Drug-Induced Bullous Disorders Clinical Presentation
- Author: David F Butler, MD; Chief Editor: William D James, MD more...
Symptomatology of cutaneous reactions varies depending upon type and extent of skin involvement.
Eczematous or spongiotic drug reactions may be the result of previous contact sensitization to the drug or may occur de novo. Incidence of contact eczematous reactions to topical medications may be as high as 12.1%. Systemic contact eczematous reactions, which result from systemic exposure (eg, oral, parenteral, rectal, intravenous, inhalation) to a previous contact sensitized drug, are less common. Eczematous drug reactions begin with diffuse pruritus but may also cause headache, malaise, fever, nausea, vomiting, and diarrhea.
Acute generalized exanthematous pustulosis (AGEP) (toxic pustuloderma) is a result of a systemic medication in 90% of cases. Onset is abrupt, usually 1-5 days after starting the medication. Patients report a diffuse pruritic or burning painful eruption associated with fever, malaise, and sometimes prostration. Seventeen percent of patients have a history of psoriasis.
Fixed drug eruptions (FDEs) are a common cause of all drug eruptions, and their frequency is second only to urticaria/angioedema. Careful patient assessment usually reveals that an FDE develops 6-48 hours after administration of the causative drug. Symptoms of pruritus and burning accompanied by fever are not uncommon. In those patients with multiple episodes of FDE, reports of increasing hyperpigmentation at the site of a previous lesion are common.
Nosology of EM is controversial and somewhat confusing. Historically, EM has been divided into 3 groups: EM minor, EM major or SJS, and TEN. Considerable overlap may exist between these 3 subgroups, and some authorities believe that TEN should be considered a distinct entity. An infectious agent, such as herpes simplex or mycoplasma, usually causes less extensive involvement of EM; drugs are implicated less often in EM minor. However, drugs cause most of the more severe and diffuse forms of EM. See the following:
EM minor may begin with prodromal symptoms suggestive of an upper respiratory infection (eg, coryza, cough, pharyngitis), but within 7-10 days skin lesions begin to develop acrally and symmetrically on the hands, feet, and distal extremities. EM minor may have involvement of the oral mucosa, but involvement of 2 or more mucosal surfaces usually indicates SJS or TEN.
EM major (SJS) affects young adult males more frequently. Prodromal symptoms of high fever, asthenia, muscular pains, diarrhea, vomiting, arthralgias, and pharyngitis precede mucosal involvement of 2 or more mucosal sites by several days. Skin involvement rapidly ensues. TEN has similar symptomatology but also demonstrates diffuse skin tenderness that resembles severe sunburn.
Drug-induced pemphigus can develop days, weeks, or months after taking the offending agent. Ruptured bullae leave painful erosions. Itching is not a common symptom. The oral mucosa is frequently involved; hoarseness, dysphagia, and unpleasant mouth odor follow. Drugs may serve as either a cause or a trigger for pemphigus. In those patients in whom drugs serve as a trigger, other autoimmune disorders such as lupus, bullous pemphigoid, and myasthenia gravis may already be present. Therefore, the development of drug-induced pemphigus seems to be determined in part by genetic predisposition.
Drug-induced pemphigoid may follow oral or topical administration of drugs. Itching is a common symptom. Involvement of the epiglottis may lead to acute airway obstruction. Patients with drug-induced pemphigoid are commonly younger than patients with idiopathic pemphigoid. Cicatricial pemphigoid is more common in patients of late middle age.
Drug-induced linear IgA dermatosis (LAD) comprises a small portion of all cases of LAD. The clinical presentation of drug-induced LAD is indiscernible from other causes of LAD, except that mucosal involvement may be less likely in drug-induced LAD. Drug-induced LAD usually develops 1-2 weeks after taking the offending agent, although reactions may develop much sooner. Patients who develop LAD usually are seriously ill. Symptoms of severe burning and pruritus are common.
Porphyria cutanea tarda (PCT) may be precipitated or exacerbated by estrogens, iron overload, environmental hepatotoxins, and several drugs, but patients who have drug-induced pseudoporphyria have no underlying abnormality of heme biosynthesis. The symptoms of photosensitivity, skin fragility, and blistering of the hands and forearms are the same in both conditions.
The physical findings of bullous drug eruptions vary greatly depending on the type of reaction.
On physical examination, the features of an eczematous drug eruption are similar to that of a diffuse contact dermatitis. These features include diffuse patches of erythema, microvesiculation, vesicles, crusts, and oozing. Other more specific features may include dyshidrotic hand dermatitis, EM-like lesions, purpura, urticarial lesions, and vasculitislike lesions. Recrudescence of a positive patch test reaction may occur after systemic exposure to the offending medication. A diffuse eczematous eruption may mimic severe atopic dermatitis.
Acute generalized exanthematous pustulosis (AGEP) manifests as a diffuse scarlatiniform rash that rapidly develops numerous (>100) small pustules. Pustules measure 1-5 mm (see the image below). Nikolsky sign may be positive. Some pustules may coalesce into bullae. Facial swelling, purpura, and targetoid lesions may occur. Oral mucosa may be involved in about 20% of cases. Once the offending drug is discontinued, the eruption rapidly dries up and desquamates within 2 weeks.
Fixed drug eruptions (FDEs) start as a few sharply demarcated erythematous macules that rapidly become erythematous plaques occurring more commonly on the lips, genitalia, and trunk. Lesions heal with hyperpigmentation and occur in the same site with readministration of the responsible drug (see the image below). In 30% of cases, macules may become vesicles and bullae, which may lead to a more severe reaction known as generalized bullous FDE resembling SJS-TEN. In patients with generalized bullous FDE, physical examination reveals clearly demarcated erythematous and edematous patches surrounded by bullae that contain clear fluid.
The characteristic physical finding of EM is the target or iris lesion. These lesions begin as sharply marginated erythematous annular macules or patches that become slightly raised (see the image below).
A concentric color change takes place; the center of the lesion becomes darker, dusky, or more violaceous, and the periphery develops a ring of erythema. The classic iris lesion has 3 zones, a central dusky area with purpura and an edematous pale ring surrounded by an erythematous ring. The central dusky macule may actually form a tense vesicle or bulla. These typical iris or target lesions are more commonly observed in EM minor caused by infections and occur acrally and progress in a centripetal fashion. Larger, confluent, irregularly shaped, coalescing lesions with involvement of the trunk and 2 or more mucosal sites are common with SJS (see the image below). The mouth and lips are the most commonly affected mucosal site in SJS, but other sites such as the pharynx, larynx, esophagus, bronchi, and genital mucosa may be involved.
TEN demonstrates diffuse sunburnlike erythema that often begins on the face and spreads downward. The hairy scalp is spared. Maximal extension occurs within 2-3 days. A characteristic feature of TEN is the sheetlike separation of the epidermis in the involved areas. Flaccid bullae may form. Nikolsky sign is positive. Two or more mucosal sites are involved in 85-95% of patients with TEN.
Drug-induced pemphigus may be clinically indistinguishable from idiopathic pemphigus vulgaris or pemphigus foliaceus (see the image below). Lesions are superficial flaccid bullae ranging in size from 1-10 cm. They may initially occur in the mouth. Nikolsky sign is positive when pressure is applied lateral to the bulla. Lesions rupture easily, leaving denuded and weeping areas, which secondarily become crusted.
Tense bullae on normal skin or on an erythematous base is the typical finding in drug-induced pemphigoid (see the image below). Denuded areas, which are left after bullae rupture, heal spontaneously. Erythematous patches, urticarial plaques, and targetoid lesions may also be observed. Lesions may be found on the face, trunk, limbs, palms, soles, and mucous membranes. Nikolsky sign may be positive, unlike in idiopathic pemphigoid. Cicatricial pemphigoid is distinguished from other forms of pemphigoid by the presence of scarring. Cicatricial pemphigoid occurs on the mucous membranes of the eyes, pharynx, genitalia, or anus. Adhesions, strictures, and the loss of function may result from the scarring process.
Physical examination of a drug-induced LAD lesion may reveal one of several pictures. The most common presentations include urticated plaques, papulovesicles resembling dermatitis herpetiformis, targetoid lesions as in EM, and bullae resembling those found in bullous pemphigoid (see the image below). Bullous eruptions can become hemorrhagic. Lesions are most commonly located on the trunk and limbs. Cases of palmar lesions, although uncommon, have been reported.
Pseudoporphyria demonstrates tense blisters, erosions, and milia especially on the dorsum of the hands and forearms (see the image below). Features of hypertrichosis, dyspigmentation, and skin sclerosis are not observed in pseudoporphyria as they are in true porphyria.
Contact sensitization to certain topical medications may result in a predisposition to a systemic eczematous reaction to the same or a chemically related medication. Also note the following:
Contact sensitivity to penicillin may cause a diffuse eczematous reaction to systemically administered penicillin or even the small amounts of penicillin in cow's milk taken orally.
Contact sensitivity to topical sulfonamides may cause a reaction to systemically administered sulfamethoxazole or sulfonylureas (ie, tolbutamide, carbutamide) but not to dapsone or sulfapyridine.
Contact sensitivity to ethylenediamine found as a preservative in some topical medications may predispose an individual to a reaction to systemically administered aminophylline, theophylline, tripelennamine, antazoline, methapyrilene, hydroxyzine, and pyrilamine.
Contact sensitivity to tetramethylthiuram disulfide predisposes a person to a reaction to the antialcohol treatment Antabuse (tetraethylthiuram disulfide).
Patients sensitized to paraphenylenediamine may react to azo dyes taken orally or the group of para drugs.
Other drugs that may cause an eczematous eruption but are not preceded by contact sensitivity are the following: carbamazepine, gold, griseofulvin, phenytoin, piroxicam, thiazide diuretics, and vitamin K.
One case of a bullous systemic contact dermatitis occurred after an intra-articular injection of a corticosteroid. 
An eczematous reaction has been reporedt to occur after intravenous immunoglobulin injections. 
Ustekinumab treatment has been reported to induce an eczematous drug eruption. 
The drugs most commonly implicated in causing AGEP are antibiotics, especially beta-lactams, macrolides, and cotrimoxazole. Ciprofloxacin has been reported in induce a bullous form of AGEP. Furosemide and nonsteroidal anti-inflammatory agents have also been reported to be associated with the development of AGEP. Diltiazem has been reported to cause AGEP several times. Other causes include acyclovir, carbamazepine, hydroxychloroquine, clindamycin, ticlopidine, terbinafine, high-dose chemotherapy, chromium picolinate, chloramphenicol, sulfapyridine, metronidazole, lacquer chicken, protease inhibitors, progesterones, mercury, nystatin, amoxapine, paracetamol, chloroquine and proguanil, nifuroxazide, lansoprazole, minocycline, dexamethasone injection, propicillin, aspirin, doxycycline, furosemide, and buphenine.
Many drugs are capable of causing FDEs. Some of the more common etiologic agents of FDEs include aspirin, barbiturates, cotrimoxazole, phenolphthalein, feprazone, sulfonamides, and tetracycline. Causative agents in generalized bullous FDEs include aminophenazone, antipyrine, barbiturates, co-trimoxazole, diazepam, mefenamic acid, paracetamol, phenazones, phenylbutazone, piroxicam, sulfadiazine, and sulfathiazole. Knowledge of the potential drugs involved in a FDE is especially important because certain drugs have a predilection to cause FDEs at certain sites. Aspirin has a predilection for the trunk and limbs, tetracyclines for the genitalia, and phenylbutazone for the lips.
No reproducible tests for the etiology of EM exist. Association with infectious agents, such as herpes simplex and mycoplasma, has been well described. Precipitation of SJS or TEN has most commonly been associated with certain medications. The most commonly associated medications are the following: antibiotics (eg, sulfonamides, trimethoprim-sulfamethoxazole, penicillins, cephalosporins, chloramphenicol, clindamycin, griseofulvin, rifampin, streptomycin, tetracycline, clarithromycin, ciprofloxacin ), nonsteroidal anti-inflammatory agents (eg, ibuprofen, acetylsalicylic acid, ketotifen, naproxen,[13, 14] piroxicam, sulindac), antihypertensives, anticonvulsants (eg, phenobarbital, carbamazepine, phenytoin), and allopurinol. More recently, COX-2 inhibitors have been reported to be associated with SJS. Sildenafil has been implicated in the development of EM minor in an HIV-positive patient and confirmed with patch testing.
Topical mechlorethamine reportedly caused a subepidermal bullous reaction in a patient with mycosis fungoides.
Methotrexate has been reported to be associated with bullous acral erythema in a child.
The thiol group of drugs is the most common agent implicated in drug-induced pemphigus. Drugs known to cause pemphigus include amoxicillin, ampicillin, captopril,[19, 20] cephalosporins, penicillamine, penicillin, pyritinol, and rifampin. Thiol drugs are more likely to cause pemphigus whereas nonthiol drugs are more likely to trigger pemphigus. For this reason, spontaneous recovery is lower in non–thiol-induced pemphigus where other factors may be predisposing a patient to develop pemphigus. Captopril has been reported to cause lichen planus pemphigoides.
Sulfur-containing drugs commonly cause drug-induced pemphigoid, with furosemide being the most common cause. Other agents commonly known to cause drug-induced pemphigoid include amoxicillin, ampicillin, phenacetin, penicillin, penicillamine, psoralen-ultraviolet-A light, and beta-blockers. One case of bullous pemphigoid was induced by an m-TOR (mammalian target of rapamycin) inhibitor in a renal transplant recipient. Cicatricial pemphigoid has occurred after the use of drugs including practolol, topical echothiophate, D-penicillamine, clonidine, topical pilocarpine, topical demecarium, indomethacin, topical glaucoma, and sulfadoxine. Oral terbinafine has been associated with the development of bullous pemphigoid.
Vancomycin is the most common cause of drug-induced LAD.[25, 26, 27] Other drugs known to cause LAD include diclofenac, somatostatin, lithium, phenytoin, captopril, amiodarone, cefamandole, amoxicillin, and ampicillin-sulbactam. Sulfasalazine was reported to cause one case of linear immunoglobulin A (IgA) bullous dermatosis.
True PCT may be precipitated by barbiturates, estrogens, griseofulvin, rifampicin, and sulfonamides. The drugs that are known to induce pseudoporphyria include furosemide, nabumetone, nalidixic acid, naproxen, oxaprozin, tetracycline, and voriconazole.
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