Febuxostat induced Stevens Johnson syndrome: A case report

Introduction

Gout is an inflammatory disease caused by deposition of monosodium urate crystals in tissues. For uric acid crystals to form, serum uric acid levels must rise over a particular threshold. Even though hyperuricemia is the primary pathogenic feature in gout, everyone with hyperuricemia does not develop gout. ¹ Two categories of gout patients can be identified: those who produce too much uric acid and those who excrete too little. Hyperuricemia can be caused by endogenous uric acid synthesis, a high rate of renal urate reabsorption, or consumption of purine-rich diet. First line treatment options are nonsteroidal anti-inflammatory drugs, corticosteroids and colchicine. Management of chronic gout aims to prevent gout flares and disease progression. It mainly includes xanthine oxidase inhibitors and uricosuric drugs. ² Xanthine oxidase inhibitors decrease uric acid production by inhibiting the conversion of hypoxanthine to xanthine, which leads to uric acid generation. ³

Febuxostat is a non-purine xanthine oxidase inhibitor that has been developed for the treatment of hyperuricemia and gout. At doses up to 120 mg per day, the frequency and spectrum of febuxostat side effects are minimal, and they only start to rise above 120 mg per day. The research on safety profile of febuxostat shows incidence of severe side effects is substantially lower (1.2–3.8% to 20.1–38.7%) than mild side effects. The most commonly reported side effects are musculoskeletal symptoms, upper respiratory tract symptoms, changes in liver function, diarrhoea and headache. ⁴ Possible risk of cardiovascular events has been recently documented. However, Severe cutaneous adverse reactions (SCARs) induced by febuxostat have been seldom reported. ⁵

We hereby report a case of Steven Johnson Syndrome to febuxostat. This report re-emphasises need for vigilant drug use.

Case report

A 46 years old female presented to Emergency department with complaints of rashes over her face, abdomen and both the limbs. The patient was a known case of gouty arthritis and was started on Tab. Paracetamol, Tab. Prednisolone 5 mg, Tab. Cetirizine 10 mg, Cap. Omeprazole 20 mg and Tab. Febuxostat (80 mg) by a general practitioner in her locality a day prior. She did not have any known allergy and had taken Tab. Febuxostat for the first time. The patient was taking non-steroidal anti-inflammatory medicines (NSAIDs) on and off for pain prior to the use of Febuxostat. On examination patient had sinus tachycardia with a heart rate of 110 beats per minute, blood pressure of 110/78 mm Hg, respiratory rate was 22 breaths per minute and body temperature 38°C. The routine laboratory investigations revealed haemoglobin 12.4 gm/dl, total leucocyte count 4400/µL, Na 135.8 mmol/L, K 4.55 mEq/L, blood urea 37.5 mg/dl, serum creatinine 0.55 mg/dl and GFR 119.6 mL/min. Chest radiograph showed no focal lesions in lung parenchyma. Urine and blood culture were sterile. The patient was admitted. The rashes progressed to the whole body and face and became hyperpigmented. The patient also developed minute blisters around the lips, eyes and all over face. A diagnosis of Stevens-Johnson Syndrome (SJS) was made and all the medications that patient was taking previously including febuxostat were stopped. The patient was then shifted to intensive care unit for further management. Treatment was started with IV fluids, IV antibiotics (Inj. Cefoperazone 1000 mg + Sulbactam 500 mg, Inj. Teicoplanin) and other supportive medications. The patient’s condition improved and was discharged after 15 days. The causality assessment as per the Naranjo scale revealed the relationship between the drug (febuxostat) and the adverse drug reaction (Steven Johnson Syndrome) to be Probable. Summary of Product Characteristic (SPC) for Febuxostat available in India does not mention association of SJS with Febuxostat as known.

Discussion

SJS is an immunological disorder that affects the skin and mucosa. It starts as a skin rash with involvement of the oral and ocular mucosa, then progresses to skin necrolysis with involvement of the mucosa of several organ systems. ¹ The acute phase often lasts for the first two weeks and manifests as skin necrolysis, desquamation of mucosa, mainly oral and ocular. For individuals who survive the acute phase, the chronic phase is marked by multi-organ damage, increasing rates of morbidity, and a poor quality of life. Each phase has its own set of disease characteristics, presentation features and therapeutic choices. ³ Various medicines have been linked in the pathophysiology of SJS/TEN, which is classified as a severe cutaneous adverse response (SCAR). ⁶ In India, the yearly incidence of SJS/TEN is unknown. A systematic review of cutaneous adverse drug reactions (CADRs) in the Indian population found a 9.22/1000 case incidence rate, with SJS/TEN being the most prevalent severe CADRs (6.84%). The most prevalent cause for SJS/TEN, according to the Indian research, was drug intake (97.14%). Antibiotics (37.3%) were the most commonly implicated medications followed by anti-epileptics (35.7%), and NSAIDs (15.9%). ⁷

In individuals with refractory gout, febuxostat is a second-line uric acid-lowering medication. ⁸ At doses of 40 mg and 80 mg daily it was linked to a larger percentage of liver function abnormalities compared with allopurinol and placebo. This was the most prevalent adverse event that led to therapy cessation in clinical trials. Other frequent side effects reported in patients taking febuxostat were rash, arthralgia, and nausea. ³

Febuxostat generally caused fewer hypersensitivity reactions than allopurinol (0.2 vs 2.7 per 1000 new users, p 0.001). In Asians, the incidence and severity of hypersensitivity reactions with febuxostat is less than allopurinol. ⁹ Allopurinol and febuxostat do not share any structural similarities but it has been shown that xanthine oxidase inhibition may cause cross reactivity. ⁸

Chen et al. analysed the incidence of hypersensitivity reactions, including maculopapular exanthema (MPE), drug reaction with eosinophilia and systemic symptom (DRESS), SJS, and toxic epidermal necrolysis (TEN) to allopurinol or febuxostat, and identified 33 patients with allopurinol-induced hypersensitivity reactions (10 SJS/TEN, 8 DRESS, and 15 MPE) and only one case was reported to have febuxostat-induced MPE. ⁹ Some researchers have summarised in their study that these hypersensitivity reactions have been linked to HLA-B∗58:01. ¹⁰

Tana et al. reported a case of A 30-year-old Filipino man who was taking allopurinol and tolerated it well for many years developed generalised exfoliativei dermatitis after bupropion was added to his regimen. It was determined that his onset of SJS was either triggered by bupropion or caused by allopurinol and was advised to discontinue its usage. Febuxostat was prescribed. However, within 24 h of its usage he developed a raised pruritic erythematous maculopapular rash on his trunk which improved within 2-3 days after discontinuing the drug. A re-challenge done 4 years later also showed development of raised pruritic erythematous maculopapular eruption, which resolved after febuxostat was discontinued. ⁸

Calogiuri et al. reported a case of hypersensitivity to febuxostat in a patient with previous allopurinol induced SJS. Steven Johnson syndrome caused by prior allopurinol therapy forced a change to febuxostat 80 mg daily. He experienced significant itching and a diffuse maculopapular rash two years after febuxostat therapy. ¹¹ Lein et al. reported a case of severe cross-reactions between allopurinol and febuxostat in a 76-year-old woman. She initially had allopurinol induced dress syndrome. Febuxostat 40 mg once daily was started after a year and after taking two pills she developed similar symptoms. This indicates the possibility of cross reactions between febuxostat and allopurinol. ¹²

Jordan et al. reported in their study that the risk of skin reactions with febuxostat increased by a factor of 3.6 in patients with known allopurinol intolerance. ⁴

Chabra et al. reported a case of SJS in a 50-year-old female who was on self-medication with allopurinol for 5 days. ¹³ Another case of SJS was documented by Gupta et al. in an 85-year-old female, who presented with diffuse maculo-papular erythematous and pruritic rash initially on the trunk and back and gradually spread to palms and soles following allopurinol administration. ¹⁴ Another case of a 43-year-old female with rash over abdomen and chest followed by spreading to the rest of the body. Rashes started as an erythematous and maculopapular rash with itching progressing to painful blister formation affecting mucous membrane of mouth and anal canal. ¹⁵

This case report is not without limitations. The first limitation is that a re-challenge of the drug could not be done. It was not possible to do a re-challenge as re-administration of the drug could have been life threatening to the patient. The second limitation was that the toxicity levels of the drug were not determined.

Conclusion

The development of a SJS type of hypersensitivity mandates caution, careful dose escalation and close monitoring. It is essential that such reactions are analysed and communicated effectively to help to avoid hypersensitivity reactions or to rapidly recognize and treat them. Once a patient has suffered SJS, the patients should always be alerted about the culprit medication and use an allergic bracelet, such approach prevents potentially lethal outcome.

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