CHAPTER 118
Benign Cutaneous Adverse Reactions to Drugs

Michael R. Ardern-Jones1 and Haur Yueh Lee2

1Dermatoimmunology, University of Southampton, Southampton General Hospital, UK

2Department of Dermatology, Singapore General Hospital; and DUKE-NUS Graduate Medical School, Singapore

Drug-induced exanthem

Definition and nomenclature

Exanthematic eruptions can be caused by a variety of drugs and resemble in appearance the classical rash of a viral infection, for which the paradigm is the morbilliform rash associated with measles. Typically, exanthematic drug reactions do not show the systemic involvement, such as fever, that would characterize a viral infection [1].

Introduction and general description

An exanthem is the most frequent of all cutaneous reactions to medicines (Box 118.1), and can occur after almost any drug at any time up to 3 weeks, but usually 1–2 weeks after administration. A variety of drugs can cause drug-induced exanthems, the commonest being penicillins, aromatic anticonvulsants, sulphonamides, non-steroidal anti-inflammatory drugs (NSAIDs) and allopurinol (listed in Box 118.1). It is not possible to identify the offending drug by the nature of the eruption.

Epidemiology

Exanthematous reactions are the most frequent presentation of non-immediate (non-immunoglobulin E (IgE)) drug allergy. The epidemiology of such reactions is not well characterized, but a French study identified 3.6 cutaneous allergic reactions per 1000 hospitalized patients, of which 56% showed exanthematous reactions [2] and a later study showed similar results [3].

Pathophysiology

The mechanism of cutaneous inflammation in drug-induced exanthems is mediated by drug-specific T cells (see Chapter 12).

Pathology

Histology is generally non-specific. However, some histological features are used to discriminate drug-induced exanthems from non-drug exanthems including: apoptotic keratinocytes, eosinophils within the inflammatory infiltrate, papillary oedema and vascular changes [4] (Figure 118.1).

Image described by caption.

Figure 118.1 Histopathology of a drug-induced exanthem, H&E. Magnification 20×. This pigmented epidermis shows orthokeratosis and mild spongiosis. The papillary dermis is mildly oedematous. There is a brisk superficial perivascular lymphocytic infiltrate with many scattered interstitial eosinophils. Melanophages are also present. (Courtesy of Dr Marianna Philippidou, King's College Hospital, London, UK.)

Clinical features

The latency from drug initiation to onset of rash ranges from 5 to 21 days, but typically occurs at 7–10 days. A drug-induced exanthem may be accompanied by pruritus. The clinical features are variable; lesions may be scarlatiniform, rubelliform or morbilliform, or may consist of a profuse eruption of small pink papules showing no close resemblance to any infective exanthem (Figures 118.2 and 118.3). Less common are eruptions with large macules, polycyclic and gyrate erythema, reticular eruptions and sheet-like erythema. The trunk and extremities are usually involved, and not uncommonly intertriginous areas may be favoured, but the face is typically spared. Palmar and plantar lesions may occur, and sometimes the eruption is generalized. Purpuric lesions, especially on the legs, and erosive stomatitis may develop. There may be relative sparing of pressure areas.

Image described by caption.

Figure 118.2 An exanthem caused by ampicillin.

Image described by caption.

Figure 118.3 A drug-induced exanthem composed of macular and papular lesions, becoming confluent on the chest.

Differential diagnosis

Viral infection is the most important differential diagnosis. Classical viral exanthems such as measles and chickenpox are readily identifiable [5]. In a recent series of atypical exanthems, morphology and laboratory investigations led to an aetiological diagnosis in 77% of cases [6]. Drugs were responsible for 25% of the exanthems (more commonly in adults) of which antibiotics and NSAIDs were most frequently implicated. It is useful in differentiating exanthematic drug eruptions from viral exanthems to remember that viral rashes tend to start on the face and acral sites with subsequent progression to involve the trunk, and are more often accompanied by fever, sore throat, gastrointestinal symptoms, conjunctivitis, cough and insomnia [6]. Pruritus is typically associated with drug causes in adults. Enanthems, which involve the mucous membranes, are more commonly associated with an infectious aetiology.

Drug reaction with eosinophilia and systemic symptoms (DRESS) (see Chapter 119) is important to exclude since the eruption in this systemic drug hypersensitivity syndrome can be exanthematous.

Complications and co-morbidities

If the administration of the drug is continued, an exfoliative dermatitis may develop, although occasionally the eruption subsides despite continuation of the medication.

Disease course and prognosis

The illness follows a benign course, and resolves without sequelae following cessation of the offending drug. Morbilliform drug eruptions usually, but not always, recur on rechallenge.

Investigations

Blood tests to exclude organ dysfunction and haematological abnormalities associated with DRESS are important. Viral serology/polymerase chain reaction (PCR) may be useful to exclude viral infections. Skin histology is not routinely undertaken as it is not diagnostic of a drug cause but may be useful to exclude other conditions where the clinical features are not characteristic.

Management

Cessation of the culprit drug is essential. On withdrawal of the drug, maculopapular drug eruptions usually fade with desquamation, sometimes with post-inflammatory hyperpigmentation. Generally, symptomatic treatment only is required; most cases benefit from emollients. Approximately 50% of exanthematous eruptions are pruritic and intermediate potency topical corticosteroids may be useful for these cases.

Resolution of drug-induced exanthems is faster than for infectious exanthems.

Drug-induced pruritus

Definition

Itch caused by a drug. Drug-induced pruritus may be localized or generalized.

Introduction and general description

Pruritus is generally a complication of systemic drugs but is also associated following the application of some topical agents, such as calcineurin inhibitors and β-adrenergic blockers [7, 8]. The systemic agents which can cause pruritus are listed in Box 118.2.

Epidemiology

Pruritus has been reported to arise in 13.3% of adverse reactions to prescribed drugs in general practice [9]. Opioid-induced pruritus is the most frequent and best recognized primary drug-induced pruritus and is reported to arise in 2–10% of patients treated with opiates [10].

Pathophysiology

Drug-induced pruritus may be primary, via neuronal/central nervous system interaction, or through secondary mechanisms. Secondary pruritus includes: (i) direct skin effects, e.g. induction of a hypersensitivity drug rash, other inflammatory skin disease or xerosis; (ii) alteration of biochemical profiles (e.g. renal or hepatic dysfunction); and (iii) other unexplained mechanisms.

Opioids can induce mast cell degranulation and histamine release causing an itchy urticarial rash, however most opioid pruritus appears to involve binding of the drug to central μ-opioid pain receptors in the medullary dorsal horn [11]. Serotonin and dopamine D(2) receptors, spinal inhibitory pathways and prostaglandins have also been implicated in opioid-induced pruritus [12].

Chloroquine can cause mast cell induced histamine pruritus. However, the precise cause of generalized pruritus seen in 60–70% of black Africans treated with antimalarials is unclear and likely to be multifactorial including μ-opioid receptor signalling as well as genetic (it is less common in white people) [13, 14]. Selective serotonin reuptake inhibitor (SSRI) induced pruritus is also well recognized and these drugs can induce itching when injected into the skin [15]. Interestingly, SSRIs can also be used to treat psychogenic itching [16].

Hydroxyethyl starch (HES) is used for colloid fluid replacement in some settings and has been associated with chronic pruritus in approximately one third of patients. HES-induced itch can arise with the administration of small volumes but the complication is more common with greater exposure. The symptoms typically arise after 1–6 weeks of HES infusion [17], can persist for 12–24 months [18] and are generally refractory to treatment [19].

Clinical features

The latency from drug initiation to onset of pruritus is usually just a few days. The patient complains of generalized itching often with signs of excoriation and/or lichenification. Dermographism is generally not present.

Differential diagnosis

Pruritus caused by other conditions must be excluded (see Chapter 83).

Disease course and prognosis

Although considered a mild adverse drug reaction, chronic pruritus can have a significantly negative effect on quality of life.

Investigations

Exclusion of other causes of itch is essential (see Chapter 83).

Management

Generally, cessation of the culprit drug brings rapid relief. However, some drug-induced pruritus, such as HES, can be long lived. Although antihistamine medications are frequently prescribed for drug-induced pruritus, they are rarely helpful. Cooling emollients such as 0.5% menthol in aqueous cream may be of benefit.

In view of the direct involvement of opioid receptors in opiate-induced pruritus, the most effective means of treatment is reduction in dose or cessation of opiate treatment. Alternatively introduction of naloxone, naltrexone (μ-receptor antagonists) or nalbuphine (partial μ-receptor agonist, μ-receptor antagonist) may be tried, but all of these approaches are likely to lead to loss of pain control. Other approaches include adding D2 receptor antagonists, serotonin (5-HT3) receptor antagonists (ondansetron, dolasetron), antihistamines and gabapentin [19]. Interestingly, μ-receptor antagonists have also been utilized in other forms of pruritus especially where endogenous endorphins are thought to be pathogenic, such as in cholestatic pruritus [20].

For more resistant cases of drug-induced pruritus, photo­therapy and other therapeutic options may be of value (see Chapter 83).

Drug-induced eczema

Definition and nomenclature

Drug-induced eczema is a systemic allergic contact dermatitis (SACD) caused by drug hypersensitivity.

Introduction and general description

A patient sensitized to a drug may develop an eczematous reaction when the same drug, or a chemically related one, is subsequently administered systemically [21–23]. The medications which most commonly cause drug-induced eczema are listed in Box 118.3. Patients with a contact allergy to ethylenediamine may develop generalized or localized eczema following injection of aminophylline preparations containing ethylenediamine as a solubilizer for theophylline [24, 25]. Patients with contact allergy to parabens may develop systemic eczema on exposure to drugs containing parabens as a preservative [26]. Similarly, sensitized patients may develop eczema following oral ingestion of neomycin or hydroxyquinolines [27]. Diabetic patients sensitized by topical preparations containing p-amino compounds, such as p-phenylenediamine hair dyes, para-aminobenzoic acid (PABA) sunscreens and certain local anaesthetic agents (e.g. benzocaine), may develop a systemic contact dermatitis with the hypoglycaemic agents tolbutamide or chlorpropamide. Sulphonylureas may also induce eczematous eruptions in sulphanilamide-sensitive patients as a result of cross-reactivity. Phenothiazines can produce allergic contact dermatitis, photoallergic reactions and eczematous contact-type dermatitis, and may cross-react with certain antihistamines. Tetraethylthiuram disulphide (disulfiram, Antabuse®) for the management of alcoholism can cause eczematous reactions in patients sensitized to thiurams via rubber gloves. Drugs given systemically have also been identified as causing eczematous drug reactions without prior contact sensitization, and approximately 50% of cases of SACD are due to penicillins or β-lactam antibiotics. The term ‘endogenic contact eczema’ [28] refers to the occurrence of an eczematous contact drug reaction following primary sensitization by oral therapy, as in the case of a patient with a drug-related exanthem who later develops localized dermatitis due to topical therapy. Symmetrical drug-related intertriginous and flexural exanthem (SDRIFE) describes a clinically distinct form of drug-induced eczema (see later).

Epidemiology

Rare.

Pathophysiology

The eczematous response is mediated by drug-specific T-cell induced inflammation in the skin (see Chapter 12).

Pathology

The principal histological features are dermatitic changes with spongiosis and a superficial perivascular infiltrate, primarily composed of mononuclear cells.

Clinical features

The latency from drug initiation to onset of eczema typically occurs at 7–14 days. The eruption tends to be symmetrical, and may involve first, or most severely, the site(s) of the original dermatitis, before becoming generalized.

Differential diagnosis
  • Idiopathic eczematous reactions.
  • Allergic contact dermatitis.
  • Irritant contact dermatitis.
Complications and co-morbidities

Following drug withdrawal, complications and co-morbidities are minimal.

Disease course and prognosis

On withdrawal of the offending drug, resolution of the clinical symptoms generally occurs in 1–3 weeks. Re-exposure to the culprit would be expected to reproduce the same clinical picture.

Investigations

Patch tests are commonly positive and usually vesicular, although histology of the eruption itself may show leukocytoclastic vasculitis. Oral challenge with the suspected antigen may be required to substantiate the diagnosis.

Management

The primary objective is cessation of the causative drug. Therapies utilized to treat eczematous dermatoses, such as topical corticosteroids, are usually effective. For severe reactions, systemic treatment with prednisolone may be appropriate.

Symmetrical drug-related intertriginous and flexural exanthem

Definition and nomenclature

A benign and self-limiting drug eruption characterized by symmetrical involvement of the gluteal and intertriginous areas, occurring in the absence of systemic involvement.

Introduction and general description

SDRIFE is a distinctive drug eruption characterized by symmetrical eruption of the gluteal region, thighs and other intertriginous areas such as the axillae, knees, elbows and neck. Previously, such cases were called drug-induced baboon syndrome – a form of systemic allergic contact dermatitis (see earlier). The term SDRIFE was proposed in 2004 as a culturally more neutral term, and also to reflect a spectrum of involvement beyond the gluteal region [37, 38]. The medications associated with SDRIFE are listed in Box 118.4.

Epidemiology
Age

Reported in all ages.

Sex

Male preponderance [37].

Pathophysiology

In SDRIFE, immunohistological findings on skin biopsies have shown an infiltration of CD4+ T cells in the dermis. The delayed latency and occasional positivity on patch testing to causative drugs support a type IV delayed hypersensitivity reaction [38]. Systemic drugs induce SDRIFE without prior skin sensitization and without cross-reactivity to known contact allergens. The reason for the peculiar distribution of the reaction is unknown. Postulated explanations include a preferential trafficking of activated memory T cells to these sites as a form of recall phenomenon from previous physical/inflammatory insult. Although excretion of drugs or their metabolites in the site has been postulated, there is no syringotropic inflammation which argues against a central role for sweat glands in the pathogenesis [39].

Pathology

There is significant heterogeneity in SDRIFE [37]. Features that have been described include: superficial perivascular lymphocytic infiltrate, which may also include neutrophils and eosinophils, spongiosis and vacuolar degeneration of the basal cells.

Clinical features
History

The latency from drug intake to the onset of SDRIFE ranges from hours to a few days [37, 38].

Presentation

This cutaneous adverse reaction is characterized by the following diagnostic criteria: (i) exposure to a systemically administered drug; (ii) sharply demarcated erythema of the gluteal/perianal area and/or V-shaped erythema of the inguinal area; (iii) involvement of at least one other intertriginous/flexural location; (iv) symmetry of the affected areas; and (v) absence of systemic symptoms and signs (Figures 118.4 and 118.5). Occasionally, the eruption may consist of small papules, pustules, vesicles and rarely bullae. Palmoplantar surfaces, face and mucosa are usually spared [37].

Image described by caption.

Figure 118.4 Symmetrical drug-related intertriginous and flexural exanthem (SDRIFE): well-defined patches of erythema involving the gluteal skin.

Image described by caption.

Figure 118.5 Symmetrical drug-related intertriginous and flexural exanthem (SDRIFE): intense erythema affecting the axillary skin.

Differential diagnosis

The differential diagnosis of intertriginous eruptions include inflammatory dermatoses such as contact dermatitis, inverse psoriasis, Hailey–Hailey disease, infective causes such as intertrigo and tinea cruris and other drug-induced reactions such as acute generalized exanthematous pustulosis (AGEP) and chemotherapy-associated toxic erythema. Although the sheets of pustules and constitutional symptoms of AGEP are usually obvious, the initial reaction may have a flexural predilection. Chemotherapeutic reactions such as neutrophilic eccrine hidradenitis/eccrine squamous metaplasia may also have a flexural predilection.

Disease course and prognosis

The reaction improves quickly on withdrawal of the culprit drug.

Investigations

Patch tests are positive in up to 50% with SDRIFE and oral provocation tests are positive in 80% of patients [38]. Prick testing and lymphocyte stimulation testing are negative in the majority of reported cases of SDRIFE.

Management

Treatment is symptomatic. The offending drug should be withdrawn and avoided in the future. No active therapy is required although topical or systemic glucocorticoids may hasten recovery [38].

Drug-induced urticaria, angio-oedema and anaphylaxis

Definition

Urticaria and angio-oedema are physical signs which involve circumscribed skin oedema and erythema (described in detail in Chapters 42 and 43). Anaphylaxis is a constellation of clinical findings which describes respiratory and cardiovascular compromise (bronchoconstriction and hypotension) in a life-threatening manner and is described in Chapter 42. This section is concerned with drug-induced causes of these reaction patterns.

Pseudoallergy (non-immune mediated) describes a presentation which is clinically indistinguishable from true allergy (IgE mediated). Pseudoallergic urticaria, angio-oedema and anaphylaxis are commonly mediated by drugs, as discussed later, and these reactions are sometimes referred to as ‘anaphylactoid’.

Introduction and general description

Drug-induced urticaria can be seen in isolation or in association with anaphylaxis and angio-oedema. Aspirin and NSAIDs are the most frequently implicated drugs in allergic reactions, most frequently causing urticaria [41] as well as exacerbating idiopathic urticaria [42].

The most frequent drug causes of anaphylaxis are antibiotics (usually β-lactams) and NSAIDs [43]. However, biologicals are increasingly common culprits. Anaphylaxis during general anaesthesia is an important problem and can be difficult to investigate if intraoperative exposures are not well recorded. Furthermore, distinction between true immune-mediated and non-immune-mediated reactions can be challenging. Common perioperative causes of anaphylaxis or anaphylactoid reactions include: anaesthetic agents (especially thiopental), neuromuscular blocking agents (may also be non-IgE mediated), analgesics (opioids are usually associated with non-IgE-mediated reactions), antibiotics, protamine and blood transfusions (mechanism unclear) [43]. Recently, anaphylaxis caused by drugs bioengineered onto medical equipment, such as chlorhexidine-coated central venous catheters, has been recognized [44]. β-blockers enhance anaphylactic reactions caused by other allergens, and may make resuscitation more difficult [45].

Epidemiology

Urticaria is the second most common type of adverse cutaneous drug eruption [46, 47]. Drug-induced urticaria is seen in 0.16% of medical in-patients and accounts for 9% of chronic urticaria or angio-oedema occurring in dermatology out-patient departments [46]. It has been estimated that 1 in 1500 of the population of England has experienced anaphylaxis at some point in their lives [48]. Of the deaths from anaphylaxis recorded each year in the UK (on average 20) at least half were due to drugs [49]. The incidence of anaphylaxis during general anaesthesia has been estimated to arise in 1 : 4000 to 1 : 25000 cases [43]. Infliximab is estimated to cause anaphylaxis or IgE-mediated reactions in 2–3% of patients [50] and reaction to other tumour necrosis factor (TNF) antagonists are also recorded [51].

Pathophysiology

The mechanisms underlying drug-induced vasodilation, oedema and itch in urticaria are identical to those seen in angio-oedema (deeper in skin) and anaphylaxis (systemic circulation). Classically, these reactions are mediated by the presence of drug-specific IgE. On exposure to the drug, cross-linking of IgE on the surface of mast cells (and possibly basophils) is followed by inflammatory mediator release (including histamine), which induces vasodilation, neuronal activation and smooth muscle contraction (see Chapter 8). Cyclo-oxygenase inhibitors, such as aspirin and indometacin, may also cause urticaria or angio-oedema by pharmacological mechanisms. Other drugs, such as radiocontrast media, local anaesthetics and dextrans (in plasma expanders) may release mast cell mediators directly. Angiotensin-converting enzyme (ACE) inhibitors can cause angio-oedema which is bradykinin mediated rather than histamine dependent and will therefore not respond to antihistamines [52].

Genetics

See Chapter 42.

Pathology

See Chapter 42.

Clinical features

Urticaria, angio-oedema and anaphylaxis arise within 24–36 h of drug ingestion at the first occasion. On re-challenge lesions may develop within minutes. Anaphylaxis usually develops on second exposure to a drug as it is thought that prolonged treatments may induce tolerization rather than allergy (in contrast to T-cell-mediated hypersensitivities). Anaphylaxis and anaphylactoid reactions usually develop within minutes to hours (the vast majority within the first hour) of drug administration.

Urticaria occurring alone is more common than urticaria arising with angio-oedema (Figure 118.6). Anaphylaxis and anaphylactoid reactions are often associated with skin or mucosal changes: in less severe cases, there may be premonitory dizziness or faintness, skin tingling and reddening of the bulbar conjunctiva, followed by urticaria, angio-oedema, bronchospasm, abdominal pain and vasomotor collapse. Intravenous administration is associated with more severe reactions and rapid progression, over minutes, to cardiac arrest. In cases of insect sting-related and food-induced anaphylaxis, the syndrome evolves more slowly [45].

Image described by caption.

Figure 118.6 Urticaria induced by acetylsalicylic acid. (Courtesy of St John's Institute of Dermatology, King's College London, UK.)

Differential diagnosis

Drug-induced urticaria needs to be distinguished from other causes of urticaria, especially infection. This distinction may require specialist testing. Drug-induced anaphylaxis needs to be distinguished from other causes of anaphylaxis.

Complications and co-morbidities

Anaphylaxis may result in death if untreated. With early intervention, treatment outcomes are good. However, it is critical that causation is addressed and investigated as necessary to prevent accidental recurrence.

Disease course and prognosis

On withdrawal of the offending culprit, clinical improvement in drug-induced urticaria and angio-oedema occurs within 24–48 h. It is important to recognize that after an initial improvement from anaphylaxis, late-phase reactions may arise 5–6 h afterwards. Deaths from drug-induced anaphylaxis are uncommon (<2%); the major predisposing risk factor for poor outcome is coexistent severe asthma [53, 54].

Investigations

The investigation of immediate drug allergy reactions (characterized by urticaria, angio-oedema or anaphylaxis) is well established and various guidelines represent consensus approaches to the investigation of the culprit drug [55]. The general approach is based upon a careful documentation of the exposure history in the hours preceding the reaction to establish the most likely causative drug. Careful record should be made of the timeline of clinical features. Testing involves an escalation of exposures which is stopped if any positive result is identified, thereby minimizing risk. In many circumstances, it is more useful to prove a negative through testing than confirm a drug allergy through testing, so as to establish what is safe for the patient to take. The testing process involves plasma sampling for drug-specific IgE, skin prick testing, intradermal testing and challenge testing.

Beta-lactam allergy reactions are due to IgE recognition of the drug bound to a carrier molecule. Skin testing is undertaken with benzylpenicilloyl polylysine ‘major antigenic determinant’ and ‘minor determinants’ (other penicillin antigens). Drug-specific IgE measured by Immunocap® (RAST®) has a high specificity but low sensitivity and therefore should only be used by specialists with access to the full range of skin testing [56]. Progression to intradermal testing and challenge if necessary is advocated by European and UK guidelines [55]. Multiple studies have shown the very low positive predictive value of labels of ‘penicillin allergy’ confirmed by negative testing including oral challenge. Although penicillin avoidance is not difficult for the majority of cases, adverse outcomes of mislabelling with penicillin allergy are increasingly recognized and confirmatory testing is recommended in specific groups [56].

Patch testing is not useful in the investigation of anaphylaxis, and caution should be employed when considering patch testing to allergens where the clinical reaction may have been IgE mediated. Anaphylaxis does occur after non-mucosal topical drug administration, especially to skin wounds or to skin with impaired barrier function [57].

Management

For evolving urticaria with or without angio-oedema or anaphylaxis, the key principal management step is to stop the offending drug and disease resolution occurs quickly.

Oral/IV antihistamines, oral/IV corticosteroids and s/c epinephrine/adrenaline may be required as per local guidelines [58]. Although cross-reactivity occurs throughout the NSAID class, selective COX-2 inhibitors are recommended in low-risk NSAID sensitive patients where anti-inflammatory therapy is required [56].

Drug-induced serum sickness-like reaction

Definition

Drug-induced serum sickness-like reactions (SSLR) are characterized by a clinical triad of fever, rash and arthralgias/arthritis.

Introduction and general description

SSLR is a drug reaction pattern, so named because of its similarity in clinical presentation to serum sickness. Classical serum sickness is a type III hypersensitivity reaction to foreign proteins resulting in the deposition of immune complexes in small blood vessels of various organs such as the skin, joints and other systems. In distinction, SSLR is typically due to medications and despite the clinical similarity, circulating immune complexes are not usually found [59].

Incidence and prevalence

SSLR accounts for about 2% of all cutaneous reactions attributed to β-lactams in a tertiary hospital [60]. Risk of SSLR is dependent on the underlying drug. Cefaclor is the most common reported trigger, occurring at 1 per 3000 cefaclor prescriptions compared to 1 per 120 000 in the case of amoxicillin.

Age

SSLR is more commonly reported in children and this may reflect the relatively frequent use of high-risk medications such as cefaclor in the young.

Pathophysiology

The pathophysiology of SSLR is not well studied. Prior in vitro studies on cefaclor suggest that drug metabolism and biotransformation of the parent drug to reactive metabolites is essential and inherited defects in the metabolism of these reactive intermediates may be a predisposing factor [61]. The downstream mechanism is unclear. However, the absence of circulating immune complexes and the lack of cross-reactivity between cases of cefaclor-induced SSLR and other cephalosporins suggest that a true hypersensitivity reaction is unlikely.

Pathology

The histological features of SSLR are consistent with an urticarial reaction pattern. Findings include dermal oedema with a superficial and deep perivascular infiltrate of lymphocytes, neutrophils and eosinophils. Vasculitis is usually absent [62].

Clinical features
History

A variety of drugs has been reported to cause SSLR eruptions and are listed in Box 118.5. The typical median latency from drug initiation to onset of rash ranges is 7 days with a range from 1 to 13 days [63, 64].

Presentation

The primary lesions of SSLR are urticarial weals which are migratory and pruritic (Figure 118.7). Some lesions may have purpuric or dusky centres and may be mistaken for erythema multiforme. Facial and periorbital oedema may coexist. No mucosal membranes are involved [64]. Other less common variants include morbilliform eruptions, urticarial or purpuric bullous plaques [62–67].

Image described by caption.

Figure 118.7 (a,b) Persistent urticarial lesions of a serum sickness-like reaction caused by penicillin.

Joints of the hands and feet are also often affected; associated symptoms include arthralgia, swelling, warmth and decreased range of movement [64]. Systemic involvement of the kidneys and liver is rare, in contrast to true serum sickness [68].

Differential diagnosis

Urticarial vasculitis, Still disease, Schnitlzer syndrome, human parvovirus B19 infection, Kawasaki disease and hereditary autoinflammatory diseases [69].

Disease course and prognosis

Cutaneous and musculoskeletal manifestations resolve on drug withdrawal. Typical median duration of rash and joint symptoms are 5 and 3 days, respectively. Long-term morbidity or sequelae are not associated with SSLR, although occasionally the duration of rash and joint symptoms may be prolonged [63, 64].

Investigations

Intradermal tests and patch tests are usually negative. Drug provocation testing is usually positive and is a safe procedure if the diagnosis needs to be confirmed [70].

Management

Withdrawal of the culprit drug is essential; the rash and joint symptoms usually resolve within 1 week of withdrawal [63]. Symptomatic treatment such as antihistamines, antipyretics and systemic corticosteroids have been prescribed, based on published series, however the impact of these medications in shortening the disease duration remains to be determined [64].

Lichenoid drug eruptions

Definition

Lichen planus (LP)-like drug eruptions are clinically indistinguishable from normal LP although are frequently more severe. Drug-induced lupus shows the clinical and immunological features of idiopathic lupus erythematosus (LE).

Introduction and general description

Lichenoid drug eruptions may present as a variety of clinical patterns including LP and LE. It has been suggested that the different clinical patterns reflect lymphocyte ‘cell rich’ (e.g. LP) and ‘cell poor’ (e.g. LE) lichenoid patterns [83]. There is no current evidence to indicate that a different disease mechanism underlies the contrasting conditions. The common causes of drug-induced LP are listed in Table 118.1. Drug-induced LE is classically caused by drugs such as procainamide, methyldopa, quinidine, minocycline and hydralazine [84–88], but many of these are no longer widely used. More recent reports of biologicals (especially anti-TNFα inhibitors) causing LE-type eruptions suggest that this may become an increasing problem [89–91]. The common causes of drug-induced LE are listed in Table 118.2.

Table 118.1 Drugs associated with drug-induced lichen planus.

Well-established culprits Less well-established culprits
Antimalarials Angiotensin-converting enzyme inhibitors
Gold β-blockers
Mercury amalgam Lithium
Non-steroidal anti-inflammatory drugs Methyldopa
Pencillamine Quinidine
Thiazide diuretics Other sulfonylureas

Adapted from Ellgehausen et al. 1998 [93] and Halevy and Shai 1993 [94].

Table 118.2 Drugs associated with drug-induced lupus erythematosus.

Important/widely used drugs Less widely used drugs Recent reports
Angiotensin-converting enzyme inhibitors (e.g. captopril) Antithyroid drugs (e.g. propylthiouracil) Biological anti-tumour necrosis factor monoclonal antibodies
β-blockers (e.g. atenolol)a Chlorpromazine Cimetidine
Calcium-channel blockers (e.g. diltiazem)b Fluorouracil (systemic)b Clobazam
Isoniazid Hydralazine Clopidogrel
Statinsa Methyldopa Clozapine
Sulfasalazine Procanamide Interferons
Terbinafineb Quinidine Interleukin 2
Thiazide diuretics Minocycline Ticlopidine
Zafirlukast

Adapted from Antonov et al. 2004 [95], Valeyrie-Allanore et al. 2007 [96] and Pretel et al. 2013 [97].

aMore typically associated with subacute cutaneous lupus erythematosus type reactions.

bMay be associated with both systemic lupus erythematosus and subacute cutaneous lupus erythematosus type reactions.

Epidemiology

Drug-induced LP reactions represent approximately 10% of all LP cases. Approximately 10% of all cutaneous LE cases are mediated by drugs.

Pathophysiology

The mechanisms underlying lichenoid drug eruptions are essentially unknown, but they may develop as a result of autoreactive T cells directed against a drug–major histocompatibility complex (MHC) antigen complex, such that keratinocytes and Langerhans cells are viewed by the immune system as ‘non-self’. Genetic factors have been strongly linked with drug-induced lupus such as hydralazine (73% HLA-DR4) [84] and minocycline (HLA-DQB1) [85], which support the prevailing concept of a T-cell-­mediated disease. Lage et al. showed a significant positive correlation between CD8 frequency and perforin expression in skin biopsies from drug-induced lichenoid eruptions versus classical LP suggesting that cytotoxic CD8 T cells may be crucial for induction of keratinocyte apoptosis [86]. However, injection of autoreactive CD4 T-cell clones has been shown sufficient to induce a lichenoid skin reaction in a murine model reaching maximal severity at day 5 [83]. The presence of epidermotropic T cells correlates with that of class II MHC (HLA-DR)-expressing keratinocytes and Langerhans cells in lichenoid eruptions [83]. The cross-reactive nature of herpes simplex virus (HSV)-specific T cells with drug has been reported suggesting that antiviral skin-resident CD8 memory T cells may cross-react with drug antigens to induce lichenoid drug eruptions [83].

Pathology

Lichenoid drug eruptions show typical histological evidence of lichenoid change including hyperkeratosis, hypergranulosis, ‘saw tooth’ acanthosis, and a band-like infiltrate in the superficial dermis. A number of histological features have been attributed to a drug trigger, including a less dense but more pleomorphic infiltrate, cytoid bodies in the cornified and granular layers, the presence of focal parakeratosis, and focal interruption of the granular layer [87] (Figure 118.8). However, a recent study found that the only distinguishing histological characteristics of drug-induced LP, as opposed to non-drug LP, were a higher frequency of necrotic keratinocytes (in clusters), and infiltrating plasma cells and eosinophils [86].

Image described by caption.

Figure 118.8 Histopathology of lichenoid drug eruption, H&E. Magnification 10×. There is compact hyperkeratosis overlying ‘sawtooth’ acanthosis of the epidermis with lymphocyte exocytosis. Basal vacuolar change and Civatte bodies accompany a band-like interface lymphocytic infiltrate. There are scattered interstitial eosinophils in the papillary dermis. (Courtesy of Dr Marianna Philippidou, King's College Hospital, London, UK.)

Clinical features

The onset of LP- and LE-like eruptions is usually months (even years) after the first exposure to the medication, but the precise reason for the typical delayed onset is not established. The skin changes of LP-like drug eruptions may be non-specific or may resemble the classical small shiny papules and plaques with Wickham's striae, as in idiopathic LP (Figures 118.9 and 118.10). Mucosal lichenoid reactions can also be caused by drugs. Photodistributed lichenoid lesions may occur with a number of drugs, including thiazide diuretics.

Image described by caption.

Figure 118.9 A lichenoid drug eruption triggered by therapeutic gold, presenting as multiple inflammatory plaques.

Image described by caption.

Figure 118.10  Pravastatin-induced lichenoid drug eruption with numerous hyperpigmented patches and plaques disseminated over the torso.

The clinical pattern of drug-induced LE is more commonly like SLE than subacute LE [88].

Differential diagnosis
  • Idiopathic LP.
  • Idiopathic cutaneous LE.
Complications and co-morbidities

If untreated, these are the same as the idiopathic conditions (see Chapters 37 and 51).

Disease course and prognosis

The diagnosis is proven by disease resolution on withdrawal of the offending drug. Disease resolution may take weeks to months.

Investigations

Skin histology is essential for the investigation of lichenoid drug eruptions. In drug-induced LE, immunological findings typically show positive antinuclear antigen and positive anti-Ro antibodies; 75% show positive antihistone antibodies (90% are ANA positive) [92].

Management

Withdrawal of the offending drug is essential. Use of a potent or super-potent topical corticosteroid is usually effective in clearing the eruption. In severe cases, therapy with oral glucocorticoids may be required.

Fixed drug eruption

Definition

Fixed drug eruption (FDE) is a cutaneous adverse drug reaction characterized by recurrent well-defined lesions occurring in the same sites each time the offending drug is taken [98, 99].

Introduction and general description

FDE is a drug eruption distinguished by its recurrence at the same sites on re-challenge, its short latency and benign nature.

History

FDE typically presents 30 min to 8 h after drug exposure. An extensive list of medications are known to cause FDE; however, the commonest culprit drugs are listed in Box 118.6. Co-trimoxazole, tetracyclines and NSAIDs have been frequently implicated as the top three causes of FDE [100, 101]. A survey of UK dermatologists yielded similar results with NSAIDs (25%), paracetamol (24%), co-trimoxazole (5%) and tetracycline (5%) being the most frequent triggers [102]. However, a recent French nationwide analysis of FDEs reports the common drugs as NSAIDs (25%), paracetamol (15%), carbocystine (7%) and amoxicillin (7%), which may be due to changing prescription practices [103]. Food and herbal medications have also been reported as aetiological agents [104–106].

Epidemiology
Incidence and prevalence

FDEs account for 4–39% of all drug eruptions [107–109].

Age

FDE has been reported in all ages. However, it is more common in adults, particularly in the range of 40–80 year olds [103].

Sex

Both genders are prone to the development of FDE, although a female preponderance may exist [103].

Pathophysiology

FDE is a form of classical delayed-type hypersensitivity reaction and skin resident T cells are believed to be the key mediators in eliciting FDE. Long after clinical resolution, ‘resting’ FDE lesions contain CD8+ T cells with an effector/memory phenotype. These cells are located at the dermal–epidermal junction and remain quiescent until drug re-challenge. On re-exposure to the drug, there is activation and expansion of these CD8+ lymphocytes with the release of interferon (IFN)-γ and cytotoxic granules resulting in keratinocyte apoptosis. At the end of the immune response, regulatory T cells are recruited into the lesions and limit further damage by inhibiting the cytotoxic T cells. Expanded and activated cytotoxic T cells are removed by apoptosis but a small population is prevented from apoptosis by keratinocyte derived interleukin (IL)-15 and remain as skin-resident memory T cells until the next activation cycle [98, 110, 111].

Genetics

A pharmacogenetic predisposition exists as drug-specific HLA associations have been reported for certain medications. These include febrazone-induced FDE and HLA-B22 and trimethoproim-sulfamethoxazole and HLA-A30 [112, 113].

Pathology

Early biopsy specimens show an interface dermatitis reaction pattern with vacuolar degeneration of basal keratinocytes, dermal oedema and a perivascular lymphocytic infiltrate of the upper dermis. Eosinophils may be present. Resolved or healing lesions are characterized by pigment-laden macrophages in the upper dermis [98, 114] (Figure 118.11).

Image described by caption.

Figure 118.11 Histopathological features of fixed drug eruption: interface vacuolar degeneration with lymphocyte exocytosis and melanin incontinence; a perivascular lymphoid infiltrate is present around the superficial dermal vessels. (Courtesy of Dr Ronald Goh, Singapore General Hospital, Singapore.)

Clinical features
History

FDE usually develops 30 min to 8 h after drug exposure.

Presentation

Typically, FDE presents as a sharply-defined, round or oval erythematous and oedematous plaque which evolves to become dusky, violaceous and occasionally vesicular or bullous (Figure 118.12). Lesions are usually solitary or few in number although multiple lesions may be present or may develop as a consequence of repeated challenges [115] (Figure 118.13a,b). Commonly affected sites include the lips, genitals, palms and soles; 5% of cases may have an exclusive mucosal involvement [103].

Image described by caption.

Figure 118.12 Fixed drug eruption: a well-defined, dusky and hyperpigmented oval plaque on the thigh.

Image described by caption.

Figure 118.13 (a) Multiple discrete lesions of fixed drug eruption induced by aspirin (Anadin). (b) Well-defined erythematous plaque over the dorsum of the hand and little finger.

Drug-specific clinical patterns have been reported. These include: NSAID-induced FDE affecting the genitals and lips; tetracycline- and trimethoprim/sulfamethoxazole-induced FDE affecting the genitals; metamizole-induced FDE of the trunk and extremities; and carbocysteine-induced FDE of the face [103, 114, 115].

Generalized bullous FDE (GBFDE) is a form of extensive FDE which may be misdiagnosed as toxic epidermal necrolysis (TEN) [98, 116] (Figure 118.14). Differentiating features from TEN include: (i) prior history of similar episodes; (ii) mucosal surfaces are relatively uninvolved; (iii) the presence of large blisters with intact intervening skin; and (iv) the absence of multiple purpuric or target lesions.

Image described by caption.

Figure 118.14 Generalized bullous fixed drug eruption: multiple bullous and eroded lesions induced by parecoxib.

Differential diagnosis

The differential diagnosis of FDE depends on the site, number of lesions and stage of evolution. Mucosal predominant lesions may mimic herpes simplex, aphthous stomatitis, pemphigus vulgaris and Stevens–Johnson syndrome (SJS). Extensive lesions in GBFDE may be diagnosed as SJS/TEN or bullous pemphigoid. In healed lesions, residual pigmentation may be reminiscent of erythema dyschromicum perstans [98, 99, 116].

Complications and co-morbidities

Patients with GBFDE generally lack visceral complications and are thought to have a benign clinical course. In contrast with SJS/TEN, GBFDE generally has modest or no mucosal involvement and is not associated with respiratory tract or intestinal involvement. However, in a case–control analysis of GBFDE versus SJS/TEN, in which cases were matched by age and extent of skin detachment, the mortality in GBFDE was not significantly lower that of SJS/TEN [117].

Disease course and prognosis

The majority of FDE is self-limiting with an excellent prognosis. Post-inflammatory hyperpigmentation can be prominent and persist for several months after the acute episode. In GBFDE, the mortality is approximately 20%. Patients with GBFDE require the same level of treatment and care as for SJS and TEN (see Chapter 119).

Investigations

Oral provocation of the implicated drug is the gold standard to confirm drug causality, however this should not be undertaken if the patient is at risk of GBFDE. Patch testing has been suggested as an alternative diagnostic method. Unlike conventional patch testing, the reagents should be placed at skin sites of previous lesions of FDE instead of the upper back. Use of non-lesional skin in patch testing for FDE usually yields a negative response [118, 119]. Patch tests on lesional skin are positive in about 50% of cases [95].

Management

Treatment involves stopping the offending drug and the use of topical corticosteroid. Systemic corticosteroids may be necessary in patients with multiple lesions. GBFDE should be treated in an intensive care centre with expertise in skin loss syndromes, or in a burns unit (see Chapter 119).

Drug-induced pityriasis rosea

Definition

A drug-induced dermatosis which clinically resembles pityriasis rosea (PR).

Introduction and general description

Drug-induced PR-like eruption is an uncommon cutaneous adverse reaction characterized by erythematous scaly papules and plaques that are typically located on the trunk [122]. A variety of drugs has been reported to cause PR-like eruptions and are listed in Box 118.7.

Epidemiology
Incidence and prevalence

Drug-induced PR-like reactions made up 2% of all cutaneous adverse reactions presenting at a drug surveillance centre [123].

Pathophysiology

The exact pathomechanism is unclear. However, some reports have shown that these reactions are dose dependent, suggesting that they may be due to the pharmacological effect of the medication (e.g. induction of increased levels of kinins by ACE inhibitors; inhibition of cyclo-oxygenase by NSAIDs) rather than a true hypersensitivity reaction [123, 124, 125].

Pathology

The histological features of such reactions are similar to classical PR, demonstrating parakeratosis and focal spongiosis with papillary dermal oedema and superficial perivascular infiltrate of lymphocytes. In contrast to classical PR eosinophils may be prominent [126, 127].

Clinical features
History

A variety of drugs have been reported to cause PR-like eruptions and are listed in Box 118.7.

Presentation

The typical latency from drug initiation to onset of rash ranges from 6 to 40 days [123, 128, 129]. Drug-induced PR-like eruptions present with erythematous, violaceous papules or plaques with a collarette of scale, arranged with their long axis parallel to the skin lines and are typically located on the trunk (Figure 118.15). Features that may distinguish drug-induced PR from its classical forms include the presence of fewer and larger lesions, variable fir-tree distribution, absence of the characteristic herald patch, persistence of rash beyond 2 months and larger bright red lesions accompanied by significant pruritus [123, 124, 128]. Oral lesions may also be present [130].

Image described by caption.

Figure 118.15 Drug-induced pityriasis rosea: erythematous papules over the lower back with some having a collarette of scales.

Differential diagnosis

Other papulosquamous eruptions such as classical pityriasis rosea, secondary syphilis, pityriasis lichenoides chronica, guttate psoriasis and nummular eczema.

Disease course and prognosis

Unlike the typical course of classical PR, drug-induced PR-like eruptions may last more than 8 weeks if the culprit drug is not withdrawn. Conversely, it resolves quickly within 1–2 weeks on drug withdrawal [124].

Investigations

Oral provocation tests, although not performed routinely, confirm the diagnosis.

Management

The cutaneous reaction often resolves without treatment on discontinuation of the culprit drug [124]. Topical corticosteroids may be useful in cases that are slow to respond [131].

Drug-induced erythema nodosum

Definition

A septal panniculitis induced by a medication.

Introduction and general description

Erythema nodosum (EN) is a cutaneous reactive septal panniculitis which may be triggered by a wide variety of stimuli including medications. Drug-induced EN is indistinguishable from that caused by other factors [146]. A number of drugs have been reported to cause EN and are listed in Box 118.8.

Epidemiology
Incidence and prevalence

The incidence of EN is estimated to be 1–5 cases per 100 000 persons per year and about 3–15% of cases can be attributed to medications [146–149].

Age

Reported in all ages but drug-induced EN is rare in children [150].

Sex

There is a female preponderance [149].

Pathophysiology

EN is believed to be a type IV delayed hypersensitivity reaction to various antigens, including medications [146, 151].

Pathology

EN is the prototypical septal panniculitis without the presence of vasculitis. Early lesions demonstrate oedema, haemorrhage and neutrophils within the septae, older lesions are characterized by fibrosis, periseptal granulation tissue, lymphocytes, histiocytes and multinucleated giant cells [146].

Clinical features
History

The latency from drug initiation to the onset of EN is usually a few weeks. However, a case of ciprofloxacin-induced EN, confirmed by repeated oral challenge had a latency of 1 day [152–154].

Presentation

The clinical features of EN are symmetrical, erythematous and tender subcutaneous nodules or plaques which are typically distributed over the anterior aspect of the limbs. Over a few days, these lesions become purplish before finally turning brown. Ulceration never occurs and the upper limbs are less often affected [146].

Occasionally, drug-induced EN may occur in the setting of a drug hypersensitivity disorder, particularly with azathioprine and minocycline, and is accompanied by fever and other visceral involvement [155, 156].

Differential diagnosis

This includes non-drug causes of EN, other forms of panniculitis and cutaneous polyarteritis nodosa.

Disease course and prognosis

The clinical course is self-limiting following drug withdrawal and usually resolves within 2–4 weeks [152–154].

Investigations

Exclusion of other causes of EN is essential. Relevant investigations include chest radiography, microbiological cultures and serological testing, such as anti-streptolysin titres, to exclude infective causes. Other tests and imaging studies may be warranted in the appropriate setting.

Management

The offending drug should be withdrawn and treatment is otherwise symptomatic. NSAIDs and compression hosiery may reduce pain and inflammation. Systemic corticosteroids are rarely indicated.

Drug-induced acneform eruptions

Definition and nomenclature

An acneform eruption which is induced by a medication.

Introduction and general description

Drug-induced acneform eruptions are inflammatory follicular reactions which resembles acne vulgaris. Clinically, monomorphic papules and pustules are seen and a variety of drugs have been implicated, including hormones, vitamins, halogens, neuropsychotherapeutic drugs, anti-tubercular treatments, immunomodulating agents, cytotoxic agents and newer targeted therapies [162–164]. Various drugs have been associated with acneform eruptions and the common drugs are summarized in Box 118.9.

Epidemiology
Incidence and prevalence

Acneform eruptions represent 1% of all drug-induced skin reactions [165].

Pathophysiology

Acneform eruptions are not hypersensitivity reactions. Pathological mechanisms vary according to the implicated agent. In acne vulgaris, Propionibacterium acnes facilitates inflammation through the binding of toll-like receptor 2 (TLR-2). Up-regulation of TLR-2 has been reported in human keratinocytes treated with glucocorticoids and this may explain why corticosteroid-associated acne consists of predominantly inflammatory lesions of papules and pustules [166]. Androgenic hormones stimulate follicular keratinocyte proliferation, promote sebaceous gland hyperplasia and increase sebum production [167, 168]. Sirolimus may induce acneform lesions via direct toxicity, chemical modification of sebum or its effects on epidermal growth factor receptors (EGFR) and testosterone synthesis [169].

Pathology

There is variation in the histopathology of drug-induced acneform eruptions dependent on the underlying drug. In steroid-induced acne initial lesions show features of focal necrosis in the infundibulum of the follicular epithelium with a localized intrafollicular and perifollicular neutrophilic inflammatory reaction [170]. EGFR-­associated acneform eruptions are characterized by ectatic follicular infundibula with rupture of the epithelial lining associated with superficial neutrophilic folliculitis [171].

Clinical features
History

A drug-induced acneform eruption is to be suspected if the onset of acne is sudden and abrupt in the absence of past history of acne vulgaris. Other presentations include an unusually severe acne flare in a patient with a past history of mild acne vulgaris, or acne developing at an unusual age of onset [162, 163]. Various drugs have been associated with acneform eruptions and the commonest drugs are listed in Box 118.9. The latency between drug initiation and onset of acne varies between various types of drugs. Shorter latencies of 1 month or less have been reported with systemic corticosteroids [170], androgens [172–174] and vitamin B [175]; latencies of greater than 1 month are usually observed with ciclosporin [176], amineptine [177], lithium [178], anti-epileptics [179] and anti-tuberculosis treatment [180]. A characteristic papulopustular eruption may occur with EGFR inhibitors (see Chapter 120). The incidence ranges from 24 to 91%, being more common in monoclonal antibodies, such as cetuximab and panitumumab, compared to oral tyrosine kinase inhibitors such as erlotinib, gefitinib and lapatinib. Median latency from drug initiation to onset of acneform eruptions is 7–10 days [181, 182, 183], with the maximum severity being reached in the second week.

Presentation

The lesions of drug-induced acne are monomorphic papules and pustules which typically lack comedones or cysts. The dermatosis can be widespread and extend beyond the seborrhoeic areas such as the arms, lower back and genitalia. However the acneform eruption induced by EGFR inhibitors is usually distributed in the seborrhoeic areas, that is, the neck, chest, shoulders and upper back [182–184].

Differential diagnosis

This includes acne vulgaris, Gram-negative folliculitis and Pityrosporum folliculitis.

Disease course and prognosis

Improves on withdrawal of the offending drug.

Management

Drug withdrawal usually improves acneform eruptions, however such a decision needs to be balanced against the drug indication and/or if alternative agents are available. Topical and systemic medications used for acne vulgaris may be useful.

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