Tab Application Banner
  • Users Online: 608
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
CASE-BASED REVIEW
Year : 2020  |  Volume : 15  |  Issue : 3  |  Page : 242-244

Leflunomide induced drug reaction with eosinophilia and systemic symptoms: A lesser known entity


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 Submission05-Feb-2020
Date of Acceptance01-Jun-2020
Date of Web Publication3-Sep-2020

Correspondence Address:
Dr. Deepak Vashisht
Department of Dermatology, Armed Forces Medical College, Pune - 411 040, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_19_20

Rights and Permissions
  Abstract 


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 article:
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 2020;15:242-4

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 [serial online] 2020 [cited 2020 Sep 26];15:242-4. Available from: http://www.indianjrheumatol.com/text.asp?2020/15/3/242/290264




  Introduction Top


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 Top


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

Click here to view


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.
Figure 2: Multiple targetoid lesions over leg and exfoliationover feet

Click here to view


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

Click here to view


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.[1] 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 Top


DRESS as a clinical entity was first described by Chaiken in 1950 as a severe adverse drug reaction to anti-convulsants.[2] 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.[1],[3]

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.[4] A solitary case of DRESS with granulomatous interstitial nephritis with vasculitis has also been mentioned.[5] Our case presented with exfoliative dermatitis and hepatitis, possibly leflunomide induced as per Naranjo scale, with a latency period of 4 weeks.[6]

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.[7] Generalised purpuric rash can at times resemble SJS-TEN.[8] 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%).[7] 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.[1]

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.[7] 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.[7],[8] 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.[2],[8] 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 Top


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.

Acknowledgements

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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Taweesedt PT, Nordstrom CW, Stoeckel J, Dumic I. Pulmonary manifestations of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: A systematic review. Biomed Res Int 2019;2019:7863815.  Back to cited text no. 1
    
2.
Criado PR, Criado RF, Avancini JM, Santi CG. Drug reaction with Eosinophilia and Systemic Symptoms (DRESS)/Drug-induced hypersensitivity syndrome (DIHS): A review of current concepts. An Bras Dermatol 2012;87:435-49.  Back to cited text no. 2
    
3.
Eshki M, Allanore L, Musette P, Milpied B, Grange A, Guillaume JC, et al. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: A cause of unpredictable multiorgan failure. Arch Dermatol 2009;145:67-72.  Back to cited text no. 3
    
4.
Pinto B, Dhir V, Krishnan S, Nada R. Leflunomide-induced DRESS syndrome with renal involvement and vasculitis. Clin Rheumatol 2013;32:689-93.  Back to cited text no. 4
    
5.
Shastri V, Betkerur J, Kushalappa PA, Savita TG, Parthasarathi G. Severe cutaneous adverse drug reaction to leflunomide: A report of five cases. Indian J Dermatol Venereol Leprol 2006;72:286-9.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Fleming P, Marik PE. The DRESS syndrome: The great clinical mimicker. Pharmacotherapy 2011;31:332.  Back to cited text no. 6
    
7.
Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg 1996;15:250-7.  Back to cited text no. 7
    
8.
Jeung YJ, Lee JY, Oh MJ, Choi DC, Lee BJ. Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and Stevens-Johnson syndrome. Allergy Asthma Immunol Res 2010;2:123-6.  Back to cited text no. 8
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Case Report
Discussion
Conclusion
References
Article Figures

 Article Access Statistics
    Viewed138    
    Printed9    
    Emailed0    
    PDF Downloaded25    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]