Patterns of Cutaneous ADRS

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Chapter: Pharmacovigilance: Dermatological ADRs

Exanthematous or maculo-papular eruptions, often reported as ‘drug rashes’ or ‘drug eruptions’, are the most common ADRs affecting the skin.


PATTERNS OF CUTANEOUS ADRS

EXANTHEMATOUS DRUG ERUPTION

Exanthematous or maculo-papular eruptions, often reported as ‘drug rashes’ or ‘drug eruptions’, are the most common ADRs affecting the skin. The main mechanism is probably immunologic, and may corre-spond to type IV delayed cell-mediated hypersensi-tivity reaction.

The eruption usually occurs between 4 and 14 days after beginning a new therapy, and even a few days after it has ceased (‘eruption of the ninth day’). However, it can develop sooner, especially in the case of rechallenge. The eruption consists of erythematous macules, papules, often symmetric. They begin on the trunk, upper extremities, and progressively become confluent (Figure 32.1). The eruption is typically poly-morphous: morbilliform or sometimes urticarial on the limbs, confluent on the thorax, purpuric on the feet. Mucous membranes are usually not involved. Pruri-tus and low-grade fever are often associated with the eruption, which frequently lasts less than 2 weeks.


Cutaneous pathological slides exhibit a very mild lymphocytic infiltrate around vessels of the dermis, and a few necrotic keratinocytes within the epider-mis. This pattern, often difficult to differentiate from normal skin is not specific, and cannot help to distinguish a drug eruption from an eruption of another cause.

The differential diagnosis of exanthematous drug reactions includes viral eruptions (EBV, CMV, HHV6, Parvovirus B19, etc.), toxinic eruptions, acute Graft-vs-Host reaction, Kawasaki syndrome, Still’s disease, and so on. Dermatologists usually consider that viral infections are the cause of most drug erup-tions in children, while drugs are more frequently responsible in adults.

Treatment is largely supportive, usually after the removal of the offending agent, associated with topi-cal corticosteroid and systemic antipruritic agents. When the suspected drug is of paramount importance for the patient (e.g. antibacterial sulphonamides in AIDS patients) treating ‘through the eruption’ can be considered as an option. In most instances, the erup-tion will disappear in about the same time as if the drug had been withdrawn. Because a few patients may experience a progressive worsening of the eruption leading to one of the severe reactions described below, the benefit–risk ratio of this attitude should be care-fully weighted and the evolution of the rash strictly monitored.

Most drugs can induce an erythematous eruption in about 1% of users. The following drugs have higher risks (more than 3% of users): allopurinol, aminopeni-cillins, cephalosporins, antibacterial sulphonamides and most antiepileptic agents.

URTICARIA AND ANGIO-OEDEMA

Urticaria is a common, transient eruption of erythe-matous and oedematous papules and plaques, usually associated with pruritus. When dermal and subcuta-neous tissues are involved, this reaction is known as angio-oedema. Most cases of angio-oedema are associated to urticaria. They can be complicated by a life-threatening anaphylactic reaction. Urticaria, angio-oedema and anaphylaxis may be a type I hypersensitivity reaction mediated by IgE antibodies (penicillin allergy). But other ‘anaphylactoid’ mecha-nisms, leading to direct and non-specific liberation of histamine or other mediators of inflammation, are also common for drug reactions (contrast media, NSAIDs including aspirin).

Clinically, itchy erythematous, oedematous papules and plaques develop in variable numbers and size (Figure 32.2). They are localized anywhere on the body, including the palm, soles and scalp. They frequently last a few hours and disappear within 24 hours, leaving the skin with a normal appear-ance. Angio-oedema is often associated with urticaria, consisting of pale or pink swellings which affect the face (eyelids, lips, ears, etc.) but also buccal mucosa, the tongue, larynx, pharynx, and so on. More severe reaction, such as anaphylaxis, can involve other systems and lead to respiratory collapse, shock and eventually death.


Urticaria is histologically non-specific with a super-ficial and deep scarce infiltrate of mononuclear cells accompanied by eosinophils and neutrophils, oedema-tous reticular dermis, vascular and lymphatic dilata-tion. The epidermis is uninvolved.

Urticaria has been classified into acute, when the eruption lasts less than 6 weeks, or chronic when it persists much longer.

It usually occurs within a few hours of drug admin-istration, but may also occur within a few minutes.

Withdrawal of the causative agent is the main treat-ment. It can sometimes be associated with histamine H1 receptor blockers. Systemic steroids and an intra-muscular injection of epinephrine are necessary in an emergency if severe angio-oedema and anaphy-laxis occur.

Many drugs can induce urticaria (most often of the acute type), but more than 80% of cases of urticaria are related to other causes (stings, food allergy, etc.). Antibiotics, especially penicillin, and general anaes-thetics are classic causes of IgE-mediated hypersen-sitivity reaction. A radioallergosorbent test (RAST) or ELISA and skin tests (prick-tests) can be useful to confirm the diagnosis. Because they may rarely induce an anaphylactic reaction, prick-tests must be performed only by experienced physicians.

The two most frequent causes of drug-induced non-IgE-mediated urticaria and angio-oedema are NSAIDs and angiotensin-converting enzyme (ACE) inhibitors. Angio-oedema occurs in 2 to 10 per 10 000 new users of ACE inhibitors (Hedner et al., 1992), a rate that is probably higher than the risk associated with penicillins (about 1 per 10 000 courses). The reac-tion begins much later than IgE-mediated urticaria, usually in the first weeks of treatment. Up to one-third of patients with angio-oedema related to ACE inhibitors have a recurrence when using angiotensin 2 receptor antagonists (van Rijnsoever et al., 1998). This suggests a pharmacologic mechanism.

PHOTOSENSITIVITY

Cutaneous photosensitivity diseases may be idio-pathic, produced by endogenous photosensitizers (e.g. porphyrins) or associated with exogenous photo-sensitizers like drugs. The association of light and a drug can be responsible for acute inflammation of the skin. The photosensitivity reactions are divided into two types: phototoxicity and photoallergy (Gould, Mercurio and Elmets, 1995).

PHOTOTOXICITY

Phototoxic disorders are not rare and always predictable. It can occur in any person who receives sufficient quantities of a phototoxic drug, together with the proper light exposure. The reaction results directly from photochemistry involving the skin. The association of light with a photosensitizing chemical in the skin creates an unstable singlet or triplet state within the electrons. This leads to the generation of reactive oxygen, which is responsible for cell damage.

Clinical manifestations usually present as an exag-gerated sunburn occurring in sun-exposed areas only (Figure 32.3). This is followed by hyperpigmentation. Photo-onycholysis and pseudoporphyria (blisters on sun-exposed parts of the limbs) are less common clin-ical forms.


Phototoxicity is histologically characterized by epidermal cell degeneration with necrotic keratinocytes, oedema, sparse dermal lymphocytic infiltrate and vasodilatation. Phototoxicity is easily documented in vitro or in vivo. A photopatch test will be positive in all individuals and will therefore not be a discriminator for causality assessment. The minimal dose of UV (UVA more often than UVB) inducing an erythema will be decreased in all subjects during treatment.

PHOTOALLERGY

A photoallergic reaction is considered as a result of cell-mediated hypersensitivity. Ultraviolet radiation is required to convert a drug into an immunopatholog-ically active compound (photo-antigen) that induces the immune response.

Photoallergic eruption is more chronic than photo-toxicity and is mainly eczematous and pruritic. A lichen planus-like reaction has also been reported. It is usually more marked in exposed sites, but may often progress outside these areas. In the chronic phase, erythema, scaling and lichenification predom-inate. Photoallergic reactions are usually transient and resolve after a variable length of time when the offending agent has been removed. Rarely, an extreme sensitivity to sun may persist for months or years (‘persistent light reactors’). Photopatch testing is valuable when photoallergy is suspected. A multitude of drugs induce photoallergic reactions, includ-ing antibiotics (sulphonamides, pyrimethamine, fluo-roquinolones), fragrances, NSAIDs, phenothiazine, thiazide diuretics, and so on.

In phototoxic reactions, the treatment requires removal of the offending agent and/or avoidance of sun exposure. For a drug with a short elimi-nation half-life, administration in the evening may be enough to decrease the risk below the clinical threshold. In photoallergy, drug withdrawal is recom-mended, because of the risk of worse reactions even with low UV doses. Topical corticosteroid, systemic antipruritic agents may be useful.

VASCULITIS

Vasculitis corresponds to immune-mediated inflam-mation and damage to a blood vessel’s wall. It may be caused by a variety of agents, especially infec-tions and collagen vascular diseases. Many cases remain idiopathic. Drug-induced vasculitis is believed to result from antibodies directed against drug-related haptens (Roujeau and Stern, 1994). Direct drug toxi-city against a vessel’s wall, autoantibodies reacting with endothelial cells and cell-mediated cytotoxic reactions against vessels were also proposed as expla-nations. The precise mechanism is still unknown.

This drug-induced eruption corresponds to a cuta-neous necrotizing vasculitis consisting of palpa-ble purpuric papules which predominate on the lower extremities (Figure 32.4). Urticaria-like lesions, ulcers, nodules, hemorrhagic blisters, Raynaud’s disease and digital necrosis may also occur. The vasculitis may involve other organs, with fever, arthralgias, myalgias, headache, dyspnea, neurologi-cal involvement and renal abnormalities, sometimes life-threatening. The histology of small blood vessels exhibits necrotizing and/or leukocytoclasic vasculitis. The direct immunofluorescence is often positive, with immunoglobulin and C3 deposits on capillary walls.


Vasculitis occurs 7 to 21 days after drug adminis-tration, and less than 3 days after rechallenge. With-drawing the drug usually leads to a rapid resolution. A systemic corticosteroid may benefit some patients.

Drug-induced cases are a minority of cases of vasculitis (no more than 10% in a large series) and have to be differentiated from other causes of cutaneous vasculitis: infection, autoimmune diseases (polyarteritis nodosa, Wegener’s granulomatosis, etc.), Schönlein-Henoch purpura and cancer.

The main drugs implicated are allopuri-nol, NSAIDs, cimetidine, penicillin, hydantoin, sulphonamides and propylthiouracil.

ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS

In 1980, Beylot et al. described an acute pustular dermatosis named ‘Acute generalized exanthematous pustulosis’ (AGEP) (Beylot, Bioulac and Doutre, 1980). Of these eruptions at least 80% could be drug-induced. Hypersensitivity to mercury and infection with enteroviruses may also be responsible. The inci-dence of AGEP has been under-estimated and many cases have been confused with pustular psoriasis. Synonyms are pustular drug rash, pustular eruption and pustuloderma (Staughton et al., 1984). Proposed diagnosis criteria (Roujeau et al., 1991) include:

•   an acute pustular eruption;

•   fever above 38 C;

•   neutrophilia with or without a mild eosinophilia;

•   subcorneal or intraepidermal pustules on skin biopsy;

•   spontaneous resolution in less than 15 days.

AGEP is characterized by fever, which generally begins the same day as the pustular rash. Numer-ous, small, mostly non-follicular pustules arise on a widespread oedematous erythema, burning pruritic or both (Figure 32.5). Oedema of the face and the hands, purpura, vesicles, blisters, erythema multiforme-like lesions and mild involvement of mucous membrane have also been associated. Pustules are mainly local-ized on the main folds (neck, axillae, groins, etc.), trunk and upper extremities.


The histopathology shows spongiform pustules located under the stratum corneum, the most superfi-cial layer of the epidermis. Papillary dermal oedema and perivascular polymorphous infiltrate are usually present. Leukocytoclasic vasculitis and focal necrotic keranocytes have also been reported.

Hyperleukocytosis with elevated neutrophils count, transient renal failure and hypocalcemia are frequently seen.

There are two different times between the drug administration and the skin eruption. For antibiotics it is usually very short, less than 2 days. A more clas-sical delay of 1–2 weeks is observed with diltiazem, another classical inducer. The eruption lasts 1 to 2 weeks, and is followed by a superficial desquamation. The withdrawal of the responsible drug is the main treatment, associated with a topical corticosteroid and sometimes a systemic antipruritic agent.

AGEP must be differentiated from acute pustular psoriasis of the von Zumbusch type. The pustules in both diseases are clinically indistinguishable; the histopathology can be helpful.

Antibiotics (béta-lactam, some macrolides and quinolones) are the main drugs implicated in AGEP.

DRESS/HYPERSENSITIVITY

‘Hypersensitivity syndrome’ refers to a specific severe skin reaction. The acronym of DRESS for Drug Reaction with Eosinophilia and Systemic Symptoms has been proposed as more specific than ‘hyper-sensitivity’, which would be appropriate for most types of drug reaction. It has been estimated to occur in between one in 1000 and one in 10 000 exposures with drugs such as antiepileptics and sulphonamides. This syndrome is typically charac-terized in its complete form by a severe eruption, lymphadenopathy, fever, hepatitis, interstitial nephri-tis, pulmonary infiltrates and sometimes arthralgias. The clinical lesions are associated with haemato-logical alterations: eosinophilia and lymphocytosis with basophil lymphocytes (Shear and Spielberg, 1988; Roujeau and Stern, 1994; Callot et al., 1996). Multivisceral involvement differentiates hypersensi-tivity syndrome from common exanthematous erup-tion. Some consider that Stevens–Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) may occur as part of a ‘hypersensitivity syndrome’. The skin lesions and visceral complications are actually differ-ent. Eosinophilia and atypical lymphocytosis are not observed in SJS and TEN.

These reactions are more frequent among persons of African ancestry. They begin 2 to 6 weeks after the first drug use, later than most other skin reactions. Fever and skin rash are the most common symptoms. Cutaneous manifestations begin as a morbilliform rash, which later becomes infiltrated with an oede-matous follicular accentuation (Figure 32.6). Erythro-derma, vesicles, tight blisters induced by dermal oedema, follicular as well as non-follicular pustules can also occur. Face, upper trunk and extremities are initially involved. Oedema of the face is frequent and evocative of diagnosis.


Prominent eosinophilia (70% of cases) and atypical lymphocytosis (50–60%) are the most characteristic biological features of this reaction. Liver abnor-malities with raised aminotransferase, alkaline phoshatase, bilirubin levels and abnormal prothrombin time are present in about 50% of patients.

Histopathology exhibits a rather dense lymphocytic infiltrate in the superficial dermis and/or perivascular, associated with dermal oedema.

Rash and hepatitis may persist for several weeks after drug withdrawal, and some of the manifestations may be life-threatening.

The differential diagnosis includes other cuta-neous drug reactions, acute viral infection, idiopathic hypereosinophilic syndrome, lymphoma and pseu-dolymphoma. Special attention should be paid to viral infection and specially to HHV6, since several publi-cations suggest a possible interaction between DRESS and reactivation of HHV6 or other lymphotropic viruses (Descamps et al., 2001; Kano, Inaoka and Shiohara, 2004).

Topical high-potency corticosteroids can be help-ful in skin manifestations. Systemic corticosteroids are often proposed when internal organ involve-ment exists.

The aromatic antiepileptic agents (phenobarbi-tal, carbamazepine, phenytoin), minocycline and sulphonamides are the most frequent causes of hyper-sensitivity syndrome; allopurinol, gold salts and dapsone may also induce this syndrome.

FIXED DRUG ERUPTION

A fixed drug eruption is an exclusively drug-induced cutaneous reaction. The lesions develop usually less than 2 days after the drug intake. Clinically, they are characterized by a solitary or few, round, sharply demarcated erythematous and oedematous plaques, sometimes with a central blister (Figure 32.7). The eruption can be located on every site of the body and may involve mucous membranes, principally the lips and genitalia. The eruption progressively fades in a few days, to leave a post-inflammatory brown pigmentation. With rechallenge with the causative drug, the lesions recur at exactly the same sites. After several relapses the eruption may involve large areas of the body. This Generalized Fixed Drug Eruption may be difficult to distinguish from TEN.


Histopathology reveals a superficial and deep dermal and perivascular infiltrate (composed of lymphocytes, eosinophils, and sometimes neutrophils) associated with necrotic keratinocytes. Dermal macrophages pigmented by melanin (melanophages) when present are considered an important clue to the diagnosis.

The drugs most frequently associated with fixed drug eruption are phenazone derivates, barbiturates, tetracycline, sulphonamides and carbamazepine (Kauppinen and Stubb, 1984).

DRUG-INDUCED PEMPHIGUS

Pemphigus is a chronic autoimmune blistering disease provoked by autoantibodies reacting with normal constituants of desmosomes, the structures that provide attachment between epidermal cells. It presents clinically with flaccid intraepidermal blis-ters and erosions of the skin and mucous membranes (Figure 32.8). Nikolsky’s sign is found.


The histology exhibits detachment of epidermal cells (acantholysis), responsible for intraepidermal blisters located subcorneally (pemphigus foliaceus) or in the lower epidermis (pemphigus vulgaris).

Direct immunofluorescence performed to a perile-sional skin biopsy specimen reveals immunoglobulin deposits around keratinocytes in the epidermis in all ‘spontaneous’ cases but in only 50% of drug-induced cases. The presence in the serum of autoantibodies reacting against the epidermis is detected by indirect immunofluorescence, Western-blot or ELISA tests.

In Western countries up to 10% of cases of pemphi-gus could be drug-induced. It begins several weeks or months after drug therapy is initiated. It presents as pemphigus foliaceus or as pemphigus vulgaris with mucosal involvement. The main drugs incriminated are d-penicillamine and other drugs containing a thiol radical, like captopril and piroxicam. The remission after drug withdrawal is not always spontaneous, particularly in cases of pemphigus attributed to drugs that do not have a thiol part.

SJS AND TEN

SJS and TEN are rare, life-threatening, drug-induced skin reactions. The incidence of TEN is evaluated to 0.4 to 1.2 cases per million person-years and of SJS from 1 to 6 cases per million person-years (Roujeau and Stern, 1994). The immunopathologic pattern of early lesions suggests a cell-mediated cyto-toxic reaction against epidermal cells. Widespread  apoptosis of epidermal cells is provoked by the activa-tion of several pathways: the interaction of Fas antigen (cell surface death receptor) and Fas ligand but also perforin plus granzyme and TNFalpha.

With others we proposed to consider SJS and TEN as severity variants of the same drug-induced disease, and to distinguish SJS from erythema multiforme major (Bastuji-Garin et al., 1993), the latter being mostly related to infections, especially with herpes (Auquier-Dunant et al., 2002).

According to this proposal, erythema multiforme (major when mucous membranes are involved) is characterized by typical concentric ‘target’ lesions acrally distributed, with limited blisters (detachment rarely involves more than 2–3% of the body surface area). The pathology shows an interface dermatitis with moderate to marked lymphocyte infiltrate in the dermis, exocytosis and mild necrosis of epidermal cells. In our experience, erythema multiforme is rarely drug-induced. Most of the cases that are reported or published as drug-induced erythema multiforme are either cases that we would label as SJS or cases of erythematous drug eruptions, because of confusion between ‘multiforme’ and the polymorphous patterns of many erythematous eruptions.

SJS is characterized by atypical targets and more often by small blisters arising on purple macules. Lesions are widespread and usually predominate on the trunk. Confluence of blisters on limited areas leads to detachment below 10% of the body surface area. The pathology can be separated from that of erythema multiforme by less lymphocyte infiltrate and more epidermal necrosis (Wolkenstein et al., 1998).

Toxic epidermal necrolysis is characterized by the same lesions as SJS but with a confluence of blis-ters leading to a positive Nikolski sign and to the detachment of large epidermal sheets on more than 30% of the body surface area (cases with detachment of between 10 and 30% are labelled overlap SJS-TEN) (Figure 32.9). Skin pathology shows necrosis of full-thickness epidermis and negative immunoflu-orescence. This is important for distinguishing TEN from exfoliative dermatitis, staphylococcal scalded skin syndrome, acute exanthematous pustulosis and paraneoplastic pemphigus, which may be misdiag-nosed as SJS or TEN.


Patients with SJS or TEN have high fever. Severe erosions of mucous membranes are nearly constant.

Systemic manifestations include mild elevation of hepatic enzymes (overt hepatitis in 10% of cases), intestinal and pulmonary manifestations (with slough-ing of epithelia similar to what happens to the skin). Leucopenia is frequent and eosinophilia unusual. Death occurs in 10% of patients with SJS and more than 30% of patients with TEN, principally from sepsis or pulmonary involvement (Roujeau and Stern, 1994).

The treatment is mainly symptomatic, consisting of nursing care, maintenance of fluid and electrolyte balance and nutritional support. Early withdrawal of all potentially responsible drugs is essential. Short courses of corticosteroids early in the disease have been advocated, but their effectiveness has never been demonstrated in controlled trials. Thalidomide has been shown to be detrimental in TEN, possibly because of a paradoxical enhancement of TNFalpha production. High-dose intravenous immunoglobulins were disappointing in our experience.

Drug reactions are responsible for at least 70% of cases of both SJS and TEN (Knowles, Uetrecht and Shear, 2000). Antibacterial sulphonamides, anticon-vulsants, oxicam and pyrazolone NSAIDs, allopurinol and chlormezanone are the drugs associated with the higher risks. An international case–control study of SJS and TEN found relative risks of between 50 and 172 for new users (treatment duration of less than 2 months) of the above-mentioned drugs and also for corticosteroids (Roujeau et al., 1995). In that study, excess risks for associated drugs were in the range of 1 to 4.5 cases for 1 million users per week (Roujeau et al., 1995).

SJS and TEN typically begin within 4 weeks of initiating therapy, usually 7 to 21 days after the first drug exposure and sometimes a few days after the drug has been withdrawn. It occurs more rapidly with rechallenge.

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