IJDVL_Jan_05.pmd


Indian J Dermatol Venereol Leprol Januar y-Februar y 2005 Vol 71 Issue 14 5

therapy in progressive systemic sclerosis. Int J Dermatol

1995;34:726-8.

Generalized hypopigmentationGeneralized hypopigmentationGeneralized hypopigmentationGeneralized hypopigmentationGeneralized hypopigmentation

due to imatinib: A fairness boon?due to imatinib: A fairness boon?due to imatinib: A fairness boon?due to imatinib: A fairness boon?due to imatinib: A fairness boon?

Sir,

Imatinib (STI571, Glivec©) is a new selective tyrosine

kinase inhibitor that is very useful in the treatment of

chronic myelogenous leukemia (CML) and

gastrointestinal stromal tumors (GIST). More side

effects are being reported with its increasing use. We

report generalized hypopigmentation with the use of

this drug.

The majority of CML and GIST patients on imatinib

mesylate experience some undesirable side effects that

involve many organ systems in the body, including the

skin. The most common dermatological side effects are

periorbital edema and dermatitis. Facial edema,

pruritus, erythema, dry skin, alopecia, night sweats and

photosensitivity reaction are infrequently reported.[1]

Over 120 patients of CML or GIST are being treated

with imatinib at our institute since 2001. For the last

one year, during routine outdoor visits, many patients

have been reporting that their skin was becoming fairer

while on imatinib. We inter viewed 26 patients

regarding this side effect; 22 of the patients and their

relatives confirmed this experience at varying durations

of treatment (median 2 months; range 2 to 8 months).

Three patients in whom the drug had to be

discontinued because of different reasons reported that

their skin complexion had reverted to the original one.

Skin biopsies were performed on seven of these ‘fair’

patients. On H and E staining, even though melanin

pigment was seen in all of these biopsy specimens, low

melanin content was observed in two of them. In the

absence of a pretreatment biopsy, quantification of the

melanin pigmentation was not possible. Currently, we

are doing electron microscopy and tyramine based

tyrosinase assay on the skin biopsies performed pre-

and post-imatinib treatment for quantification of the

melanin deposition in melanosomes.

The exact mechanism for this generalized

hypopigmentation with imatinib is not known. Apart

from inhibiting a tyrosine kinase, the BCR-ABL

oncoprotein, imatinib also inhibits platelet-derived

growth factor receptors (PDGFRs) and c-KIT receptor

tyrosine kinases.[2] The latter two kinases have

important roles in normal pigmentation.[3] Certain

hypopigmentary disorders like piebaldism and vitiligo

are associated with mutations in the c-KIT gene causing

alteration in the respective tyrosine kinases.[4] Tsao et

al recently reported a similar finding.[5] However, we

found hypopigmentation to be much more common

than they did, possibly because it is more apparent in

Blacks or Indians because of their otherwise dark skin

complexion. Based on our observation, we hypothesize

that inhibition of melanocyte c-KIT receptor tyrosine

kinase by imatinib leads to generalized

hypopigmentation. The long-term implications of this

observation need to be studied. Meanwhile, it will be

interesting to see whether topical use of imatinib is

possible in the future.

Atul Sharma, Amish Vora, Manisha Bhutani
Department of Medical Oncology, Institute Rotary Cancer Hospital,

All India Institute of Medical sciences, New Delhi, India.

Address for correspondence: Dr. Atul Sharma, Assistant Professor

of Medical Oncology, Department of Medical Oncology, Institute

Rotary Cancer Hospital, All India Institute of Medical Sciences,

New Delhi - 110029, India. E-mail: atul1@hotmail.com

REFERENCES

1. Glivec* (imatinib) Summary of Product Characteristics. Basel,

Switzerland: Novartis Pharma AG; 2001.

2. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno Jones S, Druker

BJ, et al. Abl protein-tyrosine kinase inhibitor STI 571 inhibits

in vitro signal transduction mediated by c-kit and platelet-

derived growth factor receptors. J Pharmacol Exp Ther

2000;295:139-45.

3. Luo D, Chen H, Searles G, Jimbow K. Coordinated mRNA

expression of c-Kit with tyrosinase and TRP-1 in melanin

pigmentation of normal and malignant human melanocytes

and transient activation of tyrosinase by Kit/ SCF-R. Melanoma

Res 1995;5:303-9.

4. Dippel E, Haas N, Grabbe J, Schadendorf D, Hamann K,

Czarnetzki BM. Expression of the c-Kit receptor in

hypomelanosis: A comparative study between piebaldism,

nevus depigmentosus and vitiligo. Br J Dermatol

1995;132:182-9.

5. Tsao AS, Kantarjian H, Cortes J, O’Brien S, Talpaz M. Imatinib

mesylate causes hypopigmentation in the skin. Cancer

Letters to Editor



Indian J Dermatol Venereol Leprol Januar y-Februar y 2005 Vol 71 Issue 1 4 6

2003;98:2483-7.

Amiodarone-induced angioedema:Amiodarone-induced angioedema:Amiodarone-induced angioedema:Amiodarone-induced angioedema:Amiodarone-induced angioedema:

Report of two casesReport of two casesReport of two casesReport of two casesReport of two cases

Sir,

Amiodarone, a class II long-acting anti-arrhythmic,

capable of blocking both α and β -adrenoceptors is an
iodine-containing highly lipophilic benzofuran

derivative.[1,2] Adverse reactions are common and are

duration-dependent. Frequent reactions include nausea

and other GI symptoms. Ten percent of patients may

develop photosensitization (possibly due to

phototoxicity) and bluish skin pigmentation, but

allergic skin reactions are rare.[3-6] The most serious side-

effect related to amiodarone is pulmonary alveolitis

and fibrosis.[4] Only a single case of amiodarone-induced

angioedema has been reported in the literature.[2] We

came across two unrelated cases of angioedema

triggered by the use of amiodarone in the last couple

of years.

A 65-year-old lady was admitted with pericardial

effusion and af ter a positive pericardial tap

antitubercular drugs (ATD) were started (isoniazid 300

mg, rifampin 600 mg, ethambutol 800 mg and

pyrazinamide1500 mg). She developed atrial fibrillation

and an alteration in the ventricular rate. She was put

on amiodarone 800 mg twice daily for 15 days and then

the dose was tapered to once daily. Facial angioedema

appeared within a couple of weeks and she complained

of anorexia. Chest roentgenogram was done and was

non-contributory. Laboratory evaluation was normal

(blood analysis and serum chemistry, stool examination

for parasites, IgE, thyroid tests (T3, T4 and TSH), and

urinalysis). Liver function tests yielded a mild rise in

liver enzymes like ALT, AST and serum alkaline

phosphatase; which were 93, 97 and 371 respectively.

She was anicteric. Fundoscopy was normal. Symptoms

of angioedema were unrelated to any physical activity,

stress or ingestion of any particular food. She was not

an atopic and had no clinical history of nasal polyps,

chronic rhinitis, sinusitis, asthma or chronic and

chronically relapsing dermatitis. After another four

weeks ATD were stopped. Then they were again started

one by one. No improvement was noticed. Angioedema

persisted. All medicines were stopped and she was put

on prednisolone in a reducing dosage. Within another

four weeks that was also completely tapered off. She

improved dramatically and was completely symptom-

free within 10 days. ATD were started again. No

angioedema was noticed then but it appeared within a

day when she was given a single dose (400 mg) of oral

amiodarone. Again this symptom improved when

amiodarone was taken off. Now she is without any

symptoms since the last two years.

The second patient was a 73-year-old woman with a

history of recurrent episodic facial swelling since one

year. This was treated with oral steroids, resulting in

clinical improvement. However, facial swelling

reappeared after discontinuation of the steroids for

which steroids were continued for a year. She presented

to our clinic with typical cushingoid habitus. A complete

clinical histor y was taken, and she was carefully

questioned about past history and recent symptoms.

Symptoms of angioedema were found to be unrelated

to any food ingestion, activity, or stress. She had no

clinical history of nasal polyps, chronic rhinitis, sinusitis,

or asthma. It was found that she was taking oral

corticosteroids and amiodarone 200 mg/day. This last

drug had been started by a general practitioner 3 years

back for cardiac rhythm abnormalities and had never

been discontinued. Her chest radiograph was normal

and all the laboratory tests (including blood analysis

and serum chemistry, stool examination for parasites,

IgE, thyroid profile and urinalysis) were within range

except mild hyperglycemia and low ACTH level.

Suprarenal glands were normal. A diagnosis of

iatrogenic Cushing’s syndrome was made. Complete

physical examination, ECG and echocardiography were

non-contributory. Skin patch tests with common

allergens were done and found to be negative. In view

of the patient’s previous history, the diagnosis of

amiodarone-induced angioedema was considered.

Amiodarone was discontinued, and the symptoms

disappeared with the reduction of steroids, which were

finally discontinued. In order to confirm that

amiodarone was the cause of the patient’s reaction, a

double-blind oral challenge with amiodarone was

undertaken. Within 30 min of receiving the dose (200

mg), she began to experience facial flush and facial

Letters to Editor