Sulfasalazine-induced drug rash with eosinophilia and systemic symptoms syndrome in a seronegative spondyloarthritis patient: A Case report.

The objectives were to evaluate drug rash with eosinophilia and systemic symptoms syndrome due to sulfasalazine and to carry out the pharmacoeconomic assessment associated with this adverse drug reaction (ADR). A 37-year woman was presented with rashes, fever, cough, and dyspnea. In the past 3 months, she was on sulfasalazine for inflammatory polyarthritis and seronegative spondyloarthritis. The diagnosis was based on raised eosinophils count, breathing difficulty, and typical pattern of rashes. Significant improvement was seen after discontinuation of sulfasalazine and with the initiation of parenteral corticosteroids. The casualty of this ADR was "probable" based on RegiSCAR, WHO, and Naranjo casualty assessment scales. Preventability, severity was assessed and total cost for management of the ADR was found to be ' 12,126. Thus, ADRs not only adds to patient sufferings but also increase the economic burden. Health-care providers need to be made aware of potentially fatal ADRs associated with sulfa drugs and should be keen to report such ADRs to drug safety authorities.

Introduction

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, a drug-induced adverse reaction often misconceived as a viral infection and manifested by exanthem, pyrexia, elevated white blood cells with eosinophilia or abnormal lymphocytes, swollen lymph nodes, and kidney or hepatic disorders. The incidence of DRESS ranges from 0.01% to 0.1% and contributes to death rate of 10% to 40%.[12] The quiescence span ranges from 21 days to 90 days postadministration of culprit drug.[3] Although 50 drugs are said to cause DRESS syndrome, sulfasalazine has been very rarely described before.[24] The pathogenesis of DRESS syndrome is not established clearly and usually hypothesized to be explained by complex interaction of detoxification defects leading to the formation of reactive metabolite.

Case Report

Nine months back before the incident, a 37-year-old woman came to the orthopedic outpatient department with complaints of polyarthralgia with duration of 3 months (morning stiffness) and fever. She was diagnosed with seronegative spondyloarthritis and treatment was started with deflazacort, methotrexate, folic acid, hydroxychloroquine, and Vitamin D3. Sulfasalazine 500 mg once daily was added in the next visit, it's dose was escalated to 500 mg twice daily and then to 500 mg in morning and 1000 mg at night on the following two subsequent visits. The very next month of dose escalation of sulfasalazine, she turned up again with the complaints of rashes all over the body for 3 days [Figure 1a], intermittent fever for 15 days, yellowish cough with dyspnea for 15 days. During medication history interview after her admission, she was suspected to have DRESS syndrome secondary to sulfasalazine and methotrexate-induced pneumonitis. Tropical pulmonary eosinophilia (TPE) was ruled out with the evidence of normal immunoglobulin E levels, skin involvement (not typically in TPE), and use of suspected drug (sulfasalazine) in the past.

Figure 1

(a) Characteristic rashes on the upper limb (b) The pattern of absolute eosinophil count with the progression of days

With working diagnosis of DRESS, sulfasalazine and methotrexate were discontinued. Treatment was started with hydrocortisone 100 mg IV stat dose, fexofenadine 120 mg orally once daily, hydroxyzine 10 mg orally at night, acetaminophen 1000 mg orally three times daily. The main supportive positive investigation was elevated absolute eosinophil count and its postintervention levels as shown in Figure 1b. In addition, the C-reactive protein (20 mg/L) and erythrocyte sedimentation rate (35 mm/h) were also increased. The dermatologist reassured the diagnosis of DRESS and advised fluticasone cream, levocetirizine 5 mg orally at night and increased the hydroxyzine dose to 25 mg orally at night. Furthermore, added a short course of dexamethasone injection 8 mg two times daily for 2nd day, then 4 mg twice daily for 3rd day. On 3rd and 4th day, she was found to be improving symptomatically and was discharged on 5th day with prednisolone 40 mg orally once-a-day for 3 days, then decreased to 30 mg orally once-a-day for 4 days. Alert card was issued to prevent the reoccurrence of adverse drug reaction (ADR). On the review visit, methotrexate was restarted, and dose of prednisolone was tapered to 20 mg followed by 10 mg and then to 5 mg once daily consecutively for every 3 days.

Discussion

The appearance of elevated eosinophils, temporal association of the manifestation with the initiation of therapy with sulfasalazine, and notable progress on removal of drug along with the introduction of parenteral corticosteroids were attributes congruent with the diagnosis of DRESS. The RegiSCAR score established the diagnosis of probable DRESS syndrome with the score of 4 (fever = 1, skin rash = 1, eosinophilia = 1, organ involvement = 1). The onset of manifestation of DRESS occurs usually at 2–6 weeks after starting with the therapy.[1] Postmaximum escalation of sulfasalazine, this event occurred approximately after 4 weeks in this case. This patient showed the pulmonary symptoms and a typical pattern of development of rash (from the trunk region). The cytochrome CYP450 enzymes transforms, phenytoin, phenobarbital, and carbamazepine into toxic arene oxides. Finally, these arene oxides get detoxified by glutathione transferase or epoxide hydroxylase. Any malfunction of this epoxide hydroxylase leads to the deposition of arene oxides which in turns mediates immune response or direct cellular toxicity.[5] The ADR was detected at early stage, and culprit drug was withdrawn immediately. Thus, aggressive management such as introduction of short-term methylprednisolone (30 mg/kg intravenously for 3 days), plasmapheresis and intravenous immunoglobulin, or N-acetylcysteine to neutralize reactive metabolites were not required.[4]

The ADR was documented and reported to the Pharmacovigilance Program of India (PvPI) after carrying out all assessments systematically [Table 1a]. The computerized hospital in-patients billing system was contacted for accessing the billing details, and then, total cost (calculated as the sum of direct and indirect cost) for the management of this syndrome was found to be ₹ 12,126 as shown in Table 1b. The social service department stated that the monthly earning of the patient was ₹ 5,000. This estimates the intensity of the severity of ADR in terms of economy which indicates, almost 3 months of her earning costs for compensation of the same.

Table 1

Assessment of the reactions as per the standard scales (a) causality, severity, and preventability assessment, (b) Pharmacoeconomic assessment

(a) Overall ADR assessment as per the standard scales
Parameter		Observation
Naranjo causality scale		Probable (7)
WHO assessment scale		Probable/likely
Hartwig’s severity scale		Moderate, level 4B
Seriousness of the reaction		Hospitalization
Outcome		Recovering
Predisposing factors		Age: 37 years
		Polypharmacy
		Gender: Female
Schumock and Thornton preventability scale		Not preventable
RegiSCAR score		Probable (4)
(b) Pharmacoeconomic evaluation of the ADR
Direct cost		Indirect cost
Component	Cost (`)	Component	Cost (`)
Total bed charge	3980.00	Food charge	500.00
Consultation and treatment charge	3245.00	Diet counseling charge	53.00
Medicine charge	617.00	Transportation charge	500.00
Lab charge	2831.00	Miscellaneous	400.00
Total charge	10,673.00	Total charge	1453.00

ADR=Adverse drug reaction

Conclusion

Escalation of sulfasalazine dose without proper monitoring can trigger DRESS. Clinicians need to be made aware of these potentially fatal adverse effects associated with sulfa drugs. Our study also demonstrated that ADR not only amplify patient sufferings but also augment the financial burden. The pharmacist should be keen to report such ADR to PvPI and raise awareness about such reaction among the health-care professionals.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.