INTRODUCTION

DRESS syndrome is a severe, drug-induced, idiosyncratic multisystem reaction to a drug, characterised by fever, skin rash, lymphadenopathy, haematological abnormalities, and internal organ involvement.² The European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR), introduced a diagnostic scoring system for DRESS in 2007.³Leflunomide, a disease-modifying and antirheumatic drug (DMARD) has been very rarely reported as a cause of DRESS syndrome. We report a rare case of a lady aged 32 years, presented to our hospital with a history of leflunomide intake and  symptoms of DRESS. This case study highlights the potential risk of leflunomide in causing DRESS syndrome and the poor prognosis associated with the syndrome.

CASE REPORT

A 32-year-old lady presented with complaints of a rash with itching for 20 days, fever for 17 days, vomiting and loose stools for 1 day. The rash had started from the legs and spread to the entire body. It was a maculopapular rash with mucosal involvement at the angles of the mouth. On examination, she was lethargic, febrile, and icterus was present. Systemic examination was otherwise normal.

On admission, the laboratory investigation revealed Eosinophilia, atypical Leucocytosis, deranged LFT. CBP results showed predominant leucocytosis with eosinophilia. Peripheral smear and Bone marrow aspiration showed features suggestive of reactive cellular marrow with mild eosinophilia and mild megakaryocytic hyperplasia. CRP was positive with high range. PT with INR was mild high, peripheral smear showed predominantly normocytic hypochromic picture along with few microcytes, Procalcitonin-serum showed severe systemic inflammation (5.53ng/ml), Ultrasound of abdomen on day 1 showed mild hepatomegaly, gallbladder wall oedema, minimal ascites. The detailed laboratory investigations are given in Table 1.

Table 1. Common drugs causing DRESS.³

Figure 1. Mucosal involvement of the lesions at the angles of the mouth.

Figure 2. Development of rashes on the arm due to leflunomide.

Figure 3. Development of rashes on the neck during the hospital stay.

DIFFERENTIAL DIAGNOSIS

Upon taking past medication history by the clinical pharmacist, the patient revealed that she had taken Ayurvedic medicines for jaundice, but it did not subside. She consulted a local hospital where she was treated with Doxycycline, Ceftriaxone, Ursodeoxycholic acid, and Ademethionine. She had joint pains for which Aceclofenac, Paracetamol, Rabeprazole, Domperidone, Deflazacort, and Leflunomide was advised for 1 month in suspicion of arthritis, after few weeks of medication intake she developed rashes, recurrent fever spikes with itching, hence she was shifted to our hospital for further management. On literature review, it was found that Doxycycline, certain NSAIDS and Leflunomide had documented DRESS reactions. Based on detailed literature review and results of laboratory investigations, Leflunomide-induced DRESS was considered as a final diagnosis. Our patient had a RegiSCAR score of 7 as detailed in Table 3, which makes her a case of definite DRESS Syndrome.

Table 2. Laboratory investigations of the patient during the hospital stay.

For the management, we started intravenous steroid therapy (Inj. Hydrocort 50 mg IV Q12H for 5 days followed by Tab. Wysolone 20 mg p/o Q12H) and stopped all previous medications including antibiotics and supportive care was given for liver injury. Cholestyramine was advised for the washout of Leflunomide.

The patient’s LFT and ferritin were improved, other symptoms also subsided including fever, the maculopapular lesions, and itching. Biopsy was advised on follow-up if any of the symptoms reappears. She was discharged on oral steroids and cholestyramine. She did not take cholestyramine and came for follow-up with worsening skin lesions and did not get readmitted, lost to follow-up. On a follow up call, the patient's attendant informed us about death at home.

DISCUSSION

DRESS is initiated by pyrexia with body temperature >38°C, early in the course of the disease followed by development of rashes usually maculopapular morbilliform exanthem (usually starting on the face and then generalised), with multiple follicular papules over the body mimicking pityriasis rubra pilaris.⁴ Presence of facial oedema is a characteristic manifestation of DRESS, which mostly occurs with a serious reaction.⁵

The clinical symptoms of DRESS usually occur 2-6 weeks after starting offending drug, which often causes the potential diagnostic delay⁴ or can lead to misdiagnosis by the physician. Early withdrawal of offending drugs is needed once DRESS is identified. The recovery from this condition has been reported to be slow.⁵ Upon rechallenge with the offending drug, symptoms may reappear within 1 day.⁵

Reactivation of HHV-6 is found exclusively in DRESS (role of HHV-6 is unique in DRESS).⁶ However, it was not the case in our patient.

The EUROPEAN RegiSCAR decided on a scoring system to help clinicians confirm or exclude the diagnosis of DRESS syndrome.⁷ We evaluated this case using the RegiSCAR criteria that is frequently used for the diagnosis of DRESS. 

RegiSCAR Criteria to evaluate DRESS is given in Table 3.

Our patient had a RegiSCAR score of 7, which makes her a case of definite DRESS Syndrome. Genetic factors are also important in DRESS. Gene polymorphism for drug metabolism enzymes including CYP450 enzymes and N-Acetyltransferase is one risk factor. HLA gene polymorphisms explain the genetic disposition of patients with DRESS.⁶.

DRESS is usually accompanied with internal organ impairment. Haematological changes, eosinophilia is a characteristic feature of the disease. Haematological changes involve eosinophilia and mononucleosis-like atypical lymphocytosis in DRESS with liver as the most common internal organ involved. Renal, cardiac, and lung involvement is common although neurological involvement is rare.^6,9,10

The management involves early detection, diagnosis followed by prompt withdrawal of the offending agent is vital to minimise the associated morbidity and mortality. Supportive care is recommended including local systemic treatment, systemic steroids to relieve symptoms. Systemic corticosteroids can reduce symptoms of delayed hypersensitivity reactions.¹¹ They have also been shown to block the effect of IL-5 on in vivo eosinophil accumulation.¹² Relapses have also been identified in many case reports, after tapering or withdrawal of systemic steroids ¹³, which further emphasizes their role in patients with DRESS syndrome. The mainstay of treatment is the use of topical and systemic corticosteroids, but other options such as intravenous immunoglobulin, cyclosporine, mycophenolate mofetil, rituximab, and cyclophosphamide have been described.¹⁴ According to the Spanish guidelines for DRESS, TARC/CCL17 has been recommended as a prognostic and diagnostic biomarker since acute DRESS syndrome causes higher serum levels of this protein.¹⁴ We also evaluated the cases as per the Naranjo scale used to understand the plausible causal relationship between the drug and the ADR, the score of this case was identified as 6 and was categorized as probable ADR, according to the reference Naranjo scale.¹⁵

Table 3. RegiSCAR scoring for DRESS Syndrome⁷(Garuzi M, Thomazi R, Jacinto AF. DRESS syndrome in the aged: a differential diagnosis to be considered. GeriatrGerontol Aging 2017;11:150-3).

CONCLUSION

DRESS syndrome must be recognised promptly, and the causative drug must be withdrawn. Indeed, it has been reported that the prognosis is better if drug discontinuation occurs early. Leflunomide, a drug widely used in rheumatology and orthopaedics, must be used with caution since it has the potential to cause DRESS syndrome. Clinical trials must be conducted to identify the most appropriate therapy of DRESS Furthermore, national guidelines have to be developed which will help the clinicians to diagnose DRESS and use the most appropriate therapy.

PATIENTS’ CONSENT

The authors certify that they have obtained all appropriate patient consent forms for their images and other clinical information to be reported in the journal.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest in this study.