Drug-Induced Bullous Disorders

As with other bullous disorders, drug-induced blistering reactions occur via a variety of pathophysiological mechanisms and at various levels within the epidermis/dermoepidermal junction. Examples of these mechanisms include the following: exocytosis/spongiosis, formation of subcorneal spongiform pustules, cytolysis and keratinocytic necrosis, antiepidermal antibody formation, deposition of immunoglobulin at the basement membrane zone, and photo-induced collagen alterations that lead to a mechanobullous disorder. Most bullous drug reactions are the result of an immunologically mediated inflammatory response, although pseudoporphyria cutanea tarda (pseudo-PCT) is not associated with significant inflammation. Studies have reported the preferential activation of drug-specific CD8⁺ T cells in the pathophysiology of some bullous drug eruptions.

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. ^[7]
• An eczematous reaction has been reporedt to occur after intravenous immunoglobulin injections. ^[8]  

• Ustekinumab treatment has been reported to induce an eczematous drug eruption. ^[9]

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. ^[10] Furosemide and nonsteroidal anti-inflammatory agents have also been reported to be associated with the development of AGEP. ^[11] Diltiazem has been reported to cause AGEP several times. Other causes include acyclovir, ^[12] carbamazepine, hydroxychloroquine, ^[13] 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. ^[14] Causative agents in generalized bullous FDEs include aminophenazone, antipyrine, barbiturates, co-trimoxazole, diazepam, mefenamic acid, ^[15] paracetamol, phenazones, phenylbutazone, piroxicam, sulfadiazine, and sulfathiazole. An extensive bullous fixed drug eruption was reported after the second dose of the mRNA-1273 (Moderna) COVID-19 vaccine. ^[16]  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, ^[17] ciprofloxacin ^[18] ), nonsteroidal anti-inflammatory agents (eg, ibuprofen, acetylsalicylic acid, ketotifen, naproxen, ^{[19, 20]} piroxicam, sulindac), antihypertensives, anticonvulsants (eg, phenobarbital, carbamazepine, phenytoin), and allopurinol. More recently, COX-2 inhibitors have been reported to be associated with SJS. ^[21]  Sildenafil has been implicated in the development of EM minor in an HIV-positive patient and confirmed with patch testing. ^[22]

Topical mechlorethamine reportedly caused a subepidermal bullous reaction in a patient with mycosis fungoides. ^[23]

Methotrexate has been reported to be associated with bullous acral erythema in a child. ^[24]

The thiol group of drugs is the most common agent implicated in drug-induced pemphigus. Drugs known to cause pemphigus include amoxicillin, ampicillin, captopril, ^{[25, 26]} cephalosporins, penicillamine, penicillin, pyritinol, rifampin, and dipeptidyl peptidase inhibitors (DPP-4i) or gliptins for diabetes treatment. ^[27] 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. ^[28]  There is a reported case of a bullous pemphigus reaction to the second dose of the mRNA COVID vaccine, in a 78-year-old male in Saudi Arabia. ^[29]  Guselkumab, a biologic drug for plaque psoriasis treatment, was responsible for drug-induced pemphigus in 1 patient. ^[30]

A 2020 systematic literature review concluded that drug-induced pemphigus is most commonly seen with gliptins, PD-1/PD-L1 inhibitors, loop diuretics, penicillin, and penicillin derivatives. ^[31]

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. ^[32] One case of bullous pemphigoid was induced by an m-TOR (mammalian target of rapamycin) inhibitor in a renal transplant recipient. ^[33] 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. ^[34]

Vancomycin is the most common cause of drug-induced LAD. ^{[35, 36, 37]} Other drugs known to cause LAD include diclofenac, somatostatin, lithium, phenytoin, captopril, amiodarone, cefamandole, amoxicillin, ^[38] and ampicillin-sulbactam. ^[39] Sulfasalazine was reported to cause one case of linear immunoglobulin A (IgA) bullous dermatosis. ^[40]

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. ^[41]

Frequency

United States

Overall incidence of adverse cutaneous reactions to drugs has been estimated at 0.1-2.2% of treatment courses; however, semisynthetic penicillins and sulfamethoxazole/trimethoprim may have a considerably higher incidence at 3-5% of treatment courses. Patients infected with HIV may be at greater risk for adverse cutaneous drug reactions. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have an incidence ranging from 1.8-9 cases per million and are more frequent in those younger than 20 years and older than 65 years.

International

The United Kingdom, France, Germany, and Italy have reported similar incidences of drug reactions and TEN as the United States. However, one survey in the United Kingdom found that only 2-10% of serious reactions are reported.

Race

Bullous drug reactions have no racial predilections.

Sex

In general, adverse drug reactions occur more commonly in women, although erythema multiforme (EM) has been reported to occur more frequently in men.

Age

Elderly patients who take multiple medications are at higher risk for the development of adverse drug reactions. Young men seem to be at higher risk for EM.

Most bullous drug eruptions resolve without significant sequelae once the offending drug is removed. However, the morbidity of these reactions is proportional to the extent of skin surface area and mucous membrane involvement.

Of patients who develop TEN, 25-30% die. Elderly patients have a higher mortality rate with TEN. Sepsis is the most common cause of death in TEN. SJS and TEN may result in a residual cutaneous pigmentary disorder and possible scarring of the ocular mucosa in those who survive.

Eczematous or spongiotic drug reactions usually have a good prognosis and resolve without significant sequelae.

AGEP has a good prognosis and resolves without sequelae once the causative agent is removed.

Bullous generalized FDEs have a favorable prognosis.

EM most often has a good prognosis, but SJS and TEN can be lethal depending on the extent of skin involvement and the age of the patient.

Pemphigus has a mortality rate approaching 10%. However, drug-induced pemphigus usually resolves with removal of the offending agent. In some patients, lesions may progress or persist. In these cases, the drug likely is serving as a trigger rather than a cause in patients who are already prone to develop pemphigus.

Drug-induced pemphigoid has an excellent prognosis with discontinuation of the drug. However, some cases may involve persistent lesions. Cicatricial pemphigoid, in comparison to idiopathic bullous pemphigoid, shows a small tendency for remission. In severe cases of ocular cicatricial pemphigoid, scarring and blindness in both eyes has been reported.

Drug-induced LAD has a good prognosis.

Drug-induced PCT has a good prognosis.