Adverse cutaneous drug reactions: manifestations, diagnosis and management

Side effects are always a serious consideration when prescribing or managing a patient's medications, especially in older populations who are often multimorbid and take a variety of medications. However, some of the less discussed side effects are adverse cutaneous drug reactions (ACDR). This is likely because, although such cutaneous reactions are common, many cases go unreported and, therefore, comprehensive information regarding their incidence, severity and ultimate health effects are often not available (Nayak and Acharjya, 2008).

ACDR can significantly impact a patient's quality of life; this is especially true for older adults and those who are immunocompromised. While presentation is often largely benign, early identification of the condition and the associated culprit drug is the keystone to the management and prevention of a more severe reaction (Nayak and Acharjya, 2008). Consequently, it is not only dermatologists, but all community practitioners, who should be familiar with these conditions, to facilitate early diagnosis and adequate management.

What are adverse cutaneous drug reactions?

ACDR, also known as toxidermia, are skin manifestations resulting from drug administration. ACDR are the most common adverse drug reactions reported in the literature, with the overall incidence in developed countries being 1–3% and the incidence in developing countries reported to be between 2–5% (Hina et al, 2021). Hospital Episode Statistics from 1996 to 2000 reported that drug allergies and adverse drug reactions accounted for approximately 62 000 hospital admissions in England each year (National Institute for Health and Care Excellence (NICE), 2014). There is also evidence that these reactions are increasing: between 1998 and 2005, serious adverse drug reactions rose 2.6-fold (NICE, 2014).

A wide spectrum of cutaneous manifestations, ranging from maculopapular rashes to toxic epidermal necrolysis, can be caused by different drugs (Hina et al, 2021). Approximately 2–3% of drugs cause ACDR; the majority of ACDR are related to systemic medications, but other treatments, such as eye drops and inhalers, can occasionally be responsible (Primary Care Dermatology Society (PCDS), 2021a).

The mechanism of ACDR can be immunologic and non-immunologic. Most (75–80%) adverse drug reactions are secondary to predictable non-immunologic effects, while the rest (20–25%) are caused by unpredictable effects, some of which may be immune-mediated; only 5–10% of all adverse drug reactions are immune-mediated (Al Aboud et al, 2022). ACDR encompass various clinical patterns that are without specific features, which can suggest drug causality; therefore, it is essential to search for the causative agent (Al Aboud et al, 2022).

What are some of the main types of drug reactions and drugs involved?

ACDR are typically divided into two general classifications in accordance with their severity: mild–moderate and serious adverse cutaneous drug reactions (SCAR). Most ACDR manifest around 4–14 days after commencing the drug; however, some can take months or years to develop (PCDS, 2021b).

Mild-moderate ACDR can include:

• Exanthematic eruptions: these account for up to 95% of all ACDR and usually resemble a viral infection rash in appearance (many pink-to-red macules that first appear on the trunk and then spread to the limbs and neck, with lesions tending to blanch with pressure), but without the typically accompanying fever
• Acneiform eruptions: these are characterised by papules and pustules resembling acne vulgaris
• Pustular eruptions: these are white-yellow superficial pustules that are more often generalised and known as acute generalised exanthematous pustulosis
• Purpura/cutaneous vasculitis: these are red-purple palpable lesions, most commonly found on the lower legs, which do not blanch under pressure
• Erythema nodosum: this is characterised by painful, erythematous, and sometimes, bruised-looking nodules on the anterior surface of the legs
• Erythema multiforme: this is characterised by red patches that develop into ‘target lesions’ that are typically more varied and less well-defined than those caused by the herpes simplex virus, with the exception of those triggered by antibiotics
• Skin ulceration and infarction
• Symmetrical drug-related intertriginous and flexural exanthema. This is an erythematous rash involving the skin folds, affecting the buttocks/natal cleft and/or upper inner thighs (PCDS, 2021b).

Several types of ACDR can be accompanied by itching, including exanthematic eruptions. Some drugs can occasionally cause an itch without a rash.

SCAR can include:

• Urticaria/angioedema/anaphylaxis: these are the second most common ACDR and manifest rapidly after drug administration
• Stevens–Johnson syndrome/toxic epider mal necrolysis: these are variants of the same condition and are distinct from erythema multiforme. Early symptoms include fever and flu-like symptoms; the skin then begins to blister and peel, forming painful, raw areas. Complications include dehydration, sepsis, pneumonia and multiple organ failure.
• Drug-induced hypersensitivity syndrome: this typically causes a combination of high fever, morbilliform eruption, haematological abnormalities, lymphadenopathy and inflammation of one or more internal organs
• Erythroderma: this is a term used to describe erythema, affecting more than 90% of the body surface. The term ‘exfoliative dermatitis’ is also used, and describes the exfoliation found in erythroderma (PCDS, 2022).

The drugs most commonly associated with ACDR include:

• Antibiotics, especially penicillins (e.g. amoxicillin), cephalosporins and fluoroquinolones (e.g. ciprofloxacin)
• Those containing a sulphonamide group in their chemical structure, including sulphonamide antibiotics (sulfamethoxazole, trimethoprim and co-trimoxazole) and non-antibiotic sulphonamides (sulfasalazine and dapsone, etc)
• Aromatic anti-epileptic drugs, such as carbamazepine, phenytoin and lamotrigine
• Allopurinol
• Non-steroid anti-inflammatory pain killers (NSAIDs)
• Some diuretics, such as furosemide, bumetanide and thiazides
• Some angiotensin-converting enzyme (ACE) inhibitors
• Penicillamine
• Certain anti-fungal medications, such as terbinafine (PCDS, 2021b).

Diagnosis and management

Familiarity with the drug groups most commonly responsible for immunologic reactions is helpful, as is knowledge of satisfactory alternatives (Sheffer and Pennoyer, 1984).

In most cases of mild-moderate ACDR, investigations are unnecessary. A full blood count test may be helpful in showing eosinophilia, but this is nonspecific and cannot necessarily be attributed to any particular cause (PCDS, 2021b). Biopsies and patch tests can also be useful diagnostic tools.

One approach to an ACDR is to initiate the withdrawal of medication. This approach can be used if the offending medication can be replaced with another drug, or if the skin reaction is severe enough to require rapid cessation of suspect drugs (Al Aboud et al, 2022). Most skin changes settle within a few weeks of the drug being discontinued; occasionally the skin changes can take several months to settle (PCDS, 2021b).

Treatment of mild-moderate ACDR is mainly symptomatic and supportive, consisting of topical corticosteroids to reduce inflammation and itching and oral antihistamines (Al Aboud et al, 2022). The topical corticosteroid of the lowest possible potency for effective treatment should always be used, and healthcare professionals should be mindful of the fact that topical steroid withdrawal reactions have been reported in some long-term users (Medicines and Healthcare products Regulatory Agency, 2021).

Emollients may also be used to improve dryness and symptoms. Healthcare professionals should be mindful that allergic contact dermatitis can develop in response to a particular emollient; this can be investigated through patch testing. Occlusive emollients can cause or aggravate acne, perioral dermatitis and folliculitis (Whittaker et al, 2022), and their use should be carefully managed in the instance of ACDR.

Conclusions

ACDR can be diagnostically challenging and have a wide range of presentations, with cutaneous reactions being able to confound even the most experienced specialist. Furthermore, polypharmacy can make the determination of the causative medication more difficult. However, awareness of the most common presentations and associated drugs can enable healthcare professionals to ensure their patients' quality of life, especially those who are older or immunocompromised.

Key points

• Adverse cutaneous drug reactions (ACDR) are common, but comprehensive information regarding their incidence, severity and ultimate health effects are often not available, as many cases go unreported or are difficult to identify
• There are a wide spectrum of cutaneous manifestations, ranging from rashes to toxic epidermal necrolysis, which can be caused by different drugs. Most are largely benign, but some can be fatal.
• Generally, management strategies of mild to moderate ACDR are mainly symptomatic and supportive, consisting of topical corticosteroids to reduce inflammation and itching, and oral antihistamines and emollients to improve dryness and symptoms
• Healthcare professionals' awareness of commonly responsible medications and ACDR presentations can ensure their patients' quality of life, especially those who are older or immunocompromised