|Ahead of print publication
Leflunomide induced drug reaction with eosinophilia and systemic symptoms: A lesser known entity
Deepak Vashisht1, Madhab Durga Tripathy1, Sunmeet Sandhu1, Rohit Kothari1, Surbhi Vashisht2, Arun Hegde3
1 Department of Dermatology, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Physiology, Armed Forces Medical College, Pune, Maharashtra, India
3 Department of Rheumatology, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Submission||05-Feb-2020|
|Date of Acceptance||01-Jun-2020|
Department of Dermatology, Armed Forces Medical College, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction to drugs with varied clinical manifestations. Diffuse morbilliform rash with facial edema and systemic involvement in the form of lymphadenopathy, eosinophilia and hepatic involvement are the commonest clinical presentation. Features mimicking Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN), sepsis, Kawasaki disease andhyper-eosinophilic syndrome can cause immense diagnostic dilemma. We report a case of DRESS which is unique as the triggering drug being leflunomide that has rarely been reported and atypical presentation wherein exfoliative dermatitis and erythema multiforme like lesions which evolved sequentially. A 56-year-old lady, a known case of rheumatoid arthritis on treatment, developed diffuse exanthematous rash over body with fever and hepatic dysfunction, a month after administration of leflunomide. She was diagnosed as DRESS partially managed with steroids to rebound back a week later with severe and atypical manifestations. The uniqueness of the case lies in the fact that DRESS resulted after an uncommon incriminating drug and polymorphic presentation appearing sequentially, besides, highlighting the need of slow tapering of steroids.
Keywords: Drug reaction with eosinophilia and systemic symptoms, leflunomide, severe cutaneous adverse reaction
|How to cite this URL:|
Vashisht D, Tripathy MD, Sandhu S, Kothari R, Vashisht S, Hegde A. Leflunomide induced drug reaction with eosinophilia and systemic symptoms: A lesser known entity. Indian J Rheumatol [Epub ahead of print] [cited 2020 Aug 7]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=290264
| Introduction|| |
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction to drugs with varied clinical manifestations like diffuse morbilliform rash with facial edema and systemic involvement in the form of lymphadenopathy, eosinophilia and hepatic involvement. We report a case of DRESS which is unique as the triggering drug being leflunomide that has rarely been reported and atypical presentation wherein exfoliative dermatitis and erythema multiforme like lesions evolved sequentially.
| Case Report|| |
56-year-old lady, a known case of Type 2 diabetes mellitus, primary hypertension and rheumatoid arthritis (rheumatoid-factor and anti-CCP antibodies positive, ANA-negative) on medications (metformin, telmisartan and methotrexate 15 mg/week) for last 3 years. She was started on tablet leflunomide at 20 mg/day 4 weeks prior for worsening of arthritis. She presented to a local hospital with low grade fever and generalised red rash and scaling. Investigations revealed deranged Liver function tests (LFT): Serum bilirubin-2.4 mg/dl, Alanine aminotransferase (ALT)-339 IU/L and Aspartate aminotransferase (AST)-227 IU/L, complete blood count revealed Hb-11.2 g/dl, total leukocyte count-13400/mm3 and peripheral eosinophilia of 2054/mm3. She was managed as a case of drug induced exfoliative dermatitis with stoppage of leflunomide and tablet prednisolone 40 mg was started, which was tapered off in 15 days with near complete resolution of rash and normalization of investigation parameters. Cholestyramine washout was not administered to the patient. After an asymptomatic interval of 5 days, she again developed high grade fever with generalized itchy red rash, multiple painful oral ulcers and scaling over entire body [Figure 1]. Two days later she developed multiple purpuric lesions over both legs progressing within 72 h to involve the entire lower limbs with super-imposed flaccid fluid filled blisters rapidly coalescing with each other.
|Figure 1: Multiple erosions over right upper limb and diffuse exfoliation|
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Examination at our emergency department revealed high grade fever, pallor, generalized significant lymphadenopathy and bilateral pitting pedal edema. Systemic examination revealed coarse crackles over lower zone of right lung along with diminished breath sounds. Dermatological examination revealed diffuse facial edema and erythema and scaling involving more than 90% of body surface. Multiple purpuric macules with targetoid morphology and multiple coalescing clear fluid containing flaccid bullae distributed symmetrically over the lower limbs [Figure 2]. Nikolsky's sign was negative. Patient also had oral candidiasis. A bed side Tzanck smear from a bulla revealed necrotic keratinocytes.
Peripheral blood smear (PBS) revealed normocytic normochromic anaemia, atypical lymphocytes and eosinophilia of 1550/mm3 (normal range 30–350/mm3). LFT was deranged with ALT-156 IU/L, AST-139 IU/L, serum bilirubin-2.2 mg/dl and reduced serum albumin to 1.8 g/dl. Serum procalcitonin was raised to 23 ng/ml. Viral markers including serology for herpes simplex virus were negative. Serology for Chlamydia and Mycoplasma were negative. Blood and urine cultures were sterile. Chest X-ray was suggestive of right sided lobar pneumonia with pleural effusion. Skin biopsy done from a targetoid lesion was suggestive of marked spongiosis, few apoptotic keratinocytes with predominantly eosinophilic and lymphocytic perivascular and dermal infiltrate [Figure 3].
|Figure 3: Multiple apoptotic keratinocytes with spongiosis indicated by circles|
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Patient was diagnosed as a case of DRESS fulfilling the registry of severe cutaneous adverse reaction (RegiSCAR) criteria in the form of fever, rash suggestive of DRESS involving more than 50% of body surface area with facial edema, lymphadenopathy, deranged LFTs, PBS suggestive of atypical lymphocytes and eosinophilia and biopsy suggestive of DRESS. Due to absence of epidermal detachment, typical mucosal involvement, Stevens-Johnson syndrome More Details toxic epidermal necrolysis (SJS/TEN) was ruled out. Patient was started on prednisolone at a dose of 1 mg/kg/day, parenteral antibiotics and supportive therapy, however cholestyramine washout was not administered. Patient showed good clinical improvement in the form of gradual subsidence of rash, normalization of LFT and resolution of pneumonia. The procalcitonin levels also normalized suggesting it to be a reactive phenomenon rather than septicemia. Presently, she is on tapering doses of corticosteroids and is under regular follow up for evaluation of long term complications of DRESS in form of deranged thyroid function tests and autoimmune diseases after 3 months.
| Discussion|| |
DRESS as a clinical entity was first described by Chaiken in 1950 as a severe adverse drug reaction to anti-convulsants. In 1996, Bocquet et al. coined the term “DRESS” and devised criteria for diagnosing the same. Subsequently, in 2007, the European registry of severe cutaneous adverse drug reaction (RegiSCAR) formulated specific criteria for diagnosing DRESS and is utilised till date.,
DRESS, also referred to as one of the great mimickers in dermatology, can pose numerous dilemma in diagnosis and management. Reports of leflunomide causing DRESS is sparse and only eight cases have been reported in the literature (searched on PubMed with keywords as leflunomide and DRESS) with most cases presenting with fever, morbilliform rash and/or hepatitis which responded to corticosteroids. A solitary case of DRESS with granulomatous interstitial nephritis with vasculitis has also been mentioned. Our case presented with exfoliative dermatitis and hepatitis, possibly leflunomide induced as per Naranjo scale, with a latency period of 4 weeks.
Clinical manifestation of DRESS can be diverse and polymorphic. The rash is usually a diffuse morbilliform rash with associated facial edema and constitutional symptoms. Generalised exfoliative dermatitis, blistering and purpuric targetoid lesions have been described in around 10% of the cases. Generalised purpuric rash can at times resemble SJS-TEN. Exfoliative dermatitis followed by targetoid lesions appearing sequentially in the index case makes it an uncommon presentation of DRESS. There was hepatitis (hyperbilirubinaemia and transaminitis) along with peripheral eosinophilia, which was in accordance with common systemic involvement in DRESS. Liver is involved in 50%–70% in the form of cholestasis, hepatocyte necrosis and portal inflammation leading to transaminitis (85%) and hyperbilirubinaemia (47%). Pulmonary involvement in DRESS is seen in 20%–33% of cases most commonly manifesting as interstitial infiltrates simulating interstitial pneumonitis and mediastinal lymphadenopathy. Lobar infiltrates are exceedingly rare only seen in 03 cases so far.
A complex interplay of triggering drug, viral reactivation and human leukocyte antigen (HLA) mediated immune response has been implicated in pathophysiology. Multiple HLA haplotypes are predisposed to develop DRESS. The drug acts as a hapten presented by antigen presenting cells to trigger a sustained CD8 + T-cell response and interleukin-5 driven recruitment of eosinophils which mediate the systemic effects., Multiple theories on viral reactivation has also been implicated taking into account the resemblance of clinical features to infectious mononucleosis. Serial reactivation of Epstein Barr virus, human herpes virus-6, human herpes virus-7 and finally cytomegalovirus has been postulated to contribute towards sustained inflammation, multiorgan involvement and relapse after inadequate treatment., The same was evident in the index case where patient responded well to treatment however, on rapid tapering of steroids from 40 mg prednisolone tapered over 2 weeks, resulted in relapse of the disease with more severe symptoms.
| Conclusion|| |
The uniqueness of the case lies in the fact that DRESS resulted after an uncommon incriminating drug and polymorphic presentation appearing sequentially, besides, highlighting the need of slow tapering of steroids.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
We are indebted to the patient, who gave us his consent for publication. We thank Professor P Sengupta Pathologist for the enormous help.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]