Erythema Annulare Centrifugum due to Pegylated Interferon-α

CASE REPORT
Erythema Annulare Centrifugum due to Pegylated
Interferon-a-2a plus Ribavirin Combination Therapy in a
Patient with Chronic Hepatitis C Virus Infection
Müzeyyen Gönül, Seray Külcü Çakmak, Nimet Özcan, Işıl Deniz Oǧuz, and Esra Özhamam
Background: Pegylated interferon-a combined with ribavirin is the current standard treatment for chronic hepatitis C virus
infection. During interferon and ribavirin therapy, both local and generalized mucocutaneous adverse reactions have been reported.
Erythema annulare centrifugum induced by this therapy regimen has not been reported previously.
Case Report: A 29-year-old woman was referred to our clinic for a 1-week history of slightly pruritic annular erythematous
eruptions on the lower extremities and hands. The eruptions had first occured on the hands 3 to 4 days after pegylated interferon-a2a plus ribavirin combination therapy for hepatitis C virus infection. Histopathologic examination supported the diagnosis of
erythema annulare centrifugum. The lesions completely regressed within 2 weeks after the cessation of treatment but recurred on
similar localizations within 24 hours with the same therapy. It was thought that erythema annulare centrifugum was induced by
pegylated interferon-a-2a plus ribavirin combination therapy.
Conclusion: Erythema annulare centrifugum is considered an inflammatory skin disease with unknown etiology. It is thought to
represent a hypersensitivity reaction to some triggering factors, including infections, immunologic disorders, malign neoplasms,
foods, pregnancy, and drugs. We report the first case of erythema annulare centrifigum induced by pegylated interferon-a-2a plus
ribavirin combination therapy.
Contexte: L’association d’interféron alpha pégylé et de ribavirine est le traitement usuel de l’infection chronique au virus de
l’hépatite C. La documentation fait état de réactions mucocutanées locales et générales, défavorables à cette association
médicamenteuse en cours de traitement, mais l’érythème annulaire centrifuge provoqué par cette forme de bithérapie n’avait jamais
été signalé auparavant.
Exposé de cas: Une femme de 29 ans a été dirigée vers notre établissement pour l’éruption, depuis une semaine, de lésions
érythémateuses annulaires, légèrement prurigineuses, sur les mains et sur les membres inférieurs. Ces lésions étaient d’abord
apparues sur les mains, de 3 à 4 jours après le début de la bithérapie par l’interféron alpha-2a pégylé et la ribavirine pour le traitement
d’une infection au virus de l’hépatite C. L’examen histopathologique a confirmé le diagnostic d’érythème annulaire centrifuge. Les
lésions ont disparu complètement en l’espace de 2 semaines après l’arrêt du traitement, mais celles-ci sont réapparues à peu près
aux mêmes endroits, 24 heures après la reprise du même traitement. Aussi étions-nous d’avis que l’érythème annulaire centrifuge
était provoqué par l’association d’interféron alpha-2a pégylé et de ribavirine.
Conclusions: L’érythème annulaire centrifuge est considéré comme une maladie inflammatoire de la peau, d’origine inconnue. Il
serait révélateur d’une réaction d’hypersensibilité à certains facteurs déclenchants tels que les infections, des troubles immunitaires,
des tumeurs malignes, des aliments, la grossesse et des médicaments. Sera exposé ici le premier cas d’érythème annulaire
centrifuge, provoqué par l’association d’interféron alpha-2a pégylé et de ribavirine.
From the Dermatology and Pathology Clinics, Ankara Numune
Education and Research Hospital, Sıhhıye, Ankara, Turkey.
Address reprint requests to: Müzeyyen Gönül, MD, Yıldızevler Mah. 742.
Sok., Aykon Park Sitesi A Blok No:3/3, Çankaya, Ankara, Turkey; e-mail:
[email protected].
DOI 10.2310/7750.2013.13051
# 2014 Canadian Dermatology Association
RYTHEMA ANNULARE CENTRIFUGUM (EAC) is
an eruption characterized by slowly enlarging annular or polycyclic erythematous lesions. It is thought to
represent a hypersensitivity reaction to many etiologic
factors, although the etiopathogenesis is not clear in most
patients.1,2 Cases of EAC due to some drugs, such as
chloroquine, cimetidine, etizolam, and ustekinumab, have
been reported in the literature.2 We report a case of EAC
E
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Gönül et al
induced by pegylated interferon (IFN)-a-2a plus ribavirin
combination therapy. This is the first reported case of
EAC associated with IFN plus ribavirin combination
therapy.
Case Report
A 29-year-old woman was referred to our clinic with a 1week history of slightly pruritic annular erythematous
eruptions on the lower extremities and hands. Pegylated
IFN-a-2a (180 mg/wk) plus ribavirin (1,000 mg/d)
combination therapy had been initiated for chronic
hepatitis C virus (HCV) infection 10 days previously.
The skin lesions first occurred on the hands 3 to 4 days
after the initiation of hepatitis therapy. These lesions
gradually extended outward and healed centrally to form
annular patterns. The size of the lesions ranged from 2 to
3 mm to 3 to 4 cm in diameter and were particularly
localized bilaterally on the knees, ankles, and dorsa of the
hands (Figure 1 and Figure 2). The patient’s past medical
history revealed an operation for aortic aneurysm 7 years
previously. The results of the laboratory examinations,
including complete blood count, blood chemistry profile,
Veneral Disease Research Laboratory (VDRL), antinuclear
antibody, anti–double-stranded deoxyribonucleic acid
(DNA), anti-SS-A and -B antibodies, and thyroid function
tests, were normal or negative except the elevated levels of
alanine aminotransaminase (46 U/L; normal: 10–35 U/L),
aspartate aminotransferase (58 U/L; normal: 10–35 U/L),
and HCV ribonucleic acid positivity. A potassium hydroxide (KOH) examination of the lesion was negative.
A biopsy specimen was obtained from the lesions for the
differential diagnosis of dermatoses such as EAC, granuloma annulare, and erythema multiforme, and the treatment of hepatitis was stopped. The histopathologic
examination of the lesion showed epidermal spongiosis
and lymphocyte exocytosis in addition to red cell extravasation and mild lymphocytic infiltrate in the upper
dermis (Figure 3). EAC was diagnosed clinically and
histologically. It was thought that pegylated interferon-a2a plus ribavirin combination therapy induced EAC. This
hypothesis was supported by complete improvement of the
lesions within 2 weeks after the cessation of treatment and
recurrence of similar annular lesions on similar localizations
Figure 1. Annular erythematous eruptions on the knees and hands.
Figure 3. Mild lymphocytic infiltrate in the superficial dermis
(hematoxylin-eosin stain; 3200 original magnification).
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Figure 2. Annular erythematous eruptions on the ankles.
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 18, No 1 (January/February), 2014: pp 65–68
Drug-Induced Erythema Annulare Centrifugum
within 24 hours with readministration of the same
treatment. Topical steroid and oral fexofenadine therapies
were administered to the patient without cessation of the
combination therapy, and the eruption was tolerated by the
patient during the management of hepatitis.
Discussion
Pegylated IFN-a-2a or -2b and ribavirin combination
therapy has been shown to improve anti-HCV activity of
IFN.3,4 Coadministration of ribavirin and IFN-based
treatment regimens has been accompanied by an increased
incidence of skin reactions.4–7 This therapeutic combination may cause local reactions at the sites of IFN injection
and onset or worsening of skin disorders such as psoriasis
and lichen planus. Moreover, inflammatory cutaneous
eruptions may occur at distant sites from the points of IFN
injection.4,5
Localized reactions at the sites of IFN injection are
common and are characterized by ill-defined, pruritic,
erythematous patches or plaques. They are generally
transient and do not require treatment. However,
cutaneous necrosis may develop, albeit rarely, at the site
of injection.5
In the literature, a few studies investigated the
cutaneous side effects of ribavirin and IFN combination
therapy. Eczematous lesions characterized by pruritic,
confluent, erythematous papular and microvesicular
eruptions, which are often excoriated, were the most
common cutaneous reactions reported due to this
therapeutic combination in these investigations.4–7
These eruptions were predominantly localized on the
extremities and on truncal skin sites exposed to friction,
and the onset of the inflammatory lesions ranged from 2
weeks to 4 months after implementation of the therapy.4
Xerosis, lichenoid eruptions, prurigo, photosensitivity,
malar erythema, and nonspecific eruptions were other
observed skin reactions.4–7 Also, alopecia, other hair
changes, sarcoidosis, fixed drug eruption, pigmentation
disorders, and a lot of uncommon cutaneous side effects
have been reported, but EAC has not been reported
previously.5,8
Although the etiology of EAC is mainly unknown, a
hypersensitivity reaction to etiologic factors has been
suggested and has been related to infections, immunologic
disorders, malign neoplasms, foods, pregnancy, and
drugs.1,2 The pathogenetic mechanisms of the disease
and its peripheral migration are still unresolved, but it has
been thought that they might be explained with localized
production of proinflammatory cytokines and vasoactive
peptides.9 A histopathologic study of a case of EAC
showed that most of the inflammatory cells around the
vessels were T lymphocytes (cytotoxic/suppressor) and
histiocytes. The presence of these cell types suggested that a
cell-mediated immunity might be responsible for the
pathogenesis of EAC.1 In the present case, it is not known
which drug triggered EAC as the patient used ribavirin and
IFN combination therapy. Although IFN therapy was
effective in a patient with EAC, paradoxically, IFN might
have caused EAC by changing the immune system. IFN-a
promotes the development of T helper 1 (Th1) cells and
suppresses the production of T helper 2 cytokines.10 The
increased activity of Th1 cells might have caused the
development of EAC lesions.
In the present case, the lesions occurred within a
short time, 1 week after the onset of the combination
therapy. Moreover, recurrence of the lesions occurred in
even a shorter time when the therapy was readministered. This might be due to the patient’s immunity or to
IFN, which can directly affect the immune status of the
patient.
If EAC is due to an underlying disorder, when the
underlying disorder is successfully treated, the skin lesions
will usually resolve. There are many therapeutic options,
with variable results. Topical treatments include corticosteroids, calcipotriol, tacrolimus, and metronidazole.
Systemic therapy alternatives are corticosteroids, antihistamines, and even etanercept. Although clinical remission
may be achieved, relapses are frequent when the medications are discontinued.11
Conclusion
Pegylated IFN-a and ribavirin combination therapy may
cause the development of many dermatologic disorders.
The present case is the first case of EAC induced by this
combination. The development of EAC lesions does not
require the cessation of treatment.
Acknowledgment
Financial disclosure of authors and reviewers: None
reported.
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