4. Rongioletti F, Ghigliotti G, De Marchi R, Rebora A. Cutaneous

mucinoses and HIV infection. Br J Dermatol 1998;139:

1077-80.

5. Lan CC, Yu HS, Wu CS, Kuo HY, Chai CY, Chen GS. FK506 inhibits

tumor necrosis factor-alpha secretion in human keratinocytes

via regulation of nuclear factor-kappaB. Br J Dermatol 2005;

153:725-32.

6. Nagano J, Iyonaga K, Kawamura K, Yamashita A, Ichyasu H,

Hokamoto T, et al. Use of tacrolimus, a potent antifibrotic

agent, in bleomycin-induced lung fibrosis. Eur Respir J 2006;

27:460-9.

doi:10.1016/j.jaad.2006.10.021

J AM ACAD DERMATOL

MARCH 2008

532 Letters

Early signs of liver failure after low-doseinterferon alfa-2b for cutaneous melanoma

To the Editor: High-dose interferon alfa-2b has con-siderable toxic effects including liver failure.1 Effortsto improve toxicity have included the use of lower-dose regimens. We report on the early signs of liverfailure after low-dose interferon alfa-2b for cutane-ous melanoma.

A 20-year-old woman was treated with interferonalfa-2b (Intron A, Schering Plough) at a dose of 3million U subcutaneously thrice a week, for a stageIIC cutaneous melanoma of the right leg. She hadbeen well, without any history of liver disease, intakeof hepatotoxic drug, or alcoholism. There was nei-ther known drug allergy nor change in diet. Beforetreatment, liver function tests were normal. Threeweeks later, she developed an asymptomatic hepa-totoxicity with increase of aspartate aminotransfer-ase to 162 U/L and alanine aminotransferase to 366U/L. She was taking no drugs other than interferon.Therefore, she carried on with half the dose. Weeklyblood profile showed a progressive decrease inprothrombin time, factor V, albumin, cholesterol,triglycerides, and glucose level. After 3 months, herlaboratory tests disclosed normal liver enzymes butdecreased liver function: prothrombin time 22 sec-onds, factor V 50%, albumin 30 g/L, cholesterol 3.4mmol/L, triglycerides 0.4 mmol/L, and glucose 3.5mmol/L. Renal function was normal. Moreover,serologic tests for hepatitis A, hepatitis B, hepatitis C,cytomegalovirus, Epstein-Barr virus, and HIV, andimmunologic tests for liver and kidney microsomal,mitochondrial, smooth muscle, and nuclear anti-bodies were negative. Abdominal ultrasound andabdominal computed tomography scan were nor-mal. The patient refused liver biopsy. Interferonwithdrawal induced complete improvement of liverfunction 1 week later.

Attempts to reduce recurrent melanoma withadjuvant therapy date back several decades. How-ever, the only agent that has shown a significant

and reproducible benefit in terms of survival andrelapse-free interval has been high-dose interferonalfa-2b.2 Interferon alfa-2b exerts its effect by theinduction of certain enzymes, suppression of cellproliferation, and immunomodulating activities. Theappearance of clinical manifestations of autoimmu-nity during treatment with high-dose interferonalfa-2b is associated with statistically significantimprovement in relapse-free survival and overallsurvival in patients with melanoma. Signs of autoim-munity include antithyroid, antinuclear, anti-DNA,and anticardiolipin autoantibodies and vitiligo.3 Con-versely, autoimmunity markers during treatment withlow-dose interferon did not appear to predict theseverity of the evolution or the prognosis of thedisease.4 Interferon treatment of patients with can-cer, presumably without hepatitis, results in 25% to80% of patients developing liver enzyme abnormal-ities depending on the dose used. In the majority ofcases aspartate aminotransferase or alanine amino-transferase elevations do not exceed 5 times theupper normal limit. Less frequently seen are in-creases in alkaline phosphatase or lactate dehydro-genase. In very few cases (0.04%), interferon usedas therapy for viral hepatitis has been associatedwith liver failure. In these cases, hepatic damageresults from interferon-induced immune clearanceof the virus, rather than intrinsic hepatotoxicity. Onthe other hand, interferon has been associated withthe unmasking of underlying autoimmune hepatitis,in cases where autoimmune markers were negativebefore therapy and became detectable after the startof interferon. In addition, the occurrence of hyper-thyroidism during treatment with interferon caninduce elevated liver enzyme up to 10 times theupper normal limit.5 In patients coinfected withHIV/hepatitis C virus, risk factors associated withhepatic decompensation were increased bilirubin,decreased hemoglobin, increased alkaline phos-phatase, or decreased platelets.6 In patients withmelanoma treated with high-dose interferon, liverfunction abnormalities (all grades) occurred in 63%of patients in the E1684 trial whereas 14% to 29% ofpatients developed grade 3 or 4 liver toxicity in thecooperative group trials. Liver toxicity resulted intwo deaths early in trial E1684 in the absence ofappropriate monitoring or dose modification guide-lines. Later on, it has not been a cause of mortalityin the United States cooperative group trials since1987, when vigilant monitoring and dose modifi-cation guidelines were mandated.7 However, withlow-dose interferon, only two patients were with-drawn from the French trial after developinggrade 4 liver toxicity with increase in liver en-zymes but not liver failure.8 This is a particular

Adult-onset Still’s disease revealed byfacial edema

To the Editor: Adult onset Still’s disease (AOSD) is amultisystemic inflammatory disorder characterizedby high spiking fever, sore throat, articular involve-ment, skin rash, leukocytosis with high neutrophilcounts, and high serum ferritin levels.1,2 The typicaldermatologic presentation is a salmon-pink evanes-cent rash. We report a case of facial edema as aninitial atypical presentation of AOSD.

A 58-year-old female was admitted to the derma-tology department of Saint-Louis hospital, Paris, inMay 2005, for investigation of facial edema withchills and a fever rising to 388C. The facial edema hadappeared 29 days earlier; the fever had been presentfor 13 days. She presented with a persistent, infil-trated, erythematous edema, localized symmetri-cally on the peri-orbital and malar regions (Fig 1).The day after admission, she developed a sore throat,an intermittent fever rising to 408C with a quotidianpattern, chills, a widespread, persistent maculo-papular rash, myalgia confined to the arms andthighs, and migratory oligoarthritis. Physical exami-nation revealed no lymphadenopathy or hepato-splenomegaly. Complete blood cell counts showedmild normocytic anemia (hemoglobin: 116 g/L) andhigh neutrophil counts (13 3 109/L) without throm-bocytopenia. Inflammatory markers were increased,with an erythrocyte sedimentation rate over 100 mm(normal range: \ 10 mm) and C-reactive proteinlevel of 213 mg/L (normal range: \ 5 mg/L). Bloodchemistry tests for liver function showed mixedcytolytic and cholestatic hepatitis: alanine amino-transferase, 251 U/L; aspartate aminotransferase, 156U/L; gamma-glutamyl transpeptidase, 375 U/L; andalkaline phosphatase, 275 U/L. The serum lactatedeshydrogenase level was increased (823 U/L),whereas serum creatine phosphokinase and aldolaselevels were within normal limits. The serum levelof ferritin was increased to 12660 �g/L (normal

J AM ACAD DERMATOL

VOLUME 58, NUMBER 3

Letters 533

case in which early signs of liver failure hadoccurred in a young patient without underlyingliver disease and treated with low-dose interferonalfa-2b. Alternative causes such as hepatic micro-metastases of melanoma, or infectious or autoim-mune hepatitis have been ruled out. Thechronologic sequence between interferon alfa-2band liver toxicity is established in our case. Further-more, complete remission on dechallenge givesstrong evidence that interferon alfa-2b was involved.The lengthy latent period and the progression ofliver toxicity despite dose reduction support anidiosyncratic reaction. Affected individuals may pos-sess a rare combination of genetic and nongeneticfactors.9

In conclusion, this report suggests that interferoncan induce liver failure at low dose without anyclear signs of autoimmunity. Normalization of liverenzymes is not sufficient to rule out the progressionof a toxic reaction. Thus, careful monitoring ofcomplete liver profile including prothrombin time,factor V, and albumin is necessary when signs ofliver toxicity appear. Hence, early drug withdrawalwill prohibit the progression toward an irreversiblefatal reaction.

Alfred Ammoury, MD,a,b Fouad El Sayed, MD,a,b

Caroline Farah, MD,a and Jacques Bazex, MDa

Department of Dermatology, CHU Purpan, Tou-louse, Francea; and Division of Dermatology,Faculty of Medicine, Lebanese University, Beirutb

Funding sources: None.

Conflicts of interest: None declared.

Reprint requests: Alfred Ammoury, MD, Departe-ment de Dermatologie, CHU Purpan, Place du Dr.Baylac, 31059 Toulouse, France

E-mail: docalf@yahoo.com

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doi:10.1016/j.jaad.2006.10.983