occurs in younger patients, with characteristic large

purpuric cutaneous lesions, often on the buttocks. Renal and

gastrointestinal involvement is common. IgA is deposited in

vessels104. Cryoglobulinemia-associated vasculitis has a chronic or

recurrent course. Polyarteritis nodosa and Wegener's granulomatosis

sometimes begin as a palpable purpura105. Most patients with

Wegener's granulomatosis have autoantibodies to neutrophil

cytoplasmic antigens,106 a feature that is usually absent in drug-

induced vasculitis. Infection and collagen vascular disorders can

also induce vasculitis93. Excluding infection as a cause is often the

greatest challenge. Drugs cause about 10 percent of cases of acute

cutaneous vasculitis102,103.

Only a small fraction of drug reactions take the form of

vasculitis7,8. Propylthiouracil may induce a clinically distinctive

vasculitis initially involving the face and ear lobes, with erythema

and later purpura107,108. Antinuclear antibodies and antineutrophil

cytoplasmic antibodies may be produced109,110.

Reactions resembling serum sickness (rash, fever, and arthralgias)

occur in about 1 of 2000 children given cefaclor and have also been

reported with minocycline, penicillins, propranolol, streptokinase,

and other drugs114,115,116,117,118. Since reduced concentrations of

serum complement are not generally noted, most such cases probably do

not represent true serum sickness.

Anticoagulant-Induced Skin Necrosis

A rare and devastating effect of warfarin therapy is skin necrosis, a

consequence of occlusive thrombi in vessels of the skin and

subcutaneous tissue119. Typically, warfarin-induced skin necrosis

begins three to five days after therapy is initiated. The use of

higher initial doses, obesity, and female sex appear to increase the

risk120. Red, painful plaques evolve to necrosis (Figure 15), with

hemorrhagic blisters or necrotic scars, frequently in areas with

large quantities of adipose tissue, including the breasts, hips, and

buttocks. Acral involvement is infrequent.

People with hereditary deficiency of protein C, a natural

anticoagulant protein, are at highest risk, even if they are

heterozygotes and thus have no history of recurrent

thrombosis119,120,121,122. In these persons, warfarin greatly

depresses protein C levels before decreasing other vitamin K-

dependent coagulation factors, inducing a transient hypercoagulable

state and thrombus formation119. Rapid recognition of painful, red

plaques in fatty areas is the key to diagnosis. Therapy includes

discontinuing warfarin, administering vitamin K to reverse the effect

of warfarin, giving heparin as an anticoagulant, and administering

monoclonal antibody-purified protein C concentrate123. Necrotic

tissues may require surgical debridement and grafting. If not rapidly

treated, this condition may be fatal. It develops in 1 in 10,000

patients receiving warfarin, a prevalence that is about 2 percent of

the estimated prevalence of protein C deficiency119,124. Since most

persons with protein C deficiency tolerate warfarin, other factors

must play a part. Protein S or antithrombin III deficiency also

confers an increased risk125.

Heparin can also cause thrombosis and necrosis in the skin and other

organs126. The mechanisms of heparin-induced and warfarin-induced

necrosis are almost certainly different. Heparin can induce vessel

thrombosis with fibrin thrombi at injection sites and distant skin

sites and in other organs127,128. Localized reactions at injection

sites are frequent, but devastating widespread reactions are not.

Heparin-induced platelet aggregation may be responsible for

widespread reactions. These lesions need to be differentiated from

other cutaneous reactions to heparin at injection sites, which are

most likely immunologic126,127. Neither protein C nor protein S plays

a part. In heparin-induced necrosis, levels of fibrinogen and fibrin-

split products are usually normal, but platelet counts are often

depressed126. Evidence of primary vasculitis is lacking. Heparin-

induced thrombocytopenia and thrombosis may be an immune-complex

disorder129. In addition to discontinuation of the drug, treatment

with warfarin or antiplatelet drugs is useful126.

Angioedema

Immediate-hypersensitivity reactions can produce a range of cutaneous

findings from simple urticaria to angioedema or anaphylaxis. The

mechanism and treatment of IgE-mediated immediate-hypersensitivity

reactions including anaphylaxis, which are most often induced by

insect stings and food, have been reviewed recently130,131. Many drug-

induced cases of angioedema are not mediated by IgE. We shall briefly

discuss newer drugs that cause angioedema or anaphylaxis.

Antibiotics (especially the penicillins), anesthetics, and

radiocontrast agents are the most common causes of serious IgE-

mediated, drug-induced immediate hypersensitivity130,131. Angioedema

occurs in about 1 per 10,000 courses of penicillin and leads to death

in 1 to 5 per 100,000 courses. In persons receiving long-term

penicillin prophylaxis for rheumatic fever, the risk of angioedema

persists during treatment132.

Other frequently used drugs, including angiotensin-converting-enzyme

(ACE) inhibitors, nonsteroidal antiinflammatory drugs, radiocontrast

agents, opiates, and curare, cause angioedema that is not IgE-

mediated. ACE inhibitors induce the majority of cases of angioedema

that lead to hospitalization133,134. The observed incidence of drug-

related angioedema has increased in parallel with the increased use

of ACE inhibitors, especially longer-acting ACE

inhibitors133,134,135,136. Angioedema occurs in 2 to 10 per 10,000

new users of ACE inhibitors -- a rate that is probably higher than

that associated with penicillins137. The risk is highest during the

first three weeks of therapy137. These reactions may be due to the

inhibition of kinin metabolism138. Hemodialysis with high-flux

dialysis membranes, which may increase the production of bradykinin,

greatly increases the risk of anaphylactoid reactions associated with

ACE inhibitors139,140,141. Reactions occur in up to 35 percent of

patients treated in this manner141.

Conclusions

Adverse reactions to drugs most often affect the skin, but only a

small fraction are life-threatening or lead to disabling sequelae.

Because of the low frequency of such severe reactions (usually less

than 1 reaction per 5000 exposed patients), they are unlikely to be

detected in premarketing clinical trials. Only if clinicians

recognize and report severe reactions to regulatory authorities and

manufacturers can new drugs associated with a high risk of such

reactions be identified, relabeled, or withdrawn from the

market142,143.

For many severe cutaneous reactions to drugs, including toxic

epidermal necrolysis, s- syndrome, vasculitis, and serum

sickness, medical intervention is limited to the early recognition of

the symptoms and the withdrawal of the offending drug. Even for other

reactions that may benefit from therapy, early recognition of the

symptoms and prompt withdrawal of suspect drugs are usually the most

important steps. Therefore, clinicians should carefully evaluate the

signs and symptoms of all adverse cutaneous reactions thought to be

due to drugs and immediately discontinue all drugs that are not

essential, especially when the signs or symptoms associated with more

severe reactions are present (Table 2). After recovery, patients

should be advised to avoid the drug thought to be responsible for the

reaction and all chemically related compounds. Patients with toxic

epidermal necrolysis and hypersensitivity syndrome should alert their

first-degree relatives to their elevated risk of such reactions to

the same drugs.

Supported in part by a grant from INSERM (90-0812).

Source Information

From the Department of Dermatology, Henri Mondor Hospital, University

of Paris XII, Creteil, France (J.C.R.), and Beth Israel Hospital,

Harvard Medical School, Boston (R.S.S.).

Address reprint requests to Dr. Stern at the Department of

Dermatology, Beth Israel Hospital, 330 Brookline Ave., Boston, MA

02215.

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