Life Threatening Rams

Clinics in Dermatology (2005) 23, 171 – 181

Life-threatening acute adverse cutaneous drug reactions Ronni Wolf, MDa,*, Edith Orion, MDa, Batsheva Marcos, MDa, Hagit Matz, MDb a

Dermatology Unit, Kaplan Medical Center, 76100 Rechovot, Israel Department of Dermatology, Tel-Aviv Sourasky Medical Center, 64239 Tel-Aviv, Israel

b

Abstract Adverse cutaneous reactions to drugs are frequent, affecting 2% to 3% of all hospitalized patients. Fortunately, only about 2% of adverse cutaneous reactions are severe and very few are fatal. Stevens-Johnson syndrome and toxic epidermal necrolysis are severe life-threatening diseases with a mortality rate reaching 30%, and only prompt recognition and diagnosis, withdrawal of the offensive drug, and referral to an intensive care unit or burn care unit might improve the prognosis and save the patient’s life. Drug eruption with eosinophilia and systemic symptoms syndrome, formerly termed drug hypersensitivity syndrome, is a rather distinct severe adverse drug reaction (ADR) characterized by eruption, fever, lymph node enlargement, and single or multiple organ involvement, with a high morbidity and a mortality rate of 10%. These severe ADRs, together with serum sickness–like syndrome, are discussed in this review. Other severe reactions, such as anaphylaxis and vasculitis, are discussed elsewhere in this issue. Although most of the readers, particularly those in the outpatient arena, will not be treating these patients, they are the ones who will see them first, diagnose them, realize the potential danger in their condition, and refer them to the appropriate treatment venue. Therefore, dermatologists should be familiar with these conditions and be prepared to handle them adequately. D 2005 Elsevier Inc. All rights reserved.

Introduction Adverse drug reactions (ADRs), an inevitable consequence of modern drug therapy, are among the most important causes of iatrogenic illness in terms of morbidity and mortality. They bear serious medical-legal and economic consequences. Numerous studies have shown that ADR-related hospital admissions comprise up to 10% of the total number of admissions.1-4 Complications of drug * Corresponding author. Fax: +972 9 956 0978. E-mail address: [email protected] (R. Wolf ). 0738-081X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2004.06.012

therapy are the most common type of adverse events in hospitalized patients, accounting for 19% of such occurrences. Adverse cutaneous reactions to drugs are frequent, affecting 2% to 3% of all hospitalized patients.5 Fortunately, only about 2% of adverse cutaneous reactions are severe and very few are fatal.6,7 The spectrum of severe cutaneous drug reactions includes Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), hypersensitivity syndrome (HSS), anaphylaxis and angioedema, serum sickness, and cutaneous vasculitis, and these conditions will be discussed here. There are other reactions, such as severe photosensitivity disorders, exfoliative dermatitis, lupus erythematosus–

172 like, dermatomyositis-like, scleroderma-like reactions, druginduced pemphigus, and eosinophilia-myalgia syndrome, which only rarely cause immediate mortality and they will not be covered in this review.

Toxic epidermal necrolysis and Stevens-Johnson syndrome Historical background In his classic 1866 treatise On Disease of the Skin, Ferdinand von Hebra precisely described and gave the name to erythema multiforme (EM; to be exact, erythema exudativum multiforme).8 In 1922, 2 American physicians, Stevens and Johnson9 described 2 patients, boys aged 7 and 8 years, who had ban extraordinary, generalized eruption with continued fever, inflamed buccal mucosa, and severe purulent conjunctivitis.Q Both cases were misdiagnosed by primary care physicians as hemorrhagic measles. Erythema multiforme was part of the differential diagnosis in both cases, but it was excluded because of the bcharacter of skin lesions, the lack of subjective symptoms, the prolonged high fever, and the terminal heavy crusting.Q In spite of the presence of leukopenia in both cases, in their initial report, Stevens and Johnson suspected an infectious disease of unknown etiology as the cause (http://www.emedicine.com/ oph/topic268.htm). In 1950, Thomas10 divided EM into 2 categories: EM minor (von Hebra) and EM major, also known as SJS. In 1956, Alan Lyell wrote the most highly cited article ever to appear in The British Journal of Dermatology: He described 4 patients with a scalding disease, which was later given the name toxic epidermal necrolysis (TEN), or the Lyell’s syndrome or Lyell’s disease.11 He thought that this syndrome was caused bby some (hypothetical) circulating toxin, which, after producing a prodromal period of illness, manifested itself as dscaldingT of the skinQ.12 Ironically, one of his patients had staphylococcal scalded skin syndrome, the only form of TEN cased by a toxin, which had not yet been discovered in 1956. Although the credit for being the first to describe this syndrome was for many years given to Lyell, some authors13 took note of earlier publications of this syndrome under the names of bdermatitis exfoliativa neonatorumQ by Gottfried Ritter von Rittershain 1 4 in 1878 and berythroderma with epidermolysisQ by Debre et al15 in 1939.

Definition and classification Erythema multiforme was initially described as an acute self-limited skin disease, symmetrically distributed on the extremities with typical concentric btargetQ lesions and often recurrent.8 The terminology EM minor was later proposed to separate the mild cutaneous syndrome from

R. Wolf et al. more severe forms with involvement of several mucous membranes, EM major. Stevens-Johnson syndrome had for years been considered an extreme variant of EM, and TEN as being a different entity. In 1993, a group of experts16 proposed a new classification in which they separated SJS from the EM spectrum and added it to TEN, thereby creating a new spectrum of drug-related severe diseases, for example, SJS/TEN. Two disease spectra were created: (1) EM consisting of EM minor and EM major and (2) SJS/TEN. The former are often recurrent, postinfectious disorders (especially herpes and mycoplasma) with low morbidity and almost no mortality. The latter are usually severe drug-induced reactions with high morbidity and poor prognosis. The former show the characteristic EM pattern of typical target lesions with or without blisters and a symmetrical distribution, mainly acral, with or without mucosal involvement, whereas the latter show widespread purpuric macules often confluent in limited areas, usually the trunk, with positive Nikolsky’s sign and epidermal detachment. In essence, this group of dermatologists from Canada, France, Germany, Italy, and the United States16 created a consensus definition and classification of acute bullous disorders that are attributed to drugs or infectious agents based on a photographic atlas that illustrated the various patterns of the skin lesions and extent of body surface area (BSA) detachment. The clinical pattern of the individual skin lesion was classified into 4 different types: 1.

2.

3.

4.

Typical targets: individual lesions less than 3 cm in diameter with a regular round shape, well-defined border, and at least 3 different zones, that is, 2 concentric rings around a central disk. One ring consists of palpable edema, paler than the center disk. Raised atypical targets: round, edematous, palpable lesions, similar to EM but with only 2 zones and/or a poorly defined border. Flat atypical targets: round lesions characteristic of EM but with only 2 zones and/or a poorly defined border and nonpalpable with the exception of a potential central blister. Macules with or without blisters: nonpalpable, erythematous, or purpuric macules with an irregular shape and size and often confluent. Blisters often occur on all or part of the macule.

The involved BSA should measure the extent of detached and detachable epidermis (which is often much less than the area of erythema) at the worst stage of the disease. These authors then proposed the following consensus classification into 5 categories: 1. 2.

Bullous EM: detachment b10% of BSA, localized typical targets or raised atypical targets. SJS: detachment b10% of BSA, widespread erythematous or purpuric macules of flat atypical targets.

Life-threatening acute adverse cutaneous drug reactions 3.

4. 5.

Overlap SJS/TEN: detachment between 10% and 30% of BSA, widespread purpuric macules or flat atypical targets. TEN with spots: detachment N30% of BSA, widespread purpuric macules or flat atypical targets. TEN without spots: detachment N10% of BSA, large epidermal sheets and no purpuric macules.

They went on to suggest a practical algorithm in the definition and categorization of these diseases based on their classification. The first question the clinician needs to ask is: bWhat is the percent of detachment?Q The second question is: bWhat is the nature of the discrete lesions?Q They also suggested that their purely descriptive clinical classification might indicate a causative drug, namely, that SJS, TEN, and overlap are drug-induced, while the diseases in the EM group are due to infectious agents. While there is no doubt that this classification is of great clinical/practical as well as theoretical/academic value and that it created, for the first time, generally worldwideaccepted criteria for defining this spectrum of the disease, we feel that the jury is still out, particularly with regard to the link between clinical types to causative factors. Furthermore, the percentage of detachment, a major criterion in this classification and a significant prognostic factor, is defined as BSA involved at the worst stage of the disease and thus cannot be estimated when patients are seen by the clinician for the first time.

Clinical pattern The initial symptoms of TEN, that is, before the appearance of frank mucocutaneous sloughing, include fever (all cases) as well as conjunctivitis (32% of cases), pharyngitis (25% of cases), and pruritus (28% of cases). These signs usually last 2 to 3 days and can resemble an upper respiratory tract infection. There is speculation that the fever is caused by drugs or release of pyrogens from epidermal necrosis, or both, but that it is not due to infection. Mucous membranes (in increasing order of frequency: oropharynx, eyes, genitalia, anus) are commonly affected 1 to 3 days before the skin lesions appear.17 The cutaneous lesions begin with a burning and painful eruption initially not typical. This eruption extends symmetrically from the face and upper part of the body to the entire body, predominantly on the trunk and proximal limbs. The initial lesions are poorly defined macules with darker centers. Maximal extension of lesions usually occurs in 2 or 3 days, but can be manifested in a few hours. There is a sheetlike loss of epidermis and the appearance of flaccid blisters that spread with pressure in TEN. Nikolsky’s sign is positive over large areas involved by confluent erythema. Traumatized sites leave a dark red oozing dermis. The entire skin surface may be involved, with up to 100% of epidermal sloughing. Widespread painful mucosal erosions result in impaired alimentation, photophobia, and painful micturition. Keratitis and corneal erosions are less frequent, but

173 they are known to occur. Asthenia, skin pain, and anxiety are extreme. Gastrointestinal or tracheobronchial epithelium can be involved via a process of necrosis resulting in profuse diarrhea or respiratory distress, respectively, and causing high morbidity.18,19 Blood abnormalities are also almost always present. Anemia and lymphopenia are found in virtually all patients, neutropenia in 30% of patients (indicating a poor prognosis), and thrombopenia in 15% of patients. Prerenal azotemia is common.20 Fluid losses are massive and accompanied by with electrolyte imbalance. During the first days, skin lesions are usually colonized by Staphylococcus aureus; they are later invaded by gramnegative rods. Thermoregulation is impaired and energy expenditure is increased. Alteration of immunologic functions increases the risk of sepsis.21,22 Re-epidermization begins after a few days, and most of the skin surface is re-epithelialized in 3 weeks. Pressure areas and mucosal lesions often remain eroded and crusted for 2 additional weeks. Scarring may occur in areas of pressure or infection. Disturbances in pigmentation are characteristically present and lead to a patchwork of pigmented and hypopigmented areas. Ocular sequelae are frequent and severe, affecting about 40% of the survivors.23,24 Abnormal nail regrowth, phimosis, and vaginal synechiae may be present as well.24

Laboratory changes Anemia is present in virtually every patient. It is characterized by a progressive drop in hemoglobin, accompanied by a moderate reduction in serum iron. The peculiarity of the anemia lies in its aregenerative character, with concomitant medullary erythroblastopenia and blood reticulocytopenia. It does not appear to be secondary to the inflammatory process because the regenerative capacity returns before the peak of the inflammatory phase. Lymphopenia is also commonly present (90% of patients) due to depletion of CD4+ helper T lymphocytes.25,26 When it is present, neutropenia indicates a poor prognostic sign. Thrombopenia is rarely seen and eosinophilia is very unusual. Disseminated intravascular coagulation has been reported, and some authors advocate prophylactic treatment with heparin.27 About 30% of the patients have elevated transaminase enzymes28 and elevated levels of amylase and lipase without other evidence of pancreatic involvement.29 Proteinuria is present in more than half of the patients, but usually at a level b1 g/d. Renal tubular enzyme secretion and microalbuminuria are increased in all patients, but the glomerular filtration rate remains normal. This profile is suggestive of both proximal tubule involvement and secondary effects of glomerular structure.30

Causative drugs More than 100 drugs have been associated with the development of SJS/TEN in single case reports or retro-

174 spective studies. In 1995, Roujeau et al31 published the results of the first prospective case-control study to assess the relative risk for different drugs being associated with SJS/ TEN. Until then, estimates had been done from retrospective population-based studies or case reports, but these kinds of studies did not supply reliable data and did not allow quantification of risk because of the rarity of the disease.32 In the study of Roujeau et al, sulfonamides were the most strongly associated with TEN (crude relative risk, 172; 95% confidence interval, 75-396) followed by antibiotic drugs (in descending order of frequency: cephalosporins, quinolones, aminopenicillins, tetracyclines, macrolides), imidazole antifungals, anticonvulsants (phenobarbital, phenytoin, valproic acid, carbamazepine, and lamotrigine), then nonsteriodal anti-inflammatory drugs (especially oxicam), allopurinol, and others. The role of antiepileptic drugs in SJS/TEN was analyzed in another case-control study.33 About 16% of SJS/TEN cases were associated with short-term use of antiepileptic drugs. The risk for developing TEN was largely confined to the start of antiepileptic therapy, that is, within the first 8 weeks, after which it was not associated with an increased risk. The incubation time for all other drugs varies from a few days to 2 to 3 weeks, but may be up to 1 month.

Treatment Both SJS and TEN are life-threatening diseases, and so the management of patients must be prompt. Early diagnosis with the early recognition and withdrawal of all potential causative drugs is essential to a favorable outcome. Morbidity and mortality decrease if the culprit drug is withdrawn no later than the day when blisters of erosions first occurred. No difference was seen for drugs with long half-lives.33 The patient must be transferred to an intensive care unit or a burn center. Prompt referral reduces risk of infection, mortality rate, and length of hospitalization.33-35 The main types of symptomatic treatment are the same as for burns, and the experience of burn units is helpful for the treatment of TEN: environmental temperature control, careful and aseptic handling, sterile field creation, avoidance of any adhesive material, and maintenance of venous peripheral access distant from affected areas. Intravenous fluid replacement must be initiated immediately upon admission and using macromolecules or saline solutions. The rate and amount of fluid and electrolytes administration must be adjusted daily. The early fluid requirement of TEN patients are two thirds to three fourths of those of patients with burns covering the same area.36 Like most other authors, we do not advocate the use of prophylactic antibiotics. Catheters should be changed and cultured regularly, and bacterial sampling of the skin lesions must be performed at least every 48 hours. Early initiation of massive oral nutrition by nasogastric tube to minimize protein losses promotes healing and decreases the risk of stress ulcer.

R. Wolf et al. The environmental temperature should be raised to 308C, and heat shields, infrared lamps, and an air-fluidized bed should be provided. Thromboembolism and disseminated intravascular coagulation are important causes of morbidity and death: Effective anticoagulation with heparin is recommended for the duration of hospitalization.27 Like patients with major burns, TEN patients suffer severe pain as well as emotional instability and extreme anxiety, which should be treated appropriately.34 Pulmonary care includes aerosols, bronchial aspiration, and physical therapy. Intubation and mechanical ventilation are nearly always necessary if the trachea and bronchi are involved. The SJS/TEN disease spectrum remains an important cause of severe visual loss in a significant number of patients. Therefore, daily examination by an ophthalmologist and vigorous treatment are mandatory. Antiseptic or antibiotic eye drops and eye ointments, with or without corticosteroids, should be instilled every 2 hours. Lid-globe adhesions should be cautiously removed with a glass rod twice daily to avoid occlusion of the fornices, taking care not to strip pseudomembranes, which may lead to bleeding and increased conjunctival scarring.37 There is no consensus about topical care. Topical antiseptics (0.5% silver nitrate or 0.05% chlorhexidine) are usually used to paint, bathe, or dress the patients. Silver sulfadiazine, which is very popular in burn units, should be avoided because sulfonamides are frequently implicated in the etiology of TEN and can cause hemolysis in glucose6-phosphate dehydrogenase-deficient patients. Although most surgeons of the burn units advocate large operative debridement of nonviable epidermis followed by immediate wound cover with biologic dressings, dermatologists are more conservative, leaving in place the epidermis that has not yet peeled off. Dressings may be gauzes with petrolatum, silver nitrate, polyvidone iodine, hydrogels, Hydrone, Vigilon (semipermeable dressings), SoftSorb, and others that can also be impregnated with silver nitrate.

Corticosteroids and other bdisease-modifyingQ drugs Corticosteroids have for years been the mainstay therapy for TEN and SJS in most38-46 (although not all47,48) dermatological centers, including ours, in the belief that they suppress the intensity of reaction, control the extension of the necrolytic process, decrease the involved area, reduce fever and discomfort, and prevent damage to internal organs when given at an early stage and in a sufficiently high dosage. There are no randomized clinical trials on the use of corticosteroids in the treatment of these life-threatening diseases. The early approach to treatment was followed by a complete turnabout at the beginning of the 1980s when the management of SJS/TEN shifted to specialized burn centers

Life-threatening acute adverse cutaneous drug reactions and was taken over by nondermatologists, mostly surgeons, who rejected the use of steroids almost out of hand. They regarded them as being hazardous and a potential iatrogenic source of decreased host resistance, increased morbidity and complications (eg, sepsis, leukopenia, thromboembolism, gastrointestinal ulcerations, etc), prolonged recovery, worse and deteriorated prognosis, reduced survival, and, for all intents and purposes, a contraindicated mode of therapy.49-54 In the absence of well-controlled trials, many dermatological departments adopted the concept of large burn units to avoid the use of steroids, in our opinion more as a matter of practicing bdefensive medicineQ and being on the safe (rather than on the effective) side. The simple fact is that burns and TEN are 2 separate disease entities, and although there is an acute skin failure in both conditions, they differ in etiology and pathomechanism. Specifically, burns are a one-time, immediate event that affects the skin from the outside, whereas TEN is a more complex, probably immune (T-lymphocyte)-mediated process that reaches the skin from within. And, above all, unlike thermal burns, in TEN, the disease continues to progress and becomes more intensified over a period of several days after its first appearance, and, therefore, it would make good sense to turn to aggressive diseasemodifying drugs that are capable of halting disease progression, reduce the extent of skin detachment, decrease the inflammatory cytokines and, consequently, the symptoms, discomfort, organ damage (less relevant for burns), and perhaps mortality. The important role of burn units in the treatment of these patients notwithstanding, we think it had been a mistake to ignore our collective clinical experience and own good judgment and be swayed by the stand taken by plastic surgeons who view TEN and thermal burns as the same entity. It is our hope that with the introduction of new immunomodulating drugs, the pendulum will swing once more in the opposite direction, that is, toward advocating disease-modifying agents. The first step in this long journey has already been taken with the introduction of intravenous immunoglobulins (IVIG) in the treatment of TEN patients in 1998. Following the observation that antibodies present in IVIG block Fas-mediated keratinocyte apoptosis in vitro and because the Fas-Fas ligand pathway of apoptosis is considered the first or pivotal step in the pathogenesis of TEN,55 Viard et al56 tried this treatment in their patients. In their initial article, all 10 patients benefited from this therapy, an observation that was confirmed in several additional studies,57-63 but contradicted by at least 1 prospective noncomparative study based on 34 patients from a single referral center.64 Considering the tendency to report therapy successes rather than therapy failures, taken together with the enormous difficulties in evaluating the value of any treatment of a disease as rare and poorly understood as

175 TEN, we are obliged to conclude that high-dose IVIG is still not of unequivocally proven benefit for this disease. Furthermore, there is no consensus as to the best regimen and dosage, and there are also variations between various manufacturers as well as batch-to-batch variations. Although we have serious reservations that the currently available IVIG will provide the answers we seek, the introduction of this treatment is to be welcomed if only for the change it brought in our approach toward diseasemodifying agents, which we believe might be beneficial and even represent the optimal therapeutic management for SJS/TEN patients. It is to be expected that with the meteoric advances being made in biologic therapy and the continuing development of target monoclonal antibodies against cytokines and receptors, new therapies will emerge that will more selectively and specifically target the underlying processes, thus avoiding treatment-related side effects. Until these new therapies will be available for clinical use, we advocate treating TEN patients with what we have here and now, namely, with IVIG and, yes, with corticosteroids.

Drug hypersensitivity syndrome or drug eruption with eosinophilia and systemic symptoms Definition and classification Drug eruption with eosinophilia and systemic symptoms (DRESS) syndrome, formerly termed drug hypersensitivity syndrome, is a rather distinct severe potentially fatal ADR characterized by eruption, fever, lymph node enlargement, and single or multiple organ involvement, characteristically occurring in a delayed fashion 3 to 8 weeks after starting treatment with the inciting drug for the first time. Phenytoin HSS was first described in 1939,65 1 year after phenytoin had been introduced in the treatment of convulsive disorders. In the following years, similar reactions have been reported, initially to various anticonvulsant drugs66,67 and later to many other drugs.68-70 Consequently, the name of this reaction was changed to drug HSS, instead of anticonvulsant, sulfone, or dapsone HSS. The word hypersensitivity itself, however, is ambiguous and uninformative insofar as it may apply to any idiosyncratic reaction that fits one phase of the classic Gell and Coombs classification. Therefore, a more informative, precise, and clinically relevant term has been proposed, DRESS.71 DRESS is usually defined by the triad of fever, skin eruption, and internal organ involvement. In this context, it should be mentioned that serum sickness–like reaction (SSLR), which has many common features with DRESS syndrome, is a distinct disease that has another pathogenesis and should be separated and distinguished from DRESS syndrome.

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Here is a comparison between DRESS syndrome and SSLR: Symptom

DRESS syndrome

SSLR

Eruption

Exanthematous (mostly) 1-8 wk Present Present Absent Present

Urticarial (mostly) N2 wk Present Absent Present Present

Onset of symptoms Fever Internal organ involvement Arthralgia Lymphadenopathy

Epidemiology and causative drugs The true incidence of DRESS syndrome is unknown because of the variable presentation. It is estimated to occur in between 1 in 1000 and 1 in 10,000 exposures with drugs such as anticonvulsants and sulfonamides.72 In a record linkage study, the risk for developing DRESS syndrome within 60 days of the first or second prescription in new adult users of phenytoin or carbamazepine was estimated to be 2.3 to 4.5 per 10,000 exposures, respectively.73 The aromatic anticonvulsants (phenylhydantoin, phenobarbital, carbamazepine)66,72,74-76 and sulfonamides77 are the most common causes of DRESS syndrome, but a variety of other drugs, especially lamotrigine,75,76 allopurinol,78,79 nonsteroidal anti-inflammatory drugs,80 captopril,81 antibiotics,82-84 tuberculostatic drugs,85 calcium channel blockers, 86 mood stabilizers, 87 neuroleptics, 88 dapsone, 89 terbinafine,90 methyldopa,91 minocycline,70 and antiretroviral drugs,92 have been associated with this clinical entity.

Clinical features DRESS syndrome occurs most frequently upon first exposure to the drug, with initial symptoms starting between 1 and 8 weeks after exposure to the drug.66 In previously sensitized individuals, the syndrome may occur within 1 day on rechallenge. Fever and malaise, which can be accompanied by pharyngitis and cervical lymphadenopathy, are usually the presenting symptoms. Frequently, fever is high and spiking, ranging from 388C to 408C. The spikes in temperature may generate concern for a suspected underlying infection, but results of various cultures are negative, and the temperature spikes may persist for weeks after the drug is discontinued, a finding that is especially true in patients with a severe reaction.93 A drug eruption occurs in approximately 90% of patients. In most cases, the cutaneous eruption starts as a macular erythema that often evolves into a red, symmetrical, pruritic, confluent, and papular eruption. Pustules, either follicular or nonfollicular, may also be present. Initially, the upper trunk and face are affected with later involvement of the lower extremities. Facial and periorbital edema is well recognized and can lead to such gross distortion of the patient’s features that they can become unrecognizable. Mucosal involvement

is not infrequent and can present as conjunctivitis and ulceration of the vaginal and buccal mucosae. As for internal organ involvement, there is a large degree of variability in each patient with regard to both the target organs involved and the severity of the involvement. It is important to emphasize, however, that the severity of cutaneous changes does not necessarily reflect the severity of internal organ involvement. Therefore, careful assessment is necessary for any patient with DRESS syndrome and internal organ involvement. It is also important to bear in mind that internal organ involvement may not develop for 1 to 2 weeks into the reaction and may even develop 1 month later. The liver is the most frequently involved internal organ, with tender hepatomegaly and sometimes with splenomegaly. Liver involvement can range from mild elevations in serum transaminase levels94-96 to granulomatous hepatitis or fulminant hepatic necrosis.97-100 The degree of hepatitis is related to the interval between the onset of the syndrome and the discontinuation of the drug.101 Prompt recognition of the syndrome and withdrawal of the drug are therefore of utmost importance to the prognosis. The kidney is another organ frequently involved, and the condition can range from mild hematuria to nephritis to acute renal failure usually after acute granulomatous interstitial nephritis, despite discontinuation of the offending drug.102-104 Rarer manifestations of DRESS syndrome are colitis,102,105-107 pneumonitis,104,108-110 pancreatitis,104,111 myocarditis,100,104,112 encephalitis,95,113-116 arthritis,117-119 and myositis.120-122 Thyroiditis with autoantibodies has also been reported. Its acute hyperthyroid phase may be missed by the clinician because of fever, tachycardia, and malaise, which are part of DRESS syndrome, and may thus be identified only several months later when hypothyroidism develops.123 Lymphadenopathy is perhaps the most frequent finding associated with DRESS syndrome. In the early stages of the disease, lymph node histology shows benign hyperplasia, but histological changes may progress to show atypical lymphoid cells and, in rare cases, pseudolymphoma or lymphoma may develop if the drug is not discontinued.101 Drug-induced cutaneous pseudolymphomas have also been reported. Until 1996, clinicians had used the term drug-induced pseudolymphoma interchangeably with anticonvulsant HSS. Although there are classic cases of DRESS syndrome with cutaneous histological pattern mimicking a cutaneous lymphoma, some authors suggested that DRESS syndrome and drug-induced pseudolymphoma are 2 distinct entities with different clinical and biologic features and outcome.71,124 Drug-induced pseudolymphoma has a more insidious and slow beginning, with nodules and infiltrated plaques appearing several weeks after beginning the use of the drug. It also shows better prognosis with improvement within several weeks after causative agents are discontinued. Because these 2 entities may show not only similar histological findings, but also overlapping clinical fea-

Life-threatening acute adverse cutaneous drug reactions tures,125 the justification of differentiating between them remains questionable.

Treatment DRESS is potentially life-threatening. The mortality rate is estimated at near 10%, but recovery can be total. Eruption hepatitis may persist for weeks and even for months.126 DRESS syndrome must be promptly recognized and all potential culprit drugs withdrawn. As for the controversy on the use of systemic corticosteroids, unlike their position with SJS/TEN, most authors do not regard them as either hazardous or contraindicated. Most authors suggest their use bwhen internal organ involvement exists.Q127 Because, however, internal organ involvement (together with fever and eruption) is a prerequisite for this syndrome, systemic steroids should be considered in every case of DRESS syndrome. Things become more problematic when TEN is part of DRESS syndrome. Currently, when the cutaneous manifestations of DRESS syndrome are those of SJS or TEN, the classification is DRESS syndrome with severe cutaneous reactions. Our opinion is that we, as dermatologists, should classify our diseases first and foremost according to the cutaneous lesions and thus we now suggest classifying this group as TEN (according to the cutaneous pattern) with systemic involvement rather than as DRESS syndrome with a severe cutaneous eruption. This will end the debate on the use of systemic steroids in these patients.

Serum sickness–like reaction Serum sickness–like reaction, first described in human beings by von Pirquet and Schick128 in 1905, is a syndrome resulting from the administration of heterologous serum, usually equine, serving as an antitoxin. The syndrome includes fever, cutaneous eruptions (mostly urticaria), edema, arthralgias, and lymphadenopathy. During the first 4 decades of the 19th century, it was not uncommon for up to 50% of patients to develop this reaction after treatment with horse serum as an antiserum to diphtheria, tetanus, or other organisms. It has almost disappeared in these situations with the advent of effective immunization procedures, antimicrobial therapy, and the development of specific human immune serum globulins. One SSLR that is, however, similar to classic serum sickness may result from the administration of a number of nonprotein drugs, such as antibiotics129-132 (particularly, cefaclor133-137 and minocycline 70,138-141 ), psychiatric drugs, 142-145 analgetic/anti-inflammatory drugs,146,147 monoclonal antibodies, 148 antithymocyte globulin, 149 antineoplastic drugs,150 and many others.151 The treatment of SSLR is dependent on the seriousness of disease and its activity. The necessity of prescribing glucocorticoids or immunosuppressive agents depends on the disease severity and other case-specific information.

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Urticaria, angioedema, and anaphylaxis Immediate-type hypersensitivity reactions can produce a range of cutaneous findings, from simple urticaria to angioedema or anaphylaxis. Although drugs account for a minority of cases of urticaria, drug-induced urticaria is not uncommon. Urticaria (and angioedema) is the second most common drug eruption after exanthems, accounting from 4.6% to as high as 25% of all hospital referrals of drug-related eruption.4,152-160 Antibiotics (especially the penicillins), nonsteriodal antiinflammatory drugs, anesthetics, radiocontrast agents, and angiotensin-converting enzyme inhibitors hold a prime position among an endless list of drugs that may induce immediate-type hypersensitivity.159,161,162 The incidence of serious reactions among patients without a history of penicillin treatment or allergy ranges from 1 to 4 in 10,000 treatment courses,163,164 similar to those on continuous prophylaxis.165 Death from an allergic reaction to penicillin occurs at an incidence of about 1 per 50,000 treatment courses of parenteral penicillin in the general population.164 A separate article in this issue is devoted entirely to urticaria, angioedema, and anaphylaxis.

Vasculitis Vasculitis is inflammation of vessel walls. It has many causes, although they result in only a few histological patterns of vascular inflammation. Vessels of any type in any organ can be affected, a fact that results in a wide variety of signs and symptoms. These protean clinical manifestations, combined with the etiologic nonspecificity of the histological lesions, complicate the diagnosis of specific forms of vasculitis. This is problematic because different vasculitides with indistinguishable clinical presentations have very different etiologies, associations with specific diseases, and involvement in certain organs, prognoses, and treatments. To make things even more complicated, there are many classifications and no agreed-upon diagnostic criteria for the various categories of vasculitis, particularly the smallvessel vasculitides. Drugs cause approximately 10% of vasculitic skin lesions and should be considered in any patient with small-vessel vasculitis.166-168Withdrawal of the offending agent alone is often sufficient to induce prompt resolution of clinical manifestations, obviating the need for systemic corticosteroids or more powerful forms of immunosuppression. For more details on this topic, the readers are directed to another article in Part II of this issue devoted entirely to purpura and vasculitis of any kind.

Conclusions bAny substance that is capable of producing a therapeutic effect can also produce unwanted or adverse effects.Q169

178 Adverse drug reactions had been reported since the beginning of ancient medicine. It is to be expected that the advances we have made in understanding these reactions, the improvements in diagnosing, reporting, and recording them, and the huge progress in safety and quality control on the part of pharmaceutical companies will not prevent the side effects of the drugs from increasing in the future because of the rise in drug consumption worldwide, because of our increasing goal to intensify their activity and efficacy, and because of the introduction of new therapies for major diseases (eg, antiretroviral drugs, immunomodulators, biologic therapies and target monoclonal antibodies against cytokines and receptors, anti-infective and chemotherapeutic therapies, etc). Fortunately, although adverse cutaneous reactions to drugs occur frequently, only a small proportion of them are severe and very few are fatal. Because there is no specific and definitely effective treatment for most of the severe potentially life-threatening ADRs, prompt recognition and diagnosis and early identification and withdrawal of all potential causative drugs are, for the time being, the best we can do for our patients to most significantly influence outcome and prognosis. In this review, we present practical and comprehensive information on severe acute cutaneous drug eruptions, concentrating on their definitions, classifications, clinical appearance, management, and prognosis. It is intentionally very clinically oriented and covers what is most relevant to the clinicians in their practice, omitting the theoretical aspects of the pathogenesis of the diseases unless they are relevant to diagnosis or treatment. Although most of the readers, particularly those in the outpatient arena, will not be treating these patients, they are the ones who will see them first, diagnose them, realize the potential danger in their condition, and refer them to the appropriate treatment venue. Therefore, we believe that each dermatologist should be familiar with these conditions, have the ability to recognize and diagnose them, be aware of their complications, and be informed on treatment options. Furthermore, we believe that dermatologists best know and understand cutaneous diseases, and that it is in the best interest of our patients, as well as our discipline, that dermatologists and only they manage patients with skin diseases, including those that become complicated, lifethreatening, and involve other organs.

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