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Adverse cutaneous drug reactions

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Latest update 09/07/2010

This chapter is set out as follows:

 

Introduction

  • Approximately 2-3% of drugs result in adverse cutaneous drug reactions (ACDR)
  • The mechanism of ACDR can be allergic or non-allergic
  • The majority are related to systemic medications but just occasionally other treatments such as eye drops and inhalers can be responsible
  • Patients more at risk – older, HIV, SLE and Sjorgren's
  • This chapter excludes contact allergic dermatitis (refer to chapter on eczema)

A logical approach to adverse cutaneous drug reactions (ACDR)

  • Is it a drug reaction?
  • Which drug is it? Most ACDR rashes start at around 4-14 after commencing the drug and settle within a few weeks of the drug being discontinued. However some ACDR can take months or years to evolve such as quinine, or thiazide diuretics causing a drug-induced subacute cutaneous lupus erythematosus. Likewise, once stopping the drug some rashes can take several months to settle e.g. dapsone, and drugs causing pseudoporphyria
  • Is it serious and does the patient need admission?
  • If not serious does the rash take on a photo-distribtion or not?
  • Does any specific therapy need to be given?
  • Are any investigations needed? Patch tests can be used to help confirm allergy to carbamazepine
  • Are there ary drugs that should be avoided in the future?
  • Could other family members have similar problems?

Drugs most commonly associated with ACDR

  • Antibiotics
  • The sulfa drugs (see below)
  • The aromatic anti-epileptic drugs - carbamazepine, phenytoin and lamotrigine
  • NSAIDs
  • Furosemide
  • Gold
  • Certain anti-fungal drugs such as terbinafine
  • Blood

Antibiotics
Unless associated with anaphylaxis, antibiotics tend to cause mild-moderate ACDRs and occasionally acute generalized exanthematous pustulosis (AGEP)

The Sulfa drugs (also referred to as 'sulpha')
The term 'Sulfa' refers to sulphonamide antibiotics and a number of non-antibiotic drugs that contain a sulphonamide group in their chemical structure

Sulphonamide antibitoics - these include sulfamethoxazole, trimethoprim and Septrin (co-trimoxazole), which is a combination of the two. Septrin tends to be associated with the most serious adverse effects such as Stevens-Johnson syndrome. The adverse effects of trimethoprim tend to be less severe and occur with less frequency

Non-antibitoic sulphonamides - these are less likely to cause severe adverse effects. Relevant drugs include:

  • Sulfasalazine and Dapsone - these are the two most closely related to the sulphonamide antibiotics
  • Others include the sulfonylureas e.g. glicazide, glipizide and glibenclamide. Also furosemide, hydrochlorothiazide and sumatriptan

Cross-reactivity - patients allergic to one sulphonamide antibitoic should avoid other antibiotics in the same group. However the link between the antibitoic and non-antibitoic group is less strong and cross-reactivity is unlikely to arise. However some still advocate avoiding Dapsone or sulphasalazine in patients allergic to sulphomaide antibiotics

Presentations of ACDR

Drug reactions can present in a number of ways. For the purpose of this chapter ACDR have been divided in to 3 groups

  • Group 1 – Severe ACDR
  • Group 2 – Drug induced photodermatoses
  • Group 3 – Other ACDR

Given that nearly all drugs have the potential to cause ACDR the lists below will concentrate on drugs most commonly associated. For more detailed information on other drugs please refer the Drug Eruption Reference Manual

Group 1 – Severe ACDR

Serious / potentially serious ACDR include

  • Urticaria – angioedema – anaphylaxis
  • Stevens-Johnson Syndrome / Toxic epidermal necrolysis  
  • DRESS syndrome
  • Erythroderma (syn. generalised exfoliative dermatitis)

Urticaria – angioedema – anaphylaxis and serum sickness

  • These are the second most common ACDR
  • Onset – rapid, often minutes-hours
  • Most commonly associated drugs – antibiotics (especially penicillin but also cephalosporins, sulphonamides, aminoglycasides, tetracyclines) / aspirin and other NSAIDs / vaccines containing egg protein / radiographic contrast material
  • ACEI are well-known to cause angioedema without urticaria – can occur months to years after the patient has been on the drug. Most serious reactions occur in black African patients with fatalities related to massive oedema of the tongue and pharynx. Some (but not all) patients sensitive to ACEI are able to tolerate Angiotensin II receptor blockers (ARBs)
  • Serum sickness combines urticaria and angioedema with fever, arthralgia, lymphadenopathy and occasionally internal involvement. It occurs between 1-3 weeks after initiation of the drug
Figure 1 - Urticaria
Figure 2 - Angioedema


Stevens-Johnson Syndrome / Toxic epidermal necrolysis

  • Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are now believed to be variants of the same condition and distinct from erythema multiforme
  • The term SJS is used when the disease involves less than 10% of the total body surface area. TEN is used when the disease involves more than 30% of the body surface area. Patients whose disease involves 10-30% of their body surface area are said to have SJS/TEN overlap
  • Although rare it is very serious and mortality rates increases as the percentage of involved body surface increases. The mortality rate is up to 10% for SJS and 25-40 % for TEN
  • They are normally caused by medications, more than 200 have been reported. SJS/TENS is more common in association with HIV
  • Most commonly associated drugs – allopurinol/ the antibiotic sulfa drugs (especially Septin) / certain anticonvulsants (carbamazepine, lamotrigine, phenytoin, phenobarbitol) / the oxicam NSAIDs eg piroxicam and meloxicam
  • Clinical features
    • History – symptoms often start within a few days of the drug being commenced although it can take a little longer with anticonvulsants. Patients c/o fever, malaise, myalgia and arthralgia
    • Painful / tender eythema with local erosions and blisters – quickly progresses to areas of confluent erythema with sheet-like skin and mucosal loss
    • Mucosal involvement includes the eyes, lips/mouth, oesophagus, upper respiratory tract (causing cough and respiratory distress), genital area and gastrointestinal tract – causing diarrhoea
    • Differential diagnosis – Staphylococcal scalded skin syndrome (no mucosal involvement, more superficial) and pemphigus
  • Management
    • Patients need same day assessment by a dermatologist – if the offending drug can be stopped at a very early stage patients have a better chance of survival
    • Patients are best cared for in an intensive care and/or burns unit
    • The role of systemic steroids and other drug therapy is controversial
  • Family members are more at risk of severe ACDR
Figure 3 - SJS affecting the oral mucosa
Figure 4 - Early SJS/TEN
Figure 5 - Severe mucosal involvement
Figure 6 - TEN
Figure 7 - Same patient as figure 6

Confluent erythema with sheet-like skin loss


DRESS syndrome (syn. drug hypersensitivity syndrome)

  • This is when an exanthematous reaction is associated with systemic features (DRESS = Drug Rash with Eosinophilia and Systemic Symptoms)
  • Timing – 3-6 weeks after drug started, although Dapsone can cause a much quicker reaction
  • Clinical features
    • Rash, fever, facial oedema, pharyngitis, cervical lymphadenopathy
    • Hepatitis 50%, nephritis 10%, pneumonitis 10%
    • Eosinophilia
    • 10% develop hypothyroidism after the reaction has settled
  • Mortality 10%
  • Drugs most commonly associated - the aromatic anticonvulsants eg phenytoin and carbamazepine. Cross reaction is also possible for patients also taking non-aromatics such as valproic acid. Other more commonly implicated medications include allopurinol, minocycline and sulphasalazine 
  • Managament
    • Stop drug
    • Investigations – FBC, U+E, LFT. CXR if respiratory symptoms. Check TFT on recovery
    • Prednisolone 0.5 -1 mg/kg/d for 2 months
  • If unwell discuss with on-call dermatologist
  • Family members at increased risk of ACDR
Figure 8 - DRESS syndrome
Figure 9 - DRESS syndrome caused by carbamazepine


Erythroderma (syn. generalised exfoliative dermatitis)

This is not normally caused by a drug, but if it is:

  • Timing – can start several weeks after the drug was started
  • The most commonly associated drugs include – sulphonamides / isoniazid / penicillin / antimalarials / phenytoin / captopril / cimetidine
  • See chapter on erythroderma for more information
Figure 10 - Exfoliative dermatitis

 

Group 2 – Drug induced photodermatoses

  • Clinical features include:

    • Acute sunburn-like reaction
    • Redness/scaling – 'dermatitis'
    • Blistering from contact with psoralen 'phytophotodermatitis' – can occur a few days after contact with the offending plant
    • A lichenoid eruption
    • Low grade 'pseudoporphyria' with blistering / skin fragitlity, often backs of hands – especially naproxen and furosemide
    • Photo-onycholysis (tetracyclines, ofloxacin and PUVA)
    • Pigmentary changes

  • For more information please refer to the chapter on photodermatoses

Figure 11 - Photosensitive drug eruption

Not the well-defined cut off at the neck



(Copied with kind permission of Professor Peter Farr)

 

Group 3 – Other ACDR

ACDR can present in a number of ways, the following list is not inclusive but represents the most well-recognised presentations:

  • Exanthematous
  • Lichenoid
  • Purpura / vasculitis
  • Pigmentation
  • Acneiform
  • Pustular
  • Pruritus
  • Erythema multiforme
  • Bullous
  • Fixed drug eruption
  • Ulcers / infarction
  • Drug induced lupus erythematosus
  • Erythema nodosum

Exanthematous

  • The most common presentation of ACDR causing 95% of all such rashes
  • More common if inter-current viral infection
  • Timing – most commonly occur at 7-14 days but can be earlier if been exposed to the drug before
  • Clinical features
    • Distribution - tends to start on the trunk and move to extremities, spares mucosal membranes
    • Morphology - maculopapular / morbilliform
    • If drug not stopped it may progress to an exfoliative dermatitis
  • Large numbers of drugs implicated. The most commonly associated drugs are ampicillin and penicillin / sulphonamides / isoniazid / phenytoin and carbamazepine / NSAID / gold / cephalospoins / thiazides / allopurinol
  • Treatment – stop drugs, emollients, topical steroid until settles
Figure 12 - Exanthematous rash
Figure 13 - Close up of a morbilliform rash secondary to penicillin


Lichenoid

  • Timing – can start weeks or months after drug started
  • Clinical features – can be as with idiopathic lichen planus (LP) or present quite differently with psoriasiform features or hyperpigmentation. The distribution may differ from classical LP and it can have a photodistribution. Usually lacks Wickhams striae and mucosal lesions
  • Most commonly associated medications – gold / antimalarials / thiazides / ACEI / betablockers / quinine
Figure 14 - Lichenoid eruption
Figure 15 - Lichenoid eruption caused by lisinopril


Purpura / cutaneous vasculitis

  • Tends to occur at around 3 weeks
  • Clinical findings – palpable purpura (thrombocytopenia is non palpable)
  • Many drugs implicated, the most commonly associated ones are – thiazides / aspirin and other NSAIDs / sulfa drugs / phenytoin / interferon / minocycline / influenca and Hep B vaccines
  • It is important to rule out other causes of purpura before concluding the rash is secondary to a drug
Figure 16 - Cutaneous vasculitis
Figure 17 - Leucocytoclastic vasculitis with more significant tissue damage


Pigmentation

  • Most commonly associate drugs – minocycline / amiodarone / anti-malarials / co-danthramer (can stain peri-anal and surrounding skin in paitents with incontinence) / gold
Figure 18 - Minocycline
Figure 19 - Hyperpigmentation caused by amiodarone
Figure 20 - Nail pigmentation caused by hydroxyurea


Acneiform

  • Clinical features – tends to cause monomorphic papules and pustues without comedones
  • Most commonly associated drugs – hormonal treatments (e.g. progestagens in contraceptive pills) / steroids / lithium / phenytoin / isoniazide
  • Always ask patients with very muscular physiques if they use anabolic steroids – patients may not come forward with this information at the first time of asking
Figure 21 - Acneiform rash caused by ananolic steroids


Pustular

  • Timing – within a few days
  • Pustules can be localised but more often generalised are known as acute generalized exanthematous pustulosis (AGEP)
  • Clinical features of AGEP – a generalised erythematous eruption with superficial desquamation. Small sterile pustules mainly found in he axillary and inguinal areas. Can develop blisters. Associated with fever
  • Most commonly associated drugs – often an antibiotic eg aminopenicillins and quinolones. Also terbinafine, diltiazem, hydroxychloroquine, isoniazide and the antibiotic sulphonamides
  • Good outcome – settles within 2 weeks of stopping the drug
Figure 22 - A localised reaction due to paracetamol
Figure 23 - AGEP


Pruritus

  • May be due to the drug or its withdrawal
  • Confirming whether or not a particular drug is the prime cuase for a patients pruritus is not always straightforward
  • Some of the drugs most commonly implicated in pruritus include morphine and other opioids / statins / ACEI / digoxin / chloroquine / sulphonamides  

Erythema multiforme (EM)

  • EM that occurs secondary to drugs tends to cause more varied and less well-defined target lesions than when due to herpes simplex (antibiotics can be an exception)
  • The most commonly associated medications include – the sulfa drugs / penicillins / tetracyclines / aromatic anticonvulsants / thiabendazole / aspirin and other NSAID / furosemide and thiazide diuretics / phenothiazines / quinine / progestogens / omeprazole
Figure 24 - Erythema multiforme


Bullous drug reactions

  • Can present in a number of ways
    • Fixed drug eruption
    • SJS / TEN
    • Immunobullous reactions – very uncommon
  • Immunobullous reactions include
    • Pemphigus – penicillamine / captopril / piroxicam / rifampicin
    • Pemphigoid – psoralens / furosemide / clonidine / ibuprofen / sulfa drugs
    • Linear IgA – vancomycin
    • Pseudoporphyria – furosemide / nalidix acid / naproxen
Figure 25 - A bullous reaction due to metronidazole


Fixed drug eruption

  • Timing – within 48 hours
  • Clinical features:
    • Distribution – lips, face, distal limbs, hands & feet, glans penis and perianal skin. Occurs at same site on re-exposure
    • Morphology - well-demarcated erythematous plaque that may blister,
    • Tends to heal with post-inflammatory hyperpigmentation
  • Large numbers of drugs implicated. The most commonly associated drugs – tetracyclines / sulphonaimides / NSAIDs / quinine
Figure 26 - FDE



(Copied with kind permission from Dermatoweb)
Figure 27 - FDE
Figure 28 - Post-inflammatory hyperpigmentation


Ulcers / infarction

  • Ulcers – two of the most common drugs are hydroxyurea and nicorandil
  • Infarction – warfarin
Figure 29 - Warfarin induced necrosis


Lupus erythematosus (LE)-like syndrome

  • 5% of cases of LE-like reactions are drug-induced
  • Cutaneous manifestations are rare
  • Many drugs implicated
  • Minocycline is associated with both an LE-like syndome and skin hyperpigmentation, as such this drug is now used much less frequently
  • Medications most commonly associated with drug-induced subacute cutaneous lupus erythematosus include thiazide diuretics, terbinafine and calcium channel blockers. With thiazide diuretics there can be a delay of several months to years before the onset of the rash
  • The condition usually resolves after discontinuation of the drug  

Erythema nodosum (EN)

  • Drugs are an uncommon cause of EN
  • The most commonly associated drugs are the OCP and the sulfa drugs
Figure 30 - Erythema Nodosum