Multifocal Fixed Drug Eruption with COX-2 Inhibitor-Celecoxib.

Cyclooxygenase-2 (COX-2) inhibitors are rapidly becoming the first choice nonsteroidal anti-inflammatory drugs (NSAIDs) for various rheumatological and other painful conditions. However, they might not be as safe or free of side effects as they are considered to be. These COX-2inhibitors may cause a variety of dermatological and systemic side effects of which we should be aware to avoid their indiscriminate use. We hereby report a case of multifocal fixed drug eruption (FDE) with celecoxib which has not yet been reported in Indian settings.

What was known?

The COX-2 inhibitors like celecoxib are rather indiscriminately prescribed in specialities like orthopedics for the management of acute and chronic painful conditions. It has a sulphonamide moiety which is known to cause cross-reactivity in patients allergic tosulfonamides. However, multifocal fixed drug eruption (FDE) with celecoxib has been rarely reported in the literature.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications–both by prescription and over the counter. The cyclooxygenase-2 (COX-2) inhibitors, for example, celecoxib, are becoming the drugs of choice for the treatment of various surgical and orthopedic conditions. These compounds decrease the production of prostaglandin through the inhibition of COX-2 while sparing cyclooxygenase-1 (COX-1), and thereby cause significantly fewer serious gastrointestinal adverse events such as ulceration and bleeding than the nonselective NSAIDs. They are being prescribed indiscriminately and are considered relatively free of all side effects even in patients sensitive to classical NSAIDs.[12] However, reports of their safety, both cutaneous and systemic, are rather conflicting.[3-5] Most of the known adverse cutaneous reactions to COX-2 inhibitors have been attributed to either celecoxib or rofecoxib. They include urticaria/angioedema (by far the most common), Sweet's syndrome, vasculitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and maculopapular rash. Though numerous adverse effects of celecoxib have been reported [Table 1], to our knowledge there is only one case of FDE and only a single case of multifocal FDE with celecoxib reported in the literature.[67] A second case of multifocal drug reaction from celecoxib is hereby being reported.

Table 1

All reported cutaneous drug eruptions to celecoxib till date

Case Report

A 28-year-old nonatopic man presented with multiple (12), round, well-circumscribed erythematous-to-reddish brown patches of sizes ranging from 2 × 3 cm to 10 × 12 cm in diameter. The lesions were scattered asymmetrically over the trunk and upper and lower limbs [Figure 1]. A few of the lesions had central necrosis and blistering with hemorrhagic fluid. The lesions were associated with mild pruritus and burning sensation. The patient had no fever or other constitutional symptoms. There was no mucosal involvement and Nikolsky's sign was negative. No systemic abnormalities were found on physical and routine laboratory examination. The lesions appeared two hours after theinitialingestion of 200 mg of celecoxib which was prescribed to the patient for joint pains. The patient had not taken any other drug in the past one month. However, he had previously taken NSAIDs (not COX-2 inhibitors) and sulfa drugs on several occasions without any adverse effects. A clinical diagnosis of multifocal FDE was suspected based on clinical findings and the temporal association of drug intake. Histopathologically, the lesions showed features consistent with FDE [Figure 2]. Celecoxib was thereby discontinued, and the patient was treated with antihistaminics, topical steroids, and a short course of oral steroids tapered rapidly over three weeks. After three weeks, all the lesions subsided, leaving brownish black hyperpigmentation. One month after the resolution of the eruption, oral provocation was undertaken and the patient was given 50 mg of celecoxib (1/4th of the therapeutic dose) orally. Reactivation of the lesions occurred within 24 hours which subsided with topical steroids after two weeks with residual postinflammatory hyperpigmentation.

Figure 1

Photograph showing multiple well defined erythematous to hyperpigmented plaques present over the back of the patient

Figure 2

Photomicrograph showing hyperkeratosis, focal interface degeneration with lichenoid inflammatory infiltrate and melanin incontinence (HE, ×100)

Discussion

FDEs, responsible for around 10% of all adverse drug reactions, occur frequently with NSAIDs. It characteristically presents as a round, sharply circumscribed, edematous patch with violaceous or dusky erythema associated with pruritus or burning.[2] Vesicles or bullae may develop and the lesions heal with residual hyperpigmentation. The diagnostic gold standard is drug rechallenge by oral provocation leading to recurrence of lesions at the same site or multiple newer sites. Multifocal FDE is a rare cutaneous disorder characterized by numerous erythematous to violaceous well-demarcated plaques occurring on multiple sites each time the causative or a chemically related drug is taken. Celecoxib, a selective COX-2 inhibitor, is a diaryl-substituted pyrazole derivative containing a sulphonamide substituent. Because of this structural component, celecoxib is contraindicated for use in patients who have demonstrated allergic reactions to sulfonamides. NSAIDs and COX-2 inhibitors with a sulphonamide structure could possibly cross-react with sulfonamides.[8] The sulfonamide-type reactions (erythema multiforme, Stevens-Johnson syndrome, TEN, and maculopapular rash) were found to be twice as common with celecoxib than with other COX-2 inhibitors without the sulfonamide structure. The pathogenesis of these drug reactions is T cell-mediated type IV hypersensitivity reaction. However, conflicting information exists in the literature regarding cross-reactivity among the various sulfonamide-containing medications based on biochemical data including chemistry, metabolism, immune responses, and clinical cases.[9] The major difference between sulphonamide antimicrobials and celecoxib is the presence of an aromatic amine group at the N4 position and a substituted ring at the N1 position in antimicrobials, whereas celecoxib is a nonaromatic amine lacking them. In susceptible individuals, the hydroxylamine metabolite (from the aromatic ring) and the N1 substituent lead to cytotoxic and immunological events that eventually result in adverse reactions including type I and IV hypersensitivity reactions and severe skin reactions such as TEN. Hence, these skin reactions are uncommon with celecoxib. Similarly, there is controversial data on cross-reactivity or safety of COX-2 inhibitors in patients sensitive to classic NSAIDS. Sanchez-Borges et al., in their review of cutaneous reactions to selective COX-2 inhibitors, reported that among patients previously exhibiting urticaria or angioedema triggered by classic NSAIDs, only 1.6% developed urticaria or angioedema to rofecoxib and 11.2% to celecoxib.[1] Similarly, cross-reactions toCOX-2inhibitors in patients sensitive to classical NSAIDs have been reported, but in our case, the patient had tolerated NSAIDs well on previous occasions. These COX-2 inhibitors are costlier and donot have better safety profilesthan conventional NSAIDs.[10] Rofecoxib has already been banned in view of its systemic side effects. As they are rapidly becoming the first choice of NSAIDs, the purpose of this case report is to make physicians aware ofthepossibility of these infrequent side effects and be cautious of the unwarranted use of COX-2 inhibitors.

What is new?

We report this case to highlight that a severe drug reaction like a multifocal fixed drug reaction can also occur with celecoxib; hence, caution should be exercised while prescribing them in clinical practice. We also review the literature for various cutaneous drug reactions reported for celecoxib till date.