Toxidermia: Clinic, diagnosis and treatment

• Some molecules are more likely to cause toxidermia, but all drugs can be responsible.
• It is therefore necessary to consider all drugs and not only the most common ones.

• Toxidermias can be the consequence of several mechanisms: immunological or not.
• If the cause is not immunological, then it is often possible to predict them based on the different properties of the drug.
• Pharmacodynamic properties may be particularly involved. They can cause xerosis and subretinal cheilitis.
• Nevertheless, non-immunological toxidermia can also be the result of an effect other than the main pharmacological effect sought. Toxidermia can thus be classified into two main categories¹:

Non-Immunological Toxidermia

• Dependent on a pharmacodynamic effect of the drug.
• High frequency.
• Dose-dependent.
• Low mortality risk.
• Predictable.
• Detected in controlled trials and post-authorization studies.
• Rarely lead to a market withdrawal but to a modification of the SPCs instead.

Immunological Toxidermia

• Dependent on an immunoallergic reaction.
• Rare.
• Not dose-dependent.
• Variable associated rate of mortality.
• Usually occurs within a few days to several weeks after taking the medication.
• Is not predictable.
• Is detected during post-authorization safety studies (PASS).
• May lead to market withdrawal if toxidermia is severe. In all cases, modification of SPCs is required.

The most frequent forms^1,2:

• 40 - 60% of toxidermia present as a maculopapular exanthema.
• 20 - 30% present as urticaria.

Delayed Immunoallergic Toxidermia

Maculopapular Exanthema - Not severe

• Starts 4 to 14 days after starting medication.
• Initially occurs in the torso or the limb-roots and may progress for a few days.
• Its examination is clinical. Additional examinations may be necessary in case of atypical presentation (possible eosinophilia, renal or hepatic implication). 
• It is often manifested by a moderate or absent fever, frequent pruritus of variable intensity and a polymorphism of lesions that may associate:
  • Isolated macules, with intervals of healthy skin (morbilliform drug eruption rash).
  • Lesions in confluent layers (scarlatiniform eruption).
  • Edematous papules or plaques, sometimes with an arciform disposition.
  • Petechiae purpura, mostly on the legs and more often in case of intense erythema.
  • Usually no enanthema (mucosal involvement).
• It generally evolves favorably in 1 week to 10 days after stopping treatment.  

Fixed Erythema Pigmentosum - Not severe

• Pathognomonic of toxidermia: It is the only dermatosis of almost exclusively drug origin.
• Starts within 48 hours of taking the medication (often NSAIDs or paracetamol).
• Manifested by 1 to 10 rounded erythematous macules, a few centimeters in diameter, located preferentially but not exclusively on the genitals and lips. These macules are often painful and infiltrated and may develop into plaques.
• Possibility of bullous and generalized evolution.
• Inflammatory lesions usually resolve within a few days but may leave pigmented spots.
• If the responsible drug is reintroduced: rapid recurrence in the same locations.

Acute Generalized Exanthematus Pustulosis (AGEP) - Severe

• Manifested by a severe and very febrile rash, can be mistaken for an infection.
• Usually begins 1 to 11 days after taking medication (often antibiotics) with fever, a scarlatiniform, sheet-like erythema, predominantly in the large folds.
• In only a few hours, appearance of small amicrobial pustules with lactescent content on the whole erythema.
• Although this reaction can occur in all individuals, it is less common in children and thus may manifest itself atypically³.
• Symptoms regress rapidly when the medication is stopped (about 2 weeks³).
• The pustules disappear within a few days with a diffuse desquamation.

Drug Hypersensitivity Syndrome or DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) - Severe

Rare. Recognized by several criteria:

• Severity and extent of the rash (often more than 50% of the body surface), sometimes erythrodermic (more than 90% of the surface).
• Infiltrated rash: oedema of the face and of the extremities is an important and characteristic clinical sign.
• Severe pruritus.
• High fever.
• Diffuse adenopathies.
• If visceral damage, possible life-threatening complications.

Among the drugs implicated in DRESS, the most frequently suspected are:

• Anti-epileptic medication (phenobarbital, carbamazepine, phenytoin, lamotrigine).
• Minocycline, allopurinol, dapsone.
• Some antiretroviral drugs such as nevirapine and abacavir.
• Sulfonamides such as sulfasalazine, sulfadiazine and sulfamethoxazole.
• Gold salts and proton pump inhibitors^2,4.

Stevens-Johnson Syndrome (SJS), Lyell Syndrome (Toxic Epidermal Necrolysis or TEN) - Severe

• The most severe forms of toxidermia are those that present a continuum between Stevens-Johnson syndrome and Lyell-TEN syndrome, distinguished primarily by the surface area of affected epidermis.
• These forms are considered medical emergencies.
• The same drugs can cause different levels of severity, and in many patients, the rash can spread rapidly from Stevens-Johnson syndrome to LYELL syndrome in just a few days.
• Genetic background is a risk factor for these diseases⁵.
• The first signs usually appear between 4 and 28 days after the introduction of the inducer, with mucocutaneous symptoms such as fever, burning eyes, pharyngitis and a painful erythematous rash.
• The prodromal phase develops rapidly over hours to days, with multifocal mucosal erosions and skin bullae, as well as Nikolsky's sign where epidermal flaps detach upon rubbing.
• Stevens-Johnson syndrome is distinguished from Lyell-TEN syndrome by the area of necrotic epidermis (less than 10% for the former and more than 30% for the latter)⁶.
• Patients have a fever and a severely altered general condition and may suffer from visceral involvement such as necrosis of the bronchial or the intestinal epithelium.
• Complementary biological tests may be performed to confirm the diagnosis: leukopenia, signs of multivisceral failure, hydroelectrolytic disorders.

The mortality risk for this toxidermia is high: 4.8% for SJS, 19.4% for SJS-TEN overlap and 14.8% for TEN⁶. Re-epidermalization occurs within 10 to 30 days, with frequent sequelae: pigmentation disorders and mucosal scars, especially in the eyes (synechiae).

Urticaria

• Mobile and fleeting pruritic edematous papules emerging a few minutes to a few hours after the drug is taken.
• If immediate hypersensitivity reaction is IgE-mediated (reflects previous sensitization): does not occur on first contact with the drug.
• This definitely contraindicates further use of the same drug.
• If reactions are related to the properties of the drug: constant in the same person and dose-dependent.
• Less than 10% of acute urticaria have a drug-related origin.

Angioedema and Anaphylactic Shock

Superficial and/or deep urticaria may, in rare cases, be associated with an episode of anaphylaxis.

• Respiratory signs: dysphonia, dyspnoea, bronchospasm.

• Cardiovascular signs: tachycardia or bradycardia, arterial hypotension.
• Digestive signs: nausea, vomiting, diarrhoea.
• Any anaphylactic reaction requires emergency treatment.

Photosensitivity

Rash occurring within hours of exposure to the sun. Localized on the exposed areas: photodistribution.

It depends on two distinct mechanisms:

Photoallergy

• Manifested as eczema lesions in exposed areas but may spread.
• May be caused by minimal sun exposure.
• Occurs between 7 and 21 days after the start of treatment.
• May be secondary to systemic or topical treatment.

Phototoxicity

It occurs in the hours following sun exposure.