Exanthematous (morbilliform, maculopapular drug eruption)
This is the most common drug rash. It occurs at any time within 2 weeks of taking the medicine. It is most often caused by ampicillin, amoxicillin, penicillin, carbamazepine, sulphonamides and allopurinol. It usually starts as a symmetrical, widespread, erythematous maculopapular rash on the trunk and limbs. The lesions may merge. If the medicine is continued, it turns into exfoliative dermatitis. The lesions settle within 2 weeks of stopping the medicine. They are sometimes accompanied by mild fever, itching and eosinophilia. The mechanism of exanthematous eruptions is not clear; it is thought to be a type IV reaction. In 100% of patients with Epstein-Barr virus or cytomegalovirus mononucleosis, an exanthematous drug eruption develops when ampicillin or amoxicillin is given.
Fixed drug eruption:
A fixed drug eruption is a skin reaction characterised by a usually single, sometimes multiple, erythematous plaque, blister or erosion. Its pathogenesis is unknown. The lesions appear between 30 minutes and 8 hours after the medicine is taken. When the patient is exposed to the same medicine again, the lesion appears in the same place and more quickly. The early lesion is a sharply demarcated, round or oval erythematous macule. It can be up to 10-20 mm in size. It is usually asymptomatic, but there may be itching and burning. Sometimes within a few hours the lesion turns into an oedematous, bullous, eroded plaque. It most often involves the genital, perioral and periorbital areas, but can be seen anywhere. It can also occur on the mucous membranes and conjunctiva, where it resembles herpes simplex, conjunctivitis or urethritis. The medicines most often implicated are sulphonamides, phenolphthalein, tetracycline, metronidazole, salicylates, non-steroidal anti-inflammatories, barbiturates and oral contraceptives.
A patch test gives an inflammatory response in 30% of cases.
Erythema Multiforme
Erythema multiforme is an inflammatory dermatosis involving the skin, the mucous membranes (oral mucosal ulcers) or both. The lesions are usually characterised by target-like, itchy, erythematous plaques and patches 1-3 mm in diameter. They are most often localised on the palms, forearms and lower limbs, but can rarely be seen on the trunk. Oral mucosal ulcers are usually irregular, with extensive necrotic tissue loss. Lip ulcers are covered with haemorrhagic crusts. The clinical picture appears 2-14 days after the medicine is taken. The medicines most often held responsible are sulphonamides, co-trimoxazole, phenytoin, carbamazepine and, among NSAIDs, ibuprofen and salicylates. Diagnosis is usually made clinically.
If a biopsy has been taken, necrotic keratinocytes, spongiosis, lichenification of the basal layer, oedema of the papillary dermis, perivascular lymphocytes and eosinophils, and sometimes extravasated red blood cells may be seen. For painful lesions inside the mouth, painkillers and viscous lidocaine as a gargle can be used. A diet of soft, non-acidic and non-spicy foods is recommended. Topical and systemic steroids for the lesions, and topical antibiotics for any secondary infections that may develop, have a place in treatment.
Stevens-Johnson Syndrome
A bullous variety of erythema multiforme that usually appears 1-14 days after a respiratory illness, with severe necrosis of the lips and mouth, purulent conjunctivitis and severe erosion of at least two mucosal surfaces. The clinical findings range from mild skin and mucous membrane involvement to a severe systemic disorder. Ocular symptoms include ulcerative conjunctivitis, keratitis, iritis, uveitis and sometimes blindness. Stevens-Johnson syndrome can present with mucosal lesions alone or with both mucosal and skin lesions. Precipitating factors include medicines (NSAIDs, sulphonamides, penicillins), but infectious agents such as Mycoplasma pneumoniae, Yersinia or other viruses and bacteria can also be precipitating factors.
Lyell's Syndrome
Toxic epidermal necrolysis is an acute and severe bullous skin disease characterised by extensive areas of skin necrosis accompanied by systemic toxic pathology. It can occur in all age groups. In most children, TEN develops as blistered erythematous patches and plaques that progress within a few hours to extensive areas of skin necrosis with severe epidermolysis. In a small number of children, it begins with peeling of the oral mucosa before extensive areas of skin necrosis form, with some areas of normal skin within the lesions. Malaise and fever accompany the skin tenderness and erythema. The rash rapidly covers large areas and forms large, flaccid blisters. The mucous membranes can be extensively involved. Because of the large areas of eroded skin, large amounts of body fluid are lost, causing disturbances of electrolyte and fluid balance. Several medicines, such as pyrazolones, hydantoin derivatives, sulphonamides and barbiturates, are thought to be responsible agents.
Acute Generalised Exanthematous Pustulosis
Acute generalised exanthematous pustulosis (AGEP) was first described in 1980 by Beylot and colleagues as "a distinct pustular drug eruption, very similar to generalised pustular psoriasis but often caused by medicines". AGEP, which presents with numerous pustular lesions on an erythematous and oedematous background together with systemic fever, has an incidence of 1-5 per 1,000,000 per year (3). Using the diagnostic scoring established by the European Study of Severe Cutaneous Adverse Reactions (EuroSCAR), it is differentiated from other pustular eruptions, especially pustular psoriasis. Medicines, most often antibiotics, are reported first in its aetiology, but viral and bacterial infections and hypersensitivity reactions to mercury have also been implicated.
Aetiology
There is a history of medication use in 90% of cases (1,2). Antibiotics are the agents that most often cause AGEP (65%). Particularly beta-lactam antibiotics (22%) and macrolides (24%), as well as tetracyclines, quinolones, aminoglycosides and sulphonamides, have been reported as the agents most often causing AGEP. Other medicines reported to cause AGEP include metronidazole, nystatin, isoniazid, furosemide, diltiazem, non-steroidal anti-inflammatory drugs, codeine, dexamethasone, and anticonvulsants such as carbamazepine and phenytoin. Apart from systemic medicines, viral infections – particularly parvovirus B19, coxsackievirus B4, Epstein-Barr virus, cytomegalovirus and hepatitis B virus – bacterial infections such as Mycoplasma pneumoniae, Chlamydia pneumoniae and Escherichia coli, mercury exposure and PUVA treatment are involved in the aetiology of AGEP.
Pathogenesis
Although the pathogenesis of AGEP is not fully understood, cytokines released by helper T cells and the deposition in the skin of drug- or infection-related antigen-antibody complexes are implicated. The fact that patch tests with a topical form of the suspected medicine give positive reactions in most cases suggests that a type IV hypersensitivity reaction also plays a role in the pathogenesis of the disease. Recent studies have shown that the production of interleukin-8 (IL-8), a potent neutrophil-chemoattractant cytokine produced by drug-related T-cell clones in the skin and circulation, plays an important role in the development of AGEP (14). A study of 102 cases by Halevy and colleagues highlighted four key features playing a role in the aetiopathogenesis:
1- In one third of patients with AGEP, eosinophil infiltration in the skin, within the pustules and in the dermis is seen together with eosinophilia in the blood. The presence of eosinophils in tissue and blood has been accepted as a finding showing that AGEP is a hypersensitivity reaction, most probably drug-related. This eosinophilia in AGEP has been explained by IL-8/CXCL8-producing T-cell clones enhancing the Th2 response.
2- The presence of necrotic keratinocytes seen in AGEP has also been reported in other drug-related eruptions. These necrotic keratinocytes have been shown to be produced by cytotoxic drug-specific T cells.
3- The neutrophilic inflammation seen in AGEP is rarely seen in drug reactions. The presence of dermal neutrophils has been explained by the presence of IL-8/CXCL8, a potent neutrophil-chemoattractant cytokine released by drug-specific T cells (CD4+ and CD8+). Factors produced by IL-8/CXCL8 released from T cells have been reported to cause the sterile pustular eruptions in AGEP by reducing neutrophil apoptosis and thus prolonging neutrophil survival.
4- The mid-to-deep dermal perivascular infiltration and red blood cell extravasation seen in drug-triggered AGEP eruptions also suggest that drug hypersensitivity may play a role in the aetiology.
Chemotherapy-Induced Acral Erythema
Chemotherapy-induced acral erythema is a localised reaction caused by chemotherapy agents such as cytosine arabinoside, 5-fluorouracil and doxorubicin. The variant of acral erythema with bullous lesions is most often caused by cytosine arabinoside (ARA-C) and methotrexate (MTX). Acral erythema is very rare in childhood. Chemotherapy-induced acral erythema (palmoplantar erythrodysaesthesia) is a problem encountered in oncology patients after long-term, high-dose chemotherapy. It is more common in adults and women, and rare in children. Many chemotherapy agents (such as cytarabine, 5-fluorouracil, methotrexate, paclitaxel, mercaptopurine, cyclophosphamide, mitotane, hydroxyurea, etoposide, docetaxel, taxol and doxorubicin) can cause acral erythema.
Drug-Induced Hyperpigmentation
Drug-induced hyperpigmentation accounts for 10-20% of acquired hyperpigmentation. The pathogenesis of drug-induced hyperpigmentation is very variable and is still not fully understood. Recently, however, 4 basic mechanisms have been described: 1) melanin deposition; 2) deposition triggered by the drug itself, independent of melanin (free dispersal of granules through the extracellular matrix, or within dermal macrophages); 3) synthesis of special pigments such as lipofuscin; 4) iron deposition due to damage to dermal blood vessels. The medicines most often implicated in these pictures are NSAIDs, antimalarials, amiodarone, cytotoxic drugs, tetracyclines, heavy metals and psychotropic drugs. Sun exposure or non-specific cutaneous inflammation after taking the medicine can make the picture worse. Although the histological findings vary, coloured particles are often found concentrated in dermal macrophages in association with dermal structures such as blood vessels or skin appendages. Treatment is often limited to sunscreens. Re-use of the implicated medicine should be avoided. Q-switched laser or fractional laser can be tried. Sometimes the hyperpigmentation may be permanent or resistant.
Drug-Induced Acne
Various medicines used topically or systemically can worsen acne vulgaris, and some can directly produce acne-like skin signs. The best example is the use of high-dose corticosteroids. Widespread red bumps appear on the trunk, shoulders and arms at the earliest 1-2 weeks after starting corticosteroids, or within about 3-6 weeks if the dose is low.
Apart from corticosteroids, anabolic steroids, iodides, bromides, isoniazid, lithium, hormone-containing medicines, quinine, azathioprine, rifampicin and high-dose B vitamins can also cause an acne-like skin rash.
Chemotherapy Nails
Cancer treatment, particularly radiotherapy and chemotherapy, can cause skin and nail problems depending on the person's response to treatment, the medicine used and its dose, and sometimes other factors such as anaemia. These signs are not seen in everyone, and most problems will return to normal after treatment ends. Always inform your doctor of any changes; significant skin changes in particular can cause permanent damage if not treated promptly.
Nail problems
The nails may darken or turn yellow, and they may break or crack. For example, 6 or more cycles of taxane treatment can cause the nails to fall off. Horizontal light and dark lines may form on the nails. Changes in nail shape (curving) may be seen; this is sometimes also associated with iron deficiency and anaemia. Loosening of the nails or blood collecting under them can sometimes also cause pain.