LETTRE
À LA
Thérapie 2014 Septembre-Octobre; 69 (5): 461–464 DOI: 10.2515/therapie/2014054
RÉDACTION
© 2014 Société Française de Pharmacologie et de Thérapeutique
Suspicion of Fenofibrate-related Drug Reaction with Eosinophilia andSystemicSymptoms (DRESS) Syndrome: a Case Report Lucile Safrano1, Delphine Bourneau-Martin1, Christian Le Clech2, Jean-Marie Chennebault3, Aurélie Jamet1, Guillaume Drablier1, Laurence Lagarce1 and Pascale Lainé-Cessac1 1 Regional Pharmacovigilance Center, Pharmacology-Toxicology Department, Angers University Hospital, Angers, France 2 Dermatology and Venerology Department, Angers University Hospital, Angers, France 3 Infectious and Tropical Diseases Department, Angers University Hospital, Angers, France Text received February 11th, 2014; accepted April 17th, 2014 This case report was notified to the Angers Regional Pharmacovigilance Center on September 29th, 2010. This case report was presented as a poster at the “Physiologie, Pharmacologie et Thérapeutique” Congress in Grenoble, France, in March 2011. Abstract – We describe a DRESS syndrome induced by fenofibrate. This side effect, rarely described with fenofibrate, should be known by clinicians to stop it immediately and avoid serious complications. Keywords: drug hypersensitivity; fenofibrate; eosinophilia
Résumé – Suspicion d’un DRESS syndrome sous fénofibrate : présentation d’un cas clinique. Nous décrivons le cas d’un syndrome de DRESS induit par le fénofibrate. Cet effet indésirable très rarement décrit avec le fénofibrate doit être connu par les cliniciens de façon à l’arrêter immédiatement et ainsi éviter de graves complications. Mots clés : hypersensibilité médicamenteuse ; fénofibrate ; hyperéosinophilie
1. Introduction Drug reaction with eosinophilia and systemic symptom (DRESS) is a serious hypersensitivity syndrome. The estimated incidence of this syndrome ranges from 1 in 1 000 to 1 in 10 000 drug exposures.[1] It characterised by skin rash (initially exanthematous and then maculo-papular lesions that are more or less oedematous, or even erythrodermia), visceral involvement (lymphadenopathy, myocarditis, pericarditis, hepatitis, nephritis, interstitial lung disease, etc.), and haematological disorders (eosinophilia in most cases, atypical lymphocytes, thrombocytopenia, neutropenia). DRESS usually appears between two weeks and three months after the initiation of a medication and the manifestations can persist or worsen even if the drug is withdrawn.[2-4] This syndrome is progressive, and symptoms can appear sequentially or may be absent.[2,4] It requires immediate withdrawal of the causative medication in order to reduce the risk of severe functional impairment or death. Some serious cases may require treatment with systemic glucocorticoids. We report here on the case of a male patient who presented with a clinical picture suggestive of DRESS induced by fenofibrate (Fegenor®).
2. Case report The patient was a 54-year-old man of Caucasian origin, weighing 70 kg, athletic, in good health, and with no assessed allergies. His medical history included seborrheic dermatitis, hypertension which had been treated since 2006 with a fixed combination of perindopril/indapamide (2.5 mg/0.625 mg daily) [Preterax®], and hypercholesterolemia, previously treated with simvastatin (brand name unknown) but then switched to fenofibrate (140 mg daily) in July 2010 (precise date unknown) at the request of the patient who had read about the muscle effects of statins in the package insert. On September 16, 2010, approximately two months after starting fenofibrate, the patient presented with a pruritic erythematous rash (initially distributed on sun-exposed areas), fever (38 °C), and cough. Four days later, the rash became more widespread, the fever persisted, and the patient consulted his general practitioner who prescribed: amoxicillin (2g daily, Clamoxyl®), fexofenadine (Telfast®), metoclopramide (Primperan®), and a nasal spray (combination of acetylcystein, tuaminoheptane, and benzalkonium chloride [Rhinofluimicil®]). On 21 September, a blood test revealed eosinophilia (3.7 x 109/L), abnormal liver function with aspartate aminotransferase (ASAT) elevated to 1.4N, and alanine aminotransferase (ALAT) elevated to 4.7N. On September 23, because of extension of the rash and the persistence of low-grade fever and cough, the patient was hospitalised in the Dermatology Department. At admission, clinical examination revealed some pruritic lesions in erythematous and relief plaques extending principally from the forearms to the elbows, a few papules around the navel and knees, cervical lymphadenopathy and
Article publié par EDP Sciences
462
Safrano et al.
leucocytes count
G/L
35 30 25 20 15 10
ec 3D
ov 26 -N
ov
ov
19 -N
5N
12 -N
ov
ct 29 -O
22 -O
ct
ct 15 -O
ct 8O
ct 1O
24 -S ep
5 0
Time Leucocytes (4-10 g/L)
Eosinophiles (0.04-0.5 g/L)
Neutrophiles (10.5-7.5 g/L)
Fig. 1. Results concerning leukocyte counts.
liver tests
Activity UI/L
500 400 300 200 100 0 ep -S 4 2
ct O 1-
ct O 8-
-O 15
ct
-O 22
ct
-O 29
ct
ov N 5-
Time ALAT (12-60 UI/L) GGT (10-82 UI/L)
ASAT (12-47 UI/L) PAL (40-109 UI/L)
Fig. 2. Results of liver tests. ALAT: alanine aminotransferases; ALP: alkaline phosphatase; ASAT: aspartate aminotransferase; GGT: gamma glutamyltransferase
hyperthermia (38 °C). Questioning of the patient did not reveal any notion of handling toxic chemicals, a change of toiletries or household cleaners, the consumption of watercress, or any changes to lifestyle or eating habits, except for a recent intake of passiflora and harpagophytum medicines and the use of house paint in late July and early August. A blood test revealed eosinophilic leukocytosis (10 x 109/L), abnormal liver function with elevations of ALAT to 2N (2 times the upper limit of normal values), alkaline phosphatase (ALP) to 3.9N, and gamma glutamyltransferase (GGT) to 4.8N (figures 1 and 2). ASAT and serum creatinine were normal, and the C-reactive protein (CRP) level was 38 mg/L. Chest X-ray and electrocardiogram (ECG) findings were normal. At this stage, a drug reaction was therefore suspected, so all medications except perindopril/indapamide were withdrawn (on September 23, 2010). The patient was
© Société Française de Pharmacologie et de Thérapeutique
treated with cutaneous clobetasol (Dermoval®) and levocetirizine (brand name unknown). Because the skin lesions were regressing and the laboratory parameters returning to normal, the patient was discharged after one week of hospitalization on September 30 and it was concluded that his eosinophilia had been due to fenofibrate, although no conclusions were reached concerning his skin lesions. Fourteen days after his discharge from hospital, fenofibrate was not re-introduced but the patient experienced a worsening of his rash. That's why he was therefore hospitalised again on October 20 2010. An examination of his lesions revealed an itchy maculo-papular rash which now affected more than 80% of his body surface, with an eczematoid or epidermoid rash in some areas. A secondary deterioration was seen of the initial lesions on the face and upper limbs (partial photo-distribution), but his feet and legs were relatively
Thérapie 2014 Septembre-Octobre; 69 (5)
DRESS Syndrome with Fenofibrate
spared. Scaling was observed on the face, arms, chest, midriff, knees, ankles and back. He was also suffering from swelling of his face, but there was no mucosal involvement or fever. Palpation revealed a cervical lymph node. Hepatic and renal functions were normal and eosinophilia had decreased (3.96 x 109/L). After two days in hospital and the application of topical corticosteroids, a marked improvement was seen in both the lesions and pruritus. Additional investigations performed during this second hospital stay in order to rule out diagnoses such as infectious diseases or lymphoma, all returned negative results: serological tests for hepatitis A, B and C, human immunodeficiency virus, Epstein Barr and Herpes simplex viruses, cytomegalovirus, syphilis and parvovirus B19, and the determination of microbiological infections (fascioliasis, toxocariasis, toxoplasmosis). A myelogram was performed and was normal except for an excess of eosinophils at all stages of maturation. Otherwise, a skin biopsy of an eczematoid lesion was suggestive of sub-acute and chronic eczema, whereas the papular lesions had a histologically non-specific appearance (dermal inflammatory infiltrate). The thoracic-abdominal-pelvic computed tomography (CT) scan performed was normal except for the presence of a hepatic angioma, confirmed by abdominal ultrasound; an echocardiogram performed was also within normal limits. Finally without any need for systemic corticosteroid therapy, the patient's eosinophil levels returned to normal about forty days after the discontinuation of fenofibrate (figure 2), and erythema, skin infiltration, and pruritus regressed at the same time. Examination of the patient during a control visit to the Dermatology Department on February 17, 2011 revealed an almost complete disappearance of the skin lesions. No skin test was performed.
3. Discussion This patient experienced symptoms which constitute the classical criteria for a diagnosis of DRESS and included: fever, eosinophilia higher than 1.5 × 109/L, lymphadenopathy, a skin rash lasting for more than one month with an episode of recurrence despite withdrawal of the suspected drug, and moderate liver disorders. These symptoms appeared at different times during the course of the condition but started approximately two months after the initiation of fenofibrate therapy, whereas the combination of antihypertensive had been taken previously for at least four years without a break and was pursued during and after onset of the patient's disease. These symptoms and such a chronological course enabled us to suspect a fenofibrate-induced DRESS. The additional investigations performed were able to eliminate other medical reasons for the skin rash, hepatic disorder and eosinophilia, such as non-Hodgkin's lymphoma, parasitosis (e.g. distomatosis) or a viral infection.[2-4] Unfortunately, a type 6 human herpes virus (HHV6) polymerase chain reaction was not performed in this case. Indeed, HHV6 is frequently reactivated in a context of DRESS and could have explained some of the symptoms.[5] HHV6 reactivation is considered as a
© Société Française de Pharmacologie et de Thérapeutique
463
diagnostic criterion in Japan where DRESS is referred to as druginduced hypersensitivity syndrome (DIHS).[6] Amoxicillin, which was administered during early stages of our patient's symptoms, might have induced a worsening of his condition if HHV6 reactivation had occurred.[7] But because the symptoms did not worsen with the administration of amoxicillin, it is unlikely that HHV6 was reactivated in our patient's case. The registry of severe cutaneous adverse reactions (RegiSCAR) group, which operates an international registry fed by scientists interested in severe cutaneous adverse drug reactions, has created a non-validated score which uses defined criteria to determine whether a skin reaction might constitute an unlikely, possible, probable or definite DRESS syndrome.[2] In our case, fever at 38 °C, polyadenopathy and disturbed liver parameters at the onset of symptoms, together with elevated eosinophilia, and an extension of the rash to more than 50% of the patient's body area, enabled the calculation of a score of 4, which reflects a probable DRESS. According to the Japanese study group on DIHS which has determined seven criteria that are frequently found in the context of this syndrome, the presence in our case of five of these criteria (maculo-papular exanthema, clinical signs persisting for more than 2 weeks after withdrawal of the suspected drug(s), elevated ALAT, eosinophilia and polyadenopathy) allowed us to conclude as to an atypical DIHS.[6] The French method for assessing drug-related adverse effects takes account of chronological criteria (drug challenge, dechallenges and rechallenge) and clinical criteria (predisposing factors, alternative non-drug-related explanations and specific laboratory tests) to produce a final score referred to as the “intrinsic imputability score”. Applied to our case, this method enabled the attribution of “possible” intrinsic imputability (“possible” chronological and clinical scores).[8] According to the Naranjo adverse drug reaction (ADR) scale, our case received a score of 4, which corresponds to a “possible” relationship between fenofibrate and this syndrome.[9] Skin, liver, and muscles disorders are the most frequently reported side effects of fenofibrate in the French summary of product characteristics (SPC). In a study that compared the efficacy and tolerance of simvastatin and fenofibrate,[10] eosinophilia occurred at a frequency of 7.6% with fenofibrate versus 4.3% with simvastatin. A French case report of acute hepatitis with fenofibrate described elevated eosinophilia accompanied with fever but no skin lesions.[11] A Medline search did not find any other cases of fenofibrateinduced DRESS. A “reactions database” search produced one other case, a 66-year-old woman with a history of right nephrectomy and renal failure, who developed fever, maculopapular rash, infiltration of the face, and a deterioration in renal function approximately 5 weeks after the initiation of fenofibrate. In that case, the RegiSCAR-Group score for DRESS syndrome was evaluated as 3, or a “possible case”.[12] In the French national pharmacovigilance database, one other unpublished, briefly reported case of fenofibrate-induced DRESS
Thérapie 2014 Septembre-Octobre; 69 (5)
464
Safrano et al.
is recorded. This case was similar to ours and involved a skin rash, fever (38.5 °C), arthralgia, peak eosinophilia at 4.6 X 109/L, liver disorders with elevated ALAT, and GGT, and a prolonged course. Although it is very rare, DRESS can be induced by treatment with fenofibrate and clinicians need to be aware of this potential adverse effect so that they can withdraw the drug immediately in the context of specific symptoms and thus avoid a deleterious outcome.
Conflicts of interest. None. Abbreviations. ADR: adverse drug reactions; ALAT: alanine amino transferases; ALP: alkaline phosphatase; ASAT: aspartate aminotransferase; CRP: C-reactive protein; CT: computed tomography; DIHS: drug-induced hypersensitivity syndrome; DRESS: drug reaction with eosinophilia and systemic syndrome; ECG: electrocardiogram; GGT: gamma glutamyltransferase; HHV6: human herpes virus type 6; RegiSCAR: registry of severe cutaneous adverse reactions; SPC: summary of product characteristics.
4.
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
5.
Descamps V, Mardivirin L, Janela B, et al. The drug hypersensitivity syndrome (DRESS syndrome) is nothing but a viral illness. Rev Fr Allergol 2010; 50: 171-3 (Doi: 10.1016/j.reval.2010.01.027)
6.
Shiohara T, Iijima M, Ikezawa Z, et al. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007 May; 156(5): 1083-4
7.
Mardivarin L, Valeyrie-Allanore L, Branlant-Redon E, et al. Amoxicillininduced flare in patients with DRESS (drug reaction with eosinophilia and systemic symptoms): report of seven cases and demonstration of a direct effect of amoxicilline on Human Herpes Virus 6 replication in vitro. Eur J Dermatol 2010; 20: 68-73
8.
Bégaud B, Evreux JC, Jouglard J, et al. Unexpected or toxic drug reaction assessment (imputation). Actualization of the method used in France. Therapie 1985; 40: 111-8
9.
Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239-45
10. Fricker J, Douste-Blazy P, Drouin P, et al. The efficacy and tolerance of simvastatin and fenofibrate in primary hypercholesterolemia. Presse Med 1990 Dec 8; 19(42): 1927-30 11. Lelouch S, Pelletier G, Sinico M, et al. Fenofibrate-induced acute hepatitis with pseudo-cholangitis. Gastroenterol Clin Biol 1992; 16(6-7): 597-9
References 1.
Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med 2011 July; 124 (7): 588-97
2.
Descamps V, Ben Saïd B, Sassolas B, et al. ; groupe Toxidermies de la Société française de dermatologie. Management of drug reaction with eosinophilia and systemic symptoms (DRESS). Ann Dermatol Venereol 2010 Nov; 137(11): 703-8
3.
Begon E, Roujeau JC. Drug hypersensitivity syndrome: DRESS (drug reaction with eosinophilia and systemic symptoms). Ann Dermatol Venereol 2004 Mar; 131(3): 293-7
© Société Française de Pharmacologie et de Thérapeutique
12. Lakhoua G, Chadly Z, Zalem A, et al. Dress syndrome induced by fenofibrate. Fund Clin Pharmacol 2011; 25 (suppl.1): 95[abstract]
Correspondence and offprints: Delphine Bourneau-Martin, Regional Pharmacovigilance Center, CHU d’Angers, 4 rue Larrey, 49933 Angers Cedex 9, France. E-mail: [email protected]; [email protected]
Thérapie 2014 Septembre-Octobre; 69 (5)
À LA
Thérapie 2014 Septembre-Octobre; 69 (5): 461–464 DOI: 10.2515/therapie/2014054
RÉDACTION
© 2014 Société Française de Pharmacologie et de Thérapeutique
Suspicion of Fenofibrate-related Drug Reaction with Eosinophilia andSystemicSymptoms (DRESS) Syndrome: a Case Report Lucile Safrano1, Delphine Bourneau-Martin1, Christian Le Clech2, Jean-Marie Chennebault3, Aurélie Jamet1, Guillaume Drablier1, Laurence Lagarce1 and Pascale Lainé-Cessac1 1 Regional Pharmacovigilance Center, Pharmacology-Toxicology Department, Angers University Hospital, Angers, France 2 Dermatology and Venerology Department, Angers University Hospital, Angers, France 3 Infectious and Tropical Diseases Department, Angers University Hospital, Angers, France Text received February 11th, 2014; accepted April 17th, 2014 This case report was notified to the Angers Regional Pharmacovigilance Center on September 29th, 2010. This case report was presented as a poster at the “Physiologie, Pharmacologie et Thérapeutique” Congress in Grenoble, France, in March 2011. Abstract – We describe a DRESS syndrome induced by fenofibrate. This side effect, rarely described with fenofibrate, should be known by clinicians to stop it immediately and avoid serious complications. Keywords: drug hypersensitivity; fenofibrate; eosinophilia
Résumé – Suspicion d’un DRESS syndrome sous fénofibrate : présentation d’un cas clinique. Nous décrivons le cas d’un syndrome de DRESS induit par le fénofibrate. Cet effet indésirable très rarement décrit avec le fénofibrate doit être connu par les cliniciens de façon à l’arrêter immédiatement et ainsi éviter de graves complications. Mots clés : hypersensibilité médicamenteuse ; fénofibrate ; hyperéosinophilie
1. Introduction Drug reaction with eosinophilia and systemic symptom (DRESS) is a serious hypersensitivity syndrome. The estimated incidence of this syndrome ranges from 1 in 1 000 to 1 in 10 000 drug exposures.[1] It characterised by skin rash (initially exanthematous and then maculo-papular lesions that are more or less oedematous, or even erythrodermia), visceral involvement (lymphadenopathy, myocarditis, pericarditis, hepatitis, nephritis, interstitial lung disease, etc.), and haematological disorders (eosinophilia in most cases, atypical lymphocytes, thrombocytopenia, neutropenia). DRESS usually appears between two weeks and three months after the initiation of a medication and the manifestations can persist or worsen even if the drug is withdrawn.[2-4] This syndrome is progressive, and symptoms can appear sequentially or may be absent.[2,4] It requires immediate withdrawal of the causative medication in order to reduce the risk of severe functional impairment or death. Some serious cases may require treatment with systemic glucocorticoids. We report here on the case of a male patient who presented with a clinical picture suggestive of DRESS induced by fenofibrate (Fegenor®).
2. Case report The patient was a 54-year-old man of Caucasian origin, weighing 70 kg, athletic, in good health, and with no assessed allergies. His medical history included seborrheic dermatitis, hypertension which had been treated since 2006 with a fixed combination of perindopril/indapamide (2.5 mg/0.625 mg daily) [Preterax®], and hypercholesterolemia, previously treated with simvastatin (brand name unknown) but then switched to fenofibrate (140 mg daily) in July 2010 (precise date unknown) at the request of the patient who had read about the muscle effects of statins in the package insert. On September 16, 2010, approximately two months after starting fenofibrate, the patient presented with a pruritic erythematous rash (initially distributed on sun-exposed areas), fever (38 °C), and cough. Four days later, the rash became more widespread, the fever persisted, and the patient consulted his general practitioner who prescribed: amoxicillin (2g daily, Clamoxyl®), fexofenadine (Telfast®), metoclopramide (Primperan®), and a nasal spray (combination of acetylcystein, tuaminoheptane, and benzalkonium chloride [Rhinofluimicil®]). On 21 September, a blood test revealed eosinophilia (3.7 x 109/L), abnormal liver function with aspartate aminotransferase (ASAT) elevated to 1.4N, and alanine aminotransferase (ALAT) elevated to 4.7N. On September 23, because of extension of the rash and the persistence of low-grade fever and cough, the patient was hospitalised in the Dermatology Department. At admission, clinical examination revealed some pruritic lesions in erythematous and relief plaques extending principally from the forearms to the elbows, a few papules around the navel and knees, cervical lymphadenopathy and
Article publié par EDP Sciences
462
Safrano et al.
leucocytes count
G/L
35 30 25 20 15 10
ec 3D
ov 26 -N
ov
ov
19 -N
5N
12 -N
ov
ct 29 -O
22 -O
ct
ct 15 -O
ct 8O
ct 1O
24 -S ep
5 0
Time Leucocytes (4-10 g/L)
Eosinophiles (0.04-0.5 g/L)
Neutrophiles (10.5-7.5 g/L)
Fig. 1. Results concerning leukocyte counts.
liver tests
Activity UI/L
500 400 300 200 100 0 ep -S 4 2
ct O 1-
ct O 8-
-O 15
ct
-O 22
ct
-O 29
ct
ov N 5-
Time ALAT (12-60 UI/L) GGT (10-82 UI/L)
ASAT (12-47 UI/L) PAL (40-109 UI/L)
Fig. 2. Results of liver tests. ALAT: alanine aminotransferases; ALP: alkaline phosphatase; ASAT: aspartate aminotransferase; GGT: gamma glutamyltransferase
hyperthermia (38 °C). Questioning of the patient did not reveal any notion of handling toxic chemicals, a change of toiletries or household cleaners, the consumption of watercress, or any changes to lifestyle or eating habits, except for a recent intake of passiflora and harpagophytum medicines and the use of house paint in late July and early August. A blood test revealed eosinophilic leukocytosis (10 x 109/L), abnormal liver function with elevations of ALAT to 2N (2 times the upper limit of normal values), alkaline phosphatase (ALP) to 3.9N, and gamma glutamyltransferase (GGT) to 4.8N (figures 1 and 2). ASAT and serum creatinine were normal, and the C-reactive protein (CRP) level was 38 mg/L. Chest X-ray and electrocardiogram (ECG) findings were normal. At this stage, a drug reaction was therefore suspected, so all medications except perindopril/indapamide were withdrawn (on September 23, 2010). The patient was
© Société Française de Pharmacologie et de Thérapeutique
treated with cutaneous clobetasol (Dermoval®) and levocetirizine (brand name unknown). Because the skin lesions were regressing and the laboratory parameters returning to normal, the patient was discharged after one week of hospitalization on September 30 and it was concluded that his eosinophilia had been due to fenofibrate, although no conclusions were reached concerning his skin lesions. Fourteen days after his discharge from hospital, fenofibrate was not re-introduced but the patient experienced a worsening of his rash. That's why he was therefore hospitalised again on October 20 2010. An examination of his lesions revealed an itchy maculo-papular rash which now affected more than 80% of his body surface, with an eczematoid or epidermoid rash in some areas. A secondary deterioration was seen of the initial lesions on the face and upper limbs (partial photo-distribution), but his feet and legs were relatively
Thérapie 2014 Septembre-Octobre; 69 (5)
DRESS Syndrome with Fenofibrate
spared. Scaling was observed on the face, arms, chest, midriff, knees, ankles and back. He was also suffering from swelling of his face, but there was no mucosal involvement or fever. Palpation revealed a cervical lymph node. Hepatic and renal functions were normal and eosinophilia had decreased (3.96 x 109/L). After two days in hospital and the application of topical corticosteroids, a marked improvement was seen in both the lesions and pruritus. Additional investigations performed during this second hospital stay in order to rule out diagnoses such as infectious diseases or lymphoma, all returned negative results: serological tests for hepatitis A, B and C, human immunodeficiency virus, Epstein Barr and Herpes simplex viruses, cytomegalovirus, syphilis and parvovirus B19, and the determination of microbiological infections (fascioliasis, toxocariasis, toxoplasmosis). A myelogram was performed and was normal except for an excess of eosinophils at all stages of maturation. Otherwise, a skin biopsy of an eczematoid lesion was suggestive of sub-acute and chronic eczema, whereas the papular lesions had a histologically non-specific appearance (dermal inflammatory infiltrate). The thoracic-abdominal-pelvic computed tomography (CT) scan performed was normal except for the presence of a hepatic angioma, confirmed by abdominal ultrasound; an echocardiogram performed was also within normal limits. Finally without any need for systemic corticosteroid therapy, the patient's eosinophil levels returned to normal about forty days after the discontinuation of fenofibrate (figure 2), and erythema, skin infiltration, and pruritus regressed at the same time. Examination of the patient during a control visit to the Dermatology Department on February 17, 2011 revealed an almost complete disappearance of the skin lesions. No skin test was performed.
3. Discussion This patient experienced symptoms which constitute the classical criteria for a diagnosis of DRESS and included: fever, eosinophilia higher than 1.5 × 109/L, lymphadenopathy, a skin rash lasting for more than one month with an episode of recurrence despite withdrawal of the suspected drug, and moderate liver disorders. These symptoms appeared at different times during the course of the condition but started approximately two months after the initiation of fenofibrate therapy, whereas the combination of antihypertensive had been taken previously for at least four years without a break and was pursued during and after onset of the patient's disease. These symptoms and such a chronological course enabled us to suspect a fenofibrate-induced DRESS. The additional investigations performed were able to eliminate other medical reasons for the skin rash, hepatic disorder and eosinophilia, such as non-Hodgkin's lymphoma, parasitosis (e.g. distomatosis) or a viral infection.[2-4] Unfortunately, a type 6 human herpes virus (HHV6) polymerase chain reaction was not performed in this case. Indeed, HHV6 is frequently reactivated in a context of DRESS and could have explained some of the symptoms.[5] HHV6 reactivation is considered as a
© Société Française de Pharmacologie et de Thérapeutique
463
diagnostic criterion in Japan where DRESS is referred to as druginduced hypersensitivity syndrome (DIHS).[6] Amoxicillin, which was administered during early stages of our patient's symptoms, might have induced a worsening of his condition if HHV6 reactivation had occurred.[7] But because the symptoms did not worsen with the administration of amoxicillin, it is unlikely that HHV6 was reactivated in our patient's case. The registry of severe cutaneous adverse reactions (RegiSCAR) group, which operates an international registry fed by scientists interested in severe cutaneous adverse drug reactions, has created a non-validated score which uses defined criteria to determine whether a skin reaction might constitute an unlikely, possible, probable or definite DRESS syndrome.[2] In our case, fever at 38 °C, polyadenopathy and disturbed liver parameters at the onset of symptoms, together with elevated eosinophilia, and an extension of the rash to more than 50% of the patient's body area, enabled the calculation of a score of 4, which reflects a probable DRESS. According to the Japanese study group on DIHS which has determined seven criteria that are frequently found in the context of this syndrome, the presence in our case of five of these criteria (maculo-papular exanthema, clinical signs persisting for more than 2 weeks after withdrawal of the suspected drug(s), elevated ALAT, eosinophilia and polyadenopathy) allowed us to conclude as to an atypical DIHS.[6] The French method for assessing drug-related adverse effects takes account of chronological criteria (drug challenge, dechallenges and rechallenge) and clinical criteria (predisposing factors, alternative non-drug-related explanations and specific laboratory tests) to produce a final score referred to as the “intrinsic imputability score”. Applied to our case, this method enabled the attribution of “possible” intrinsic imputability (“possible” chronological and clinical scores).[8] According to the Naranjo adverse drug reaction (ADR) scale, our case received a score of 4, which corresponds to a “possible” relationship between fenofibrate and this syndrome.[9] Skin, liver, and muscles disorders are the most frequently reported side effects of fenofibrate in the French summary of product characteristics (SPC). In a study that compared the efficacy and tolerance of simvastatin and fenofibrate,[10] eosinophilia occurred at a frequency of 7.6% with fenofibrate versus 4.3% with simvastatin. A French case report of acute hepatitis with fenofibrate described elevated eosinophilia accompanied with fever but no skin lesions.[11] A Medline search did not find any other cases of fenofibrateinduced DRESS. A “reactions database” search produced one other case, a 66-year-old woman with a history of right nephrectomy and renal failure, who developed fever, maculopapular rash, infiltration of the face, and a deterioration in renal function approximately 5 weeks after the initiation of fenofibrate. In that case, the RegiSCAR-Group score for DRESS syndrome was evaluated as 3, or a “possible case”.[12] In the French national pharmacovigilance database, one other unpublished, briefly reported case of fenofibrate-induced DRESS
Thérapie 2014 Septembre-Octobre; 69 (5)
464
Safrano et al.
is recorded. This case was similar to ours and involved a skin rash, fever (38.5 °C), arthralgia, peak eosinophilia at 4.6 X 109/L, liver disorders with elevated ALAT, and GGT, and a prolonged course. Although it is very rare, DRESS can be induced by treatment with fenofibrate and clinicians need to be aware of this potential adverse effect so that they can withdraw the drug immediately in the context of specific symptoms and thus avoid a deleterious outcome.
Conflicts of interest. None. Abbreviations. ADR: adverse drug reactions; ALAT: alanine amino transferases; ALP: alkaline phosphatase; ASAT: aspartate aminotransferase; CRP: C-reactive protein; CT: computed tomography; DIHS: drug-induced hypersensitivity syndrome; DRESS: drug reaction with eosinophilia and systemic syndrome; ECG: electrocardiogram; GGT: gamma glutamyltransferase; HHV6: human herpes virus type 6; RegiSCAR: registry of severe cutaneous adverse reactions; SPC: summary of product characteristics.
4.
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
5.
Descamps V, Mardivirin L, Janela B, et al. The drug hypersensitivity syndrome (DRESS syndrome) is nothing but a viral illness. Rev Fr Allergol 2010; 50: 171-3 (Doi: 10.1016/j.reval.2010.01.027)
6.
Shiohara T, Iijima M, Ikezawa Z, et al. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007 May; 156(5): 1083-4
7.
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Correspondence and offprints: Delphine Bourneau-Martin, Regional Pharmacovigilance Center, CHU d’Angers, 4 rue Larrey, 49933 Angers Cedex 9, France. E-mail: [email protected]; [email protected]
Thérapie 2014 Septembre-Octobre; 69 (5)
