# Internal Medicine/Cutaneous Drug Reactions

Skin reactions are the most common adverse effects of medications, accounting for 10-15% of reported cases of adverse drug reactions. While most of these reactions are not severe, some can be life-threatening. Swift identification of severe reactions, discontinuation of the medication, and appropriate medical interventions can help minimize harm.

## Use of Drugs

In the United States, over 4 billion prescriptions for more than 60,000 different drugs are dispensed annually. Hospitalized patients alone receive approximately 120 million courses of drug therapy each year, and half of adult Americans are prescribed medications on a regular basis. Adverse effects from prescription medications can result in 4.5 million urgent or emergency care visits and more than 7,000 deaths annually in the United States. Many patients also use over-the-counter drugs, which can sometimes lead to skin reactions.

## Incidence

Recent prospective studies have shown that acute skin reactions to medications affect between 2.2 and 10 out of every 1,000 hospitalized patients. These reactions typically occur within a few days to four weeks after starting treatment. In a study involving 48,005 inpatients over a 20-year period, morbilliform rashes (91%) and urticaria (6%) were the most common skin reactions, with antimicrobials, radiocontrast agents, and nonsteroidal anti-inflammatory drugs (NSAIDs) being the most frequently associated medications. Severe hypersensitivity reactions to drugs occur in approximately 1 in 1,000 to 2 per million users, depending on the specific reaction. Although rare, severe skin reactions to drugs have a significant impact on health due to potential long-term effects, the need for hospitalization, prolonged hospital stays, and even life-threatening situations. Some groups, such as elderly patients, individuals with autoimmune conditions, recipients of hematopoietic stem cell transplants, and those with acute Epstein-Barr virus (EBV) or human immunodeficiency virus (HIV) infections, are at a higher risk of experiencing drug reactions. The exact reasons for this association are not fully understood but may involve immune dysregulation.
People with advanced HIV disease (e.g., CD4 T lymphocyte count <200 cells/μL) are at a substantially increased risk of adverse reactions to sulfamethoxazole and also face a higher risk of severe hypersensitivity reactions.
Apart from acute skin eruptions, prolonged use of certain medications can lead to or worsen various skin conditions, including itching, changes in pigmentation, nail or hair disorders, psoriasis, bullous pemphigoid, photosensitivity, and even cutaneous neoplasms. Although these drug-induced skin reactions are not common, their overall impact on public health has not been adequately assessed.

## Pathogenesis

Adverse skin reactions to medications can occur through immunological or non-immunological mechanisms.
* Non-immunologic Drug Reactions: These reactions include changes in skin pigmentation due to the accumulation of drugs or their byproducts in the skin, alterations in hair follicles caused by certain drugs, and metabolic effects leading to lipodystrophy associated with anti-HIV medications. These side effects are predictable and can sometimes be prevented.
* Immunologic Drug Reactions: Most acute drug eruptions appear to have an immunological basis. Drug reactions can result from the immediate release of inflammatory mediators, antibody-mediated reactions, immune complex deposition, and antigen-specific responses. Drug-specific CD4+ and CD8+ T cells have been found in the blood and skin lesions of patients with various drug allergies, suggesting that these T cells play a role in drug allergy in an antigen-specific manner. The presentation of drugs to T cells is restricted by major histocompatibility complex (MHC) molecules and likely involves the recognition of drug-peptide complexes by specific T-cell receptors (TCRs).
When a drug triggers an immune response, the type of reaction is determined by the nature of the effectors involved, such as cytotoxic (CD8+) T cells in blistering and certain hypersensitivity reactions, chemokines for reactions mediated by neutrophils or eosinophils, and B cell collaboration in producing specific antibodies for urticarial reactions. These immunologic reactions have been categorized into subtypes based on specific immune pathways.
* Type I Reactions: These are mediated by IgE antibodies and involve immediate release of inflammatory mediators, leading to symptoms like pruritus, urticaria, nausea, and bronchospasm. Examples include anaphylactic reactions, often seen with NSAIDs and radiocontrast media.
* Type II Reactions: These are mediated by IgG antibodies and can result in drug-induced hemolysis and thrombocytopenia, typically associated with drugs like penicillin.
* Type III Reactions: These involve immune complex formation and can lead to vasculitis, serum sickness, and drug-induced lupus.
* Type IV Reactions: These are mediated by T lymphocytes and can cause various skin reactions, including contact dermatitis and severe conditions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
Genetic Factors and Cutaneous Drug Reactions
Genetic factors can predispose individuals to severe drug reactions by influencing either drug metabolism or immune responses to drugs. Polymorphisms in cytochrome P450 enzymes, drug acetylation, methylation (e.g., thiopurine methyltransferase activity and azathioprine), and other forms of metabolism (such as glucose-6-phosphate dehydrogenase and dapsone) may enhance susceptibility to drug toxicity, underdosing, or the risk of medication interactions, highlighting differences in pharmacokinetics or pharmacodynamics. The routine screening of P450 enzymes for predicting cutaneous reactions has not been established, although it has been suggested as potentially cost-effective for specific populations, such as patients with seizure disorders or depression and those considering certain therapies like tamoxifen or warfarin.
Associations between drug hypersensitivities and HLA haplotypes indicate a significant role for immune mechanisms, particularly those leading to skin involvement. For example, hypersensitivity to the anti-HIV drug abacavir is closely linked with HLA-B57:01. In Taiwan, a strong correlation exists between SJS/TEN associated with carbamazepine and HLA-B15:02, as well as between HLA-B*58:01 and SJS, TEN, or DIHS related to allopurinol. These associations are drug-specific and phenotype-specific, suggesting that drug-specific T-cell stimulation by medications triggers distinct reactions. However, while these genetic associations are robust, they alone are insufficient to cause severe drug hypersensitivity reactions.
Global Considerations
Recognizing HLA associations with drug hypersensitivity has led to recommendations for screening high-risk populations. Genetic screening for HLA-B57:01 to prevent abacavir hypersensitivity, which carries a 100% negative predictive value when confirmed by patch testing and a 55% positive predictive value applicable across different racial backgrounds, is becoming the standard of care globally (with a number needed to treat of 13). The U.S. Food and Drug Administration recommends HLA-B15:02 screening for Asian individuals before prescribing carbamazepine. The American College of Rheumatology advises HLA-B58:01 screening for Han Chinese patients receiving allopurinol. To date, screening for a single HLA haplotype (but not multiple HLA haplotypes) in specific populations has been found to be cost-effective (e.g., HLA-B1301 screening for Chinese patients with leprosy treated with dapsone). Genetic testing for specific HLA haplotypes and functional screening for TCR repertoire to identify at-risk patients is increasingly available, heralding the era of personalized medicine and pharmacogenomics.

## Nonimmune Cutaneous Reactions

* Exacerbation or Induction of Dermatologic Diseases: Various drugs can worsen existing skin conditions or trigger new ones, which may or may not resolve after discontinuing the causing medication. For example, drugs like NSAIDs, lithium, beta-blockers, tumor necrosis factor (TNF) antagonists, interferon-alpha (IFN-α), and angiotensin-converting enzyme (ACE) inhibitors can aggravate plaque psoriasis, while antimalarials and stopping systemic glucocorticoids can worsen pustular psoriasis. Interestingly, TNF-α inhibitors, used to treat psoriasis, may induce psoriasis in some patients receiving treatment for other conditions. Acne can be induced by glucocorticoids, androgens, lithium, and antidepressants. Follicular eruptions resembling acne often occur with drugs like epidermal growth factor receptor (EGFR) antagonists and mitogen-activated protein kinase (MEK) inhibitors. Autoimmune diseases can also be induced or exacerbated by certain medications. For instance, checkpoint inhibitors can trigger systemic autoimmune reactions, including skin manifestations. Interleukin (IL) 2, IFN-α, and anti-TNF-α drugs are linked to new-onset systemic lupus erythematosus (SLE). Additionally, various drugs can lead to lupus-like conditions with characteristic antibodies. Subacute cutaneous lupus erythematosus (SCLE) can be triggered by several drugs, including thiazide diuretics, proton pump inhibitors, and TNF inhibitors. Some drugs may cause granulomatous diseases, sarcoidosis, or autoimmune blistering diseases, such as pemphigus or bullous pemphigoid. Certain medications can lead to highly specific cutaneous reactions, like nephrogenic systemic fibrosis linked to gadolinium contrast use, and neutrophilic dermatoses induced by drugs like granulocyte colony-stimulating factor, azacitidine, or levamisole-contaminated cocaine. Reactions may even develop during long-term medication therapy due to dosing changes or host metabolism alterations.
* Photosensitivity Eruptions: Photosensitivity eruptions often affect sun-exposed areas but can extend to protected regions. These reactions are primarily caused by phototoxicity, resulting in symptoms resembling sunburn. They can occur with the first exposure to a drug. Blistering may occur in drug-induced pseudoporphyria, most commonly due to NSAIDs. The reaction's severity depends on factors like the drug's tissue level, its efficiency as a photosensitizer, and the extent of exposure to specific wavelengths of ultraviolet (UV) light. Common orally administered photosensitizing drugs include fluoroquinolones, tetracycline antibiotics, and trimethoprim/sulfamethoxazole. Chlorpromazine, thiazides, NSAIDs, and BRAF inhibitors are among the less common drugs implicated. Voriconazole use may result in severe photosensitivity, accelerated skin aging, and increased skin cancer risk. Sunscreens that block UV-A light, avoidance of UV radiation, and treating the reaction like sunburn are typically effective remedies. In rare cases, individuals may develop persistent light reactivity, requiring long-term sun avoidance. Methotrexate can induce a UV-recall reaction, characterized by erythematous, slightly scaly eruptions at sites previously exposed to intense sunlight.
* Pigmentation Changes: Medications, whether taken systemically or applied topically, can cause various pigmentary changes in the skin. This can result from increased melanin production triggered by the drug or deposition of drug or drug metabolites in the skin. Examples include oral contraceptives causing melasma, long-term minocycline or amiodarone causing blue-gray pigmentation, and phenothiazine, gold, and bismuth leading to gray-brown pigmentation in sun-exposed areas. Some cancer chemotherapy drugs are associated with specific pigmentation patterns, as well as clofazimine causing a red-brown coloration. Antimalarials can induce hyperpigmentation on the face, mucous membranes, and other areas. Quinacrine can cause generalized yellow discoloration. Pigmentation changes can also affect mucous membranes, conjunctiva, nails, hair, and teeth.
* Warfarin Necrosis of Skin: Warfarin-induced skin necrosis, although rare (0.01–0.1%), typically occurs between the third and tenth days of warfarin therapy, more commonly in women. The affected areas often include the breasts, thighs, and buttocks. Lesions are characterized by well-defined, erythematous or purpuric areas that may progress to form large, hemorrhagic bullae with necrotic tissue. This reaction is attributed to a further reduction in already low levels of endogenous anticoagulants (protein C or S) due to warfarin, allowing hypercoagulability and microvascular thrombosis in the skin.
* Drug-Induced Hair Disorders: Medications can affect hair follicles at different stages of their growth cycle, leading to hair loss (anagen or telogen effluvium) or excessive hair growth (hirsutism or hypertrichosis). Anagen effluvium occurs rapidly after drug administration, particularly with certain chemotherapeutic drugs. Telogen effluvium has a delay of 2–4 months after starting a new medication. Many drugs have been associated with hair loss, including antineoplastic agents, anticonvulsants, beta blockers, antidepressants, antithyroid drugs, IFNs, oral contraceptives, and cholesterol-lowering drugs. Some medications, like anabolic steroids, oral contraceptives, testosterone, and corticotropin, can lead to excessive hair growth in a masculine pattern (hirsutism). Hypertrichosis involves distinct hair growth patterns, typically on the forehead and temporal regions. Medications responsible for hypertrichosis include anti-inflammatory drugs, glucocorticoids, vasodilators, diuretics, anticonvulsants, immunosuppressive agents, psoralens, and zidovudine.
* Changes in Hair Color or Structure: Although uncommon, certain drugs can cause alterations in hair color or structure. Chloroquine, IFN-α, chemotherapeutic agents, and tyrosine kinase inhibitors may induce nail bed hyperpigmentation by stimulating melanocytes. Changes in hair structure have been observed with drugs like EGFR inhibitors, BRAF inhibitors, tyrosine kinase inhibitors, and acitretin.
* Drug-Induced Nail Disorders: Drug-related nail disorders typically involve all 20 nails and may persist for months after discontinuing the medication. Toxic mechanisms are often implicated. These disorders encompass various issues like Beau's lines (transverse depressions of the nail plate), onycholysis (distal nail plate detachment), onychomadesis (proximal nail plate detachment), pigmentation changes, and paronychia (inflammation around the nails). Onycholysis can occur with various drugs, including tetracyclines, fluoroquinolones, retinoids, NSAIDs, and several chemotherapeutic agents. Onychomadesis, characterized by temporary arrest of nail matrix mitotic activity, may result from drugs.
* Toxic Skin Reactions Due to Chemotherapy and Other Cancer Medications: Many drugs used in cancer chemotherapy work by inhibiting cell division, and this sensitivity to their effects extends to rapidly growing skin components like hair, mucous membranes, and appendages. A diverse range of skin reactions linked to chemotherapy has been documented, including conditions such as neutrophilic eccrine hidradenitis, sterile cellulitis, exfoliative dermatitis, and flexural erythema. These reactions are now collectively classified as "toxic erythema of chemotherapy" (TEC). Acral erythema is characterized by discomfort and a reddened, swollen rash on the palms and soles. Common culprits behind these reactions include drugs like cytarabine, doxorubicin, methotrexate, hydroxyurea, fluorouracil, and capecitabine. The advent of new cancer treatment agents like monoclonal antibodies and small molecular signaling inhibitors has brought about an array of skin and hair-related side effects. Some of the most common among these are briefly described here:
** EGFR antagonists: These drugs can lead to follicular eruptions and nail issues, typically appearing around 10 days after treatment initiation. Common problems include dry skin (xerosis), eczema-like rashes, acneiform eruptions, and itching. Erlotinib, in particular, is associated with noticeable changes in hair texture.
** Sorafenib: A tyrosine kinase inhibitor, Sorafenib can result in follicular eruptions and, in some cases, blisters on the palms, soles, and areas prone to friction or pressure.
** BRAF inhibitors: These drugs are linked to photosensitivity, thickening of the skin on the palms and soles (palmoplantar hyperkeratosis), changes in hair texture, rashes resembling Grover's disease, benign skin tumors with thickened skin (hyperkeratotic benign cutaneous neoplasms), and squamous cell carcinomas resembling keratoacanthoma. Skin issues like rashes, itching, and skin depigmentation have been associated with ipilimumab (an anti-CTLA4 drug).
** Immune checkpoint inhibitors: This class of drugs, including anti-CTLA4, anti-PD-1, and anti-PD-L1 agents, can cause a wide range of skin eruptions beyond just skin depigmentation (vitiligo). These reactions include lichenoid rashes, eczema-like eruptions, granulomatous skin reactions, papulosquamous eruptions, and panniculitis.

## Immune-Mediated Skin Reactions: Common

Maculopapular Eruptions:
* Maculopapular eruptions are the most frequently encountered drug-induced skin reactions.
* These eruptions often begin on the trunk or skin folds and present as reddish, blanching macules and papules that are symmetric and tend to merge.
* When macules appear non-blanching, dusky, or intensely red or when they affect mucous membranes, there's a concern for a more severe reaction.
* Facial involvement in maculopapular eruptions is rare, and extensive facial lesions with facial swelling may indicate Drug-Induced Hypersensitivity Syndrome (DIHS).
* Laboratory tests and skin biopsies rarely assist in the diagnosis of maculopapular eruptions.
* Common culprits include aminopenicillins, cephalosporins, antibacterial sulfonamides, allopurinol, and antiepileptic drugs.
* While beta blockers, calcium channel blockers, and ACE inhibitors are rarely responsible, any drug can trigger a maculopapular rash.
* Some drugs, such as nevirapine and lamotrigine, have a high propensity to cause maculopapular eruptions, even without DIHS reactions.
* Lamotrigine-associated maculopapular rash is linked to factors like high starting doses, rapid dose escalation, concomitant use of valproate, and administration in children.
* Maculopapular reactions typically develop within a week of starting therapy and last less than two weeks. They may resolve even with continued drug use, but discontinuation is advisable, especially if the rash worsens.
* It's worth noting that the rash can continue to worsen for up to a week following drug discontinuation. Pruritus (itchiness) is a common symptom, and antihistamines and emollients can provide relief. In some cases, short courses of potent topical glucocorticoids may reduce inflammation and symptoms. Systemic glucocorticoid treatment is rarely needed.
Pruritus:
* Pruritus (itchiness) is a common symptom in almost all drug-induced skin reactions and may be the sole manifestation of the adverse cutaneous reaction.
* Antihistamines like hydroxyzine or diphenhydramine can alleviate pruritus, and specific medications may be required for drug-related pruritus.
Urticaria/Angioedema/Anaphylaxis:
* Urticaria, characterized by itchy red wheals of varying sizes that typically resolve within 24 hours, is the second most common type of drug-induced skin reaction.
* While nearly all drugs can potentially cause urticaria, common offenders include ACE inhibitors, aspirin, NSAIDs, penicillin, and blood products.
* However, medications are responsible for only 10-20% of cases of acute urticaria.
* Angioedema, involving deep swelling within the skin and subcutaneous tissues, may affect mucous membranes in the respiratory and gastrointestinal tracts. Urticaria and angioedema may be part of a life-threatening anaphylactic reaction.
* Drug-induced urticaria can result from different mechanisms, including IgE-dependent, immune complex-mediated (serum sickness), and non-immunologic activation of effector pathways.
* IgE-dependent urticarial reactions usually occur within 36 hours of drug exposure but can happen within minutes. Immune complex-induced urticaria linked to serum sickness reactions typically arises 6-12 days after initial exposure.
* Treatment depends on the severity of the reaction, with epinephrine and intravenous glucocorticoids being essential in severe cases.
* For patients with urticaria without angioedema or anaphylaxis, drug withdrawal and oral antihistamines are usually sufficient.
* Future avoidance of the offending drug is recommended, and rechallenge should be performed with caution in an intensive care setting in individuals with severe reactions.
Anaphylactoid Reactions:
* Vancomycin can cause red man syndrome, an anaphylactoid reaction characterized by flushing, a widespread rash of red papules, and low blood pressure.
* Rarely, rapid intravenous administration of vancomycin can lead to cardiac arrest.
Irritant/Allergic Contact Dermatitis:
* Patients using topical medications may develop irritant or allergic contact dermatitis in response to the medication itself or its constituents, including preservatives.
* Common irritants include neomycin sulfate, bacitracin, polymyxin B, and adhesive tapes.
* Contact dermatitis can also result from harsh disinfectant skin cleansers.
Fixed Drug Eruptions:
* Fixed drug eruptions are less common and manifest as sharply delineated, dull red to brown patches, sometimes with central dusky violet-red areas and a central blister.
* These eruptions often leave behind hyperpigmentation once the acute inflammation subsides.
* With repeated drug exposure, fixed drug eruptions typically recur in the same location but can also spread to new areas.
* Common causes include pseudoephedrine, phenolphthalein, sulfonamides, tetracyclines, NSAIDs, barbiturates, and others.

## Immune Cutaneous Reactions: Rare and Severe

Drug-Induced Hypersensitivity Syndrome The Drug-Induced Hypersensitivity Syndrome (DIHS) is a systemic reaction caused by drugs, also known as DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome. However, because eosinophilia doesn't always occur, the term DIHS is preferred. Clinically, DIHS starts with fever and flu-like symptoms for several days, followed by the development of a widespread rash, often affecting the face. Swelling of the face and hands/feet is common. It can also lead to systemic symptoms like lymph node enlargement, fever, and changes in blood counts, liver, kidney, lung, and gastrointestinal involvement. The timing and organs affected can vary depending on the causative drug. For instance, allopurinol often leads to DIHS with kidney involvement, while minocycline is more likely to involve the heart and lungs. The rash usually appears 2-8 weeks after starting the medication and can persist even after discontinuation. Symptoms may continue for weeks, especially those related to hepatitis. Reintroducing the drug can cause the rash to recur. Certain medications, like aromatic anticonvulsants (e.g., phenytoin, carbamazepine), can lead to cross-reactions in DIHS. Other drugs causing DIHS include antibacterial sulfonamides and various antibiotics. Recent research suggests that some drugs may reactivate latent human herpes viruses, which can worsen the condition. Mortality rates can be as high as 10%, often due to liver failure. Treatment typically involves systemic glucocorticoids and careful monitoring of clinical symptoms and laboratory tests. Steroid-sparing agents may be necessary in some cases, and discontinuing the causative drug is essential. Cardiac evaluation may be needed in severe cases or when heart involvement is suspected. Patients should be monitored for long-term complications, such as autoimmune thyroiditis and diabetes, which can develop months after the initial symptoms.
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe skin conditions characterized by blistering and widespread skin detachment due to full-thickness epidermal necrosis. SJS describes cases with less than 10% skin detachment, SJS/TEN overlap for 10-30% detachment, and TEN for over 30% detachment. Other blistering conditions with mucositis can mimic SJS/TEN. Patients with SJS/TEN initially experience high fever, sore throat, conjunctivitis, and the development of painful, atypical skin lesions. These conditions can be life-threatening, with mortality rates ranging from 10% for SJS to over 30% for TEN. Common drug triggers include sulfonamides, allopurinol, antiepileptic drugs (e.g., lamotrigine, phenytoin, carbamazepine), NSAIDs, antibiotics, and nevirapine. Timely diagnosis, discontinuation of the suspected drug, and supportive care are critical for a better outcome. There is no consensus on the best treatment, but systemic glucocorticoids, intravenous immunoglobulin, cyclosporine, or etanercept may be beneficial. Close monitoring and management of fluid balance, wound care, infection prevention, and ophthalmologic and respiratory support are essential.
Pustular Eruptions Acute Generalized Exanthematous Pustulosis (AGEP) is a rare skin reaction often linked to drug exposure. It presents with widespread erythema or erythroderma, high fever, and leukocytosis, followed by the development of numerous tiny pustules on the skin, typically in body fold areas. The pustules may merge and lead to superficial erosion. AGEP may initially resemble Drug-Induced Hypersensitivity Syndrome (DIHS) due to fever and erythroderma or Stevens-Johnson Syndrome (SJS) in its early stages. However, AGEP typically involves more superficial erosions and lacks prominent mucosal involvement. The principal differential diagnosis is acute pustular psoriasis, which has a similar appearance but different timing and pathogenesis. AGEP usually starts within 24-48 hours of drug exposure, whereas psoriasis-related eruptions are different. Common drug triggers include beta-lactam antibiotics, calcium channel blockers, macrolide antibiotics, and others. Some patients may have a personal or family history of psoriasis. Treatment includes immediate drug discontinuation and supportive care.
Overlap Hypersensitivity Syndromes Overlap syndromes can occur in severe drug eruptions and may involve combinations of DIHS, SJS, TEN, and AGEP-like features. These syndromes share some pathophysiologic mechanisms and may not fit into a single diagnosis based on cutaneous and extracutaneous features. Treatment should address the dominant clinical features. Timing of rash onset, systemic involvement, and clinical presentation are essential factors in determining the diagnosis and treatment approach.
Vasculitis Cutaneous small-vessel vasculitis (CSVV) typically manifests as purpuric papules and macules, often on the lower extremities. CSVV can be drug-induced in about 15% of cases. Many different drugs, particularly antibiotics, can cause CSVV. It can also affect internal organs, making a thorough clinical evaluation important. CSVV associated with drug reactions may show perivascular eosinophils on skin biopsy, suggesting drug involvement.
Managing Patients Suspected of Having a Drug Eruption
When dealing with a suspected drug eruption, there are four primary questions to address:
* Is the observed rash a result of a medication?
* Is the reaction severe or accompanied by systemic symptoms?
* Which drug or drugs are suspected, and should they be discontinued?
* What recommendations can be made for future medication use?

## Early Identification of Severe Eruptions

Swift recognition of potentially serious or life-threatening reactions is crucial. Initially, a suspected drug eruption can be defined by what it is not, such as Stevens-Johnson syndrome (SJS) or drug-induced hypersensitivity syndrome (DIHS). Certain clinical and laboratory features can indicate a severe reaction. Any suspicion of a serious reaction should lead to immediate consultation with a dermatologist or referral to a specialized center.

## Confirmation of Drug Reaction

The likelihood of drug involvement varies with the pattern of the reaction. Fixed drug eruptions are always drug-induced, whereas morbilliform eruptions are typically viral in children but drug-induced in adults. Severe reactions like SJS, TEN, AGEP, DIHS, and DRESS are mostly drug-induced. Skin biopsy helps describe the reaction but doesn't confirm drug causality. Blood tests, liver and renal function tests, and other assessments are crucial to evaluate organ involvement and detect abnormalities that may suggest a drug reaction. While mild elevation of liver enzymes and high eosinophil counts are common in drug reactions, they are not specific. Blood tests, serologic tests, and tests for infections may be necessary to identify an alternative cause.

## Identifying Suspected Drugs and Their Withdrawal

Most drug eruptions occur during initial treatment with a new medication, but exceptions exist, like IgE-mediated urticaria and anaphylaxis that develop upon rechallenge. The timing of onset following drug administration is characteristic for different types of eruptions. Maintaining a drug chart that records all medications and their timing relative to the rash is vital for identifying the causative drug. Medications introduced within the relevant time frame are prime suspects. Previous experiences with the drug (or related drugs) and consideration of alternative causes also help determine causality. The decision to discontinue or continue a medication depends on factors like reaction severity, the seriousness of the underlying condition, suspicion of causality, and the availability of alternative treatments. In potentially fatal drug reactions, immediate discontinuation of all possible suspect drugs is essential. Some rashes may resolve when the offending drug is continued, but this should be an exception rather than the rule. In general, suspected drugs should be discontinued, but important drugs not under suspicion may be continued, as withdrawal may have adverse consequences.

## Recommendations for Future Drug Use

The goals are to prevent recurrence of the drug eruption and avoid excluding potentially useful medications for future treatment. Assessing drug causality is based on reaction timing, consideration of other potential causes, and the effects of drug withdrawal or continuation. Certain instruments like the Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) may be used to rank the likelihood of drug causality in specific conditions like SJS/TEN. Medications with a "definite" or "probable" causality should be contraindicated, and patients should be informed, given warning cards, or provided with medical alert tags. The implicated drugs should also be documented as allergies in the patient's medical chart.

## Cross-Sensitivity

Cross-sensitivity, where a patient reacts to structurally related drugs, can occur due to pharmacologic interactions or immune recognition of structurally related drugs. The risk of cross-sensitivity varies depending on the specific drugs and their chemical structures. Recent data suggest that the list of drugs to avoid after a drug reaction should be limited to the causative one(s) and a few very similar medications. Additionally, family members of patients with severe cutaneous reactions may also be advised to avoid causative agents.

## Role of Testing for Causality and Drug Rechallenge

The utility of laboratory tests and skin testing to determine causality is debated and may have limited practical value. Skin-prick testing can be useful in cases of immediate IgE-mediated reactions to drugs like penicillin. However, its sensitivity is limited in delayed-type hypersensitivity reactions. Desensitization procedures may be considered for patients who need to use a medication to which they previously reacted but cannot avoid. Desensitization carries risks, and patients should be monitored closely during the process. Despite desensitization, some patients may still experience non-life-threatening reactions during therapy with the culprit drug.