CASE BASED REVIEW

Leflunomide-induced DRESS syndrome with renalinvolvement and vasculitis

Benzeeta Pinto & Varun Dhir & Sabari Krishnan & Ritambhra Nada

Received: 13 November 2012 /Accepted: 10 December 2012 /Published online: 28 December 2012# Clinical Rheumatology 2012

Abstract DRESS or drug reaction (or rash) with eosinophiliaand systemic symptoms belongs to the severe cutaneous ad-verse reaction group and is characterized by hematologicalabnormalities and visceral organ involvement. Although mostoften related with anticonvulsant and sulfonamide use, it isreported with numerous other drugs. We report an unusualcase of DRESS syndrome due to Leflunomide, also compli-cated by renal involvement in the form of granulomatousinterstitial nephritis and vasculitis. On a review of the litera-ture, eight similar cases were found, and these are discussed.

Keywords DRESS . Drug rash with eosinophilia andsystemic symptoms . Leflunomide . Vasculitis

Introduction

DRESS or drug rash with eosinophilia and systemic symptomsbelongs to the severe cutaneous adverse reaction (SCAR)group. Although the term DRESS was first used by Bocquetin 1996, the entity has long been recognized under other namessuch as “drug-induced pseudolymphoma,” “anticonvulsant hy-persensitivity,” and “drug-induced hypersensitivity syndrome”[1–3]. The RegiSCAR group, in order to differentiate this entityfrom the infinite other cutaneous drug reactions, has proposedcriteria to better classify this entity [4]. Leflunomide or N-(trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide

(active form A77 1726) is a disease-modifying antirheumaticdrug for rheumatoid arthritis that works by inhibiting dihydroo-rate synthetase involved in the synthesis of pyrimidines [5]. Wereport an unusual case of DRESS syndrome due to Lefluno-mide, also complicated by renal involvement in the form ofgranulomatous interstitial nephritis, and review the literature.

Case report

This 50-year-old male presented with fever, loose stools,and erythematous rash for 15 days and oliguria since10 days. He had a history of knee pain for 8 months, withoutearly morning stiffness or swelling for which he had beenprescribed oral Leflunomide 10 mg twice a day for the last4 weeks elsewhere, which he had stopped himself since1 day. On examination, he had generalized erythematousscaly rash over the body with desquamation and mucositis(Fig. 1). He was febrile with normal vitals. Systemic exam-ination was within normal limits.

Investigation showed leukocytosis with eosinophilia, acutekidney injury, and elevated liver enzymes (Table 1). Peripheralsmear showed activated lymphocytes. Urine and blood culturewere sterile, ANA andANCAwere negative, and viral markerswere negative. A provisional diagnosis of DRESS syndromewas made. The patient was given one session of hemodialysis,and oral administration of prednisolone 1 mg/kg was started.In addition, cholestyramine was administered at 8 g TDS, andceftriaxone of 1 g twice a day was given intravenously.

A kidney biopsy was performed, which showed intersti-tial nephritis with eosinophilia and granulomatous reaction(Fig. 2). In addition, few vessels showed vasculitis (Fig. 2inset). With steroids, his renal function improved rapidly,fever settled, and eosinophilia reduced (Table 1). Hepatitiscontinued to worsen initially, with liver enzymes and jaun-dice reaching a maximum on days 6–8, which then showed

B. Pinto :V. Dhir (*) : S. KrishnanDepartment of Internal Medicine (Rheumatology Unit),Post Graduate Institute of Medical Education and Research,Chandigarh 160012, Indiae-mail: varundhir@gmail.com

R. NadaDepartment of Histopathology,Post Graduate Institute of Medical Education and Research,Chandigarh 160012, India

Clin Rheumatol (2013) 32:689–693DOI 10.1007/s10067-012-2152-8

a downward trend. He was discharged on full-dose steroidsbut readmitted after 10 days with high-grade fever withcough and epigastric pain. Chest radiograph showed leftlower zone infiltrates, and he was started on antibioticsgiven intravenously. He underwent an upper GI endoscopythat revealed deep duodenal ulcers, which were biopsied.Histopathology showed nonspecific infiltrate by inflamma-tory cells in the mucosa but no evidence of vasculitis (notshown). He subsequently developed perforation peritonitisto which he succumbed.

Discussion

This report describes a case of DRESS due to Leflunomide.This patient had skin rash, eosinophilia, hepatitis, and renalfailure due to interstitial nephritis with granulomatousreaction.

DRESS syndrome is one of the SCAR syndrome. It hasbeen reported to occur by a variety of drugs, most

commonly anticonvulsants, allopurinol, and sulfonamides.The syndrome itself has been variably named, starting fromdrug-induced pseudolymphoma, anticonvulsant hypersensi-tivity, and drug-induced hypersensitivity syndrome to thecurrently popular name of DRESS, as first used by Bocquetin 1996 [1–3]. The pathogenesis of DRESS syndrome isincompletely understood. Failure of drug detoxificationmechanisms and accumulation of toxic metabolites has beensuggested, especially in case of anticonvulsants [6]. Animmune response, by CD4 and CD8 drug-specific cellsgenerating IL-5, may trigger eosinophil activation and dam-age [7]. In addition, viral reactivation especially HHV 6 hasbeen suggested to play an important role in the most severeforms of DRESS [8].

The clinical features of this disease can be diverse. Aprominent feature is a rash—most commonly maculopapu-lar and extensive but can be vesicular or pustular. Inaddition, fever is prominent, along with visceral organ in-volvement. A review of 172 cases of DRESS found internalorgan involvement in 88 %, with the liver being the mostcommon, usually with elevation of transaminases (59 %) butalso fulminant hepatic failure [2]. Renal involvement wasseen in only 8 % of cases and pulmonary, cardiac, andnervous system involvement, in less than 5 %. Renal in-volvement usually presents as acute kidney injury due tointerstitial nephritis, which may be granulomatous [9, 10].In order to better characterize DRESS, the RegiSCAR grouphas suggested a series of inclusion criteria and scoringsystem. Also, another criterion has been proposed by theJapanese consensus group for drug-induced hypersensitivitysyndrome, a synonym for DRESS (Table 2) [4, 11]. Ourpatient fulfilled the inclusion criteria by RegiSCAR, scoredby six points on the scoring system, and also fulfilled eight

Fig. 1 Back of the patient showing erythema and exfoliation

Table 1 Investigations of the index patient

Day 1 Day 4 Day 9 Day 16

Hemoglobin (g/dl) 12.6 12.9 11.3 9.7

White blood count (per μl) 29,600 26,500 32,600 9700

Differential leucocyte count N35, L18, M4, E45 N71, L17, M2, E10 N40, L56, M3, E1 N70, L24, M4, E2

Platelet (per μl) 178,000 85,000 64,000 145,000

Urea (mg/dl) 206.7 73 67.1 34

Creatinine (mg/dl) 9.74 2.8 0.84 0.8

Bilirubin (mg/dl) 0.5 1.3 6.1 2.2

Bilirubin (conjugated) (mg/dl) 4.3 1.8

Protein (g/dl) 4.8 5.2 4.3 5.5

Albumin (g/dl) 2.7 2.7 1.8 2.8

Aspartate aminotransferase (IU/L) 94.8 410 235 49

Alanine aminotransferase (IU/L) 85.0 200 294 86

Alkaline phosphatase (IU/L) 379 679 591 465

Urine routine microscopy Albumin, +; sugar, nil; no WBC or RBC

N neutrophil %, L lymphocyte %, E eosinophil %, M monocyte %

690 Clin Rheumatol (2013) 32:689–693

criteria of the Japanese group, thereby conforming to defi-nite DRESS.

Leflunomide has been reported to cause severe cutaneoushypersensitivity reactions like skin necrosis and hepatotox-icity even leading to liver failure [12, 13]. However, thereare sparse reports of Leflunomide-induced DRESS syn-drome—this is the ninth case reported of Leflunomide-

induced DRESS in the English literature (Table 3). Interest-ingly all of them are Indians, leading one to speculate someintrinsic genetic background that makes Indians susceptible.The liver was the commonest internal organ involved inseven of nine cases. Gastrointestinal involvement in theform of diarrhea was another feature noted in six cases, anunusually high proportion, unlike other cases of DRESS dueto other drugs. This was also higher (67 %) than the usualfrequency reported with Leflunomide therapy in other series(17 %) [14]. Renal involvement was only seen in two casesincluding our patient. Four of these patients had a fataloutcome, including our case, while outcome was not knownin one case.

Our patient also had evidence of vasculitis on kidneybiopsy. Churg–Strauss vasculitis was considered in the dif-ferential diagnosis; however, this patient had no history ofasthma or neuropathy. His renal function improved withsteroids alone. Leflunomide-associated vasculitis has previ-ously been reported in the literature [15, 16]. However, theoccurrence of both DRESS and vasculitis in the same pa-tient has not been reported previously.

In conclusion, Leflunomide may cause serious adversedrug reactions including DRESS and vasculitis. DRESS

Fig. 2 Photomicrograph shows fibrous crescent, dense eosinophil-richinterstitial infiltrate with granulomatous reaction especially aroundvessel (arrow) (Hematoxylin and Eosin, ×40). The inset shows arteri-ole with fibrinoid necrosis (Hematoxylin and Eosin, ×100)

Table 2 Criteria for DRESS/DIHS syndrome

RegiSCAR inclusion criteria (4) RegiSCAR scoring systema (4) Japanese consensus groupb (11)

Hospitalization Fever >38.5 °C (no=−1, yes=0) 1. Maculopapular rash developing>3 weeks after starting with thesuspected drug

Reaction suspected to be drug-related Enlarged lymph nodes (no=0, yes=1) 2. Prolonged clinical symptoms2 weeks after discontinuationof the suspected drug

1. Acute rashc Eosinophilia (no=0, 700–1,499/μL=1, >1,500/μL=2) 3. Fever (>38 °C)

2. Fever >38 °Cc Atypical lymphocytes (no=1, yes=1) 4. Liver abnormalities (alanineaminotransferase >100 U/L)

3. Enlarged lymph nodes of at leasttwo sitesc

Skin involvement; skin rash extent (% body surface area)>50 % (no=0, yes=1); skin rash suggesting DRESS(no=−1, yes=1); biopsy suggesting DRESS (no=−1, yes=0)

5. Leucocyte abnormalities

4. Involvement of at least one internalorganc

Organ involvement; liver, kidney, lung, muscle/heart,pancreas, other organ (for each no=0, yes=1)

6. Leucocytosis (>11×109/L)

5. Blood count abnormalities(lymphopenia or lymphocytosisc,eosinophiliac, thrombocytopeniac)

Resolution ≥15 days (no=−1, yes=0) 7. Atypical lymphocytosis (>5 %)

Evaluation of other potential causes, antinuclear antibody,blood culture, serology for HAV/HBV/HCV,chlamydia/mycoplasma (if none positive and ≥3of above negative, score 1)

8. Eosinophilia (> 1.5×109/L)

9. Lymphadenopathy

10. Human herpesvirus 6reactivation

In addition unknown also scored in most cases to as equivalent to “no”, except in skin rash suggesting dress and in biopsy suggesting dress (scored 0)a Final score >5=definite case in RegiSCAR scoring system (4)b Seven of ten criteria are required for definitive DIHS/DRESS in Japanese criteria (11)c Three of criteria required for considering a diagnosis in RegiSCAR

Clin Rheumatol (2013) 32:689–693 691

syndrome due to Leflunomide is associated with high mor-tality. It is important for clinicians to be aware of thiscomplication so that the drug can be immediately withdrawnand steroids, initiated.

Disclosures None

References

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15. Holm EA, Balslev E, Jemec GB (2001) Vasculitis occurring duringleflunomide therapy. Dermatology 203(3):258–259

16. Macdonald J, Zhong T, Lazarescu A, Gan BS, Harth M (2004)Vasculitis associated with the use of leflunomide. J Rheumatol 31(10):2076–2078

17. Uppal MRR, Srinivas CR (2004) Leflunomide induced drug rashand hepatotoxicity. Indian J Dermatol 49:154–155

18. Shastri V, Betkerur J, Kushalappa PA, Savita TG, Parthasarathi G(2006) Severe cutaneous adverse drug reaction to leflunomide: a

report of five cases. Indian J Dermatol Venereol Leprol 72(4):286–289

19. Do-Pham G, Charachon A, Duong TA, Thille AW, Benhaiem N,Bagot M et al (2011) Drug reaction with eosinophilia and systemicsymptoms and severe involvement of digestive tract: description oftwo cases. Br J Dermatol 165(1):207–209

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