Download Full Text PDF

terbinafine
Severe Generalized Pustular Psoriasis Provoked by
Oral Terbinafine
Jeng-Wei Tjiu
Tsen-Fang Tsai
Chia-Yu Chu
Terbinafine is an allylamine antifungal agent. Its severe cutaneous adverse effects are rare, but
toxic epidermal necrolysis, pustular drug eruption, acute generalized exanthematous pustulosis,
Stevens-Johnson syndrome, and erythema multiforme had been reported. Terbinafine was also reported
to induce flare-up of chronic psoriasis or development of pustular psoriasis. Here we report a psoriatic
patient who developed pustular eruptions in four weeks after treatment with terbinafine for his presumptive tinia unguium without a definitive mycological evidence. The skin eruptions progressed to
severe, generalized pustular psoriasis in the following two weeks even though he discontinued
terbinafine treatment. It is well recognized that terbinafine may aggravate and induce psoriasis.
Terbinafine is a highly effective antifungal agent. However, with the indiscriminate use, terbinafine may
cause unnecessary risk, as in our patient. With the increased systemic administration of terbinafine,
severe adverse effects might become more common. Therefore, we suggest mycological examinations
are essential prior to commencing terbinafine therapy for suspected onychomycosis. (Dermatol Sinica
22 : 187-192, 2004)
Key words: Terbinafine, Pustular psoriasis
Terbinafine
Stevens - Johnson
Terbinafine
terbinafine
Terbinafine
terbinafine
Terbinafine
terbinafine
terbinafine
terbinafine
(
22 : 187 - 192, 2004 )
From the Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan
Accepted for publication: January 30, 2004
Reprint requests: Chia-Yu Chu, M.D., Department of Dermatology, National Taiwan University Hospital, No. 7, Chung-Shan South
Road, Taipei 100, Taiwan, R.O.C.
TEL: 886-2-23562141 FAX: 886-2-23934177
187
INTRODUCTION
Terbinafine is an allylamine fungicidal
agent widely used for the treatment of onychomycoses and other dermatophyte infection.
Adverse effects occur in 10.4% of the patients,
with cutaneous side-effects in 1.8%.1 The cutaneous adverse effects reported with terbinafine
include erythema multiforme,2, 3 toxic epidermal
necrolysis / Stevens - Johnson syndrome,4 - 6 fixed
drug deruption,7 acute generalized exanthematous pustulosis ( AGEP ),8 - 13 erythema annulare
centrifugum - like psoriatic drug eruption. 14
Terbinafine has recently been linked to flaring
of stable chronic plaque psoriasis 15 - 17 and the
development of pustular psoriasis. 15, 18-20 We
report a further case of severe pustular psoriasis
provoked by the oral administration of
terbinafine.
Fig. 1A
Generalized pustular eruptions on erythematous, edematous
plaques
CASE REPORT
A 59-year-old man had a 10-year history
of localized pustular psoriasis involving his finger and toe nails as well as bilateral palms.
There is no papular or plaque lesions on the
trunk, extremities and scalp. He had no known
drug allergy history before. None of his family
member suffered from psoriasis. Onychomycosis had been diagnosed clinically by a general
practitioner and he was treated with terbinafine
250 mg daily. No other skin lesion was noted at
Fig. 2
Fig. 1B
Close-up showing pustules on an erythematous background.
188
Histological examinations showed hyperkeratosis and parakeratosis with subcorneal and intraepidermal spongiotic pustules filled with neutrophils (H & E, x200).
Dermatol Sinica, June 2004
terbinafine
that time. No mycological investigations were
performed.
Terbinafine was discontinued four weeks
later due to development of pustular eruptions.
Terbinafine aggravated pustular psoriatic eruption was diagnosed. He was treated with oral
antihistamine, potent topical corticosteroid and
Calcipotriene ointment. The skin lesions progressed with diffuse erythematous macular
eruption. Two weeks after onset of symptoms,
the generalized, bright - red, symmetric plaques
studded with flaccid pustules developed ( Fig.
1 ). Pus lakes formed on the trunk, thighs and
arms. There was exfoliation of skin in some
areas. His finger and toe nails showed irregular
pitting, salmon patches of the nail bed, onycholysis with an erythematous border, but no evident
whitish discoloration of the nail plate or subungual hyperkeratosis. He was admitted to our
hospital two weeks after onset of the symptoms.
On admission, he was acute illness looking
with high fever ( 39˚C ). He had a widespread
pustular eruption. Routine investigations
showed a raised white cell count ( 22.68 x
10 9 / L, normal range 4 - 10 x 10 9 / L ), segments
81 %, banded neutrophils 2 %, lymphocytes
14 %, hyperbilirubinemia ( serum bilirubin 1.67
mg / dL, normal range: < 1 mg / dL) and slightly
elevated liver enzyme ( aspartate aminotransferase 48 U / L, normal 0 - 35 U / L; alanine
aminotransferase 88 U / L, normal < 40 U / L ).
Anti-streptolysin O titer and immunoglobulin A
were normal. Bacterial culture of the pustules
was negative and a skin biopsy was made.
Histopathological examinations showed several
subcorneal neutrophil - rich pustules and also
neutrophilic and lymphocytic infiltration in the
upper dermis with spongiosis and mild dermal
edema. It was consistent with a pustular psoriasis (Fig. 2). He was treated with acitretin 20 mg
daily initially and the dose was increased gradually to 40 mg daily. Betamethasone dipropionate
cream was applied twice daily. The pustules
subsequently dried up and desquamated. One
month after the treatment, the erythema faded
and the skin was clear. The hospital course was
complicated with pneumonia of nosocomial ori-
Dermatol Sinica, June 2004
gin methicillin-resistant Staphylococcus aureus
( MRSA ) with empyema. He was treated with
surgical drainage and intravenous vancomycin
for 2 weeks and was discharged after recovery.
Two months after recovery, patch tests
were performed with European standard series;
5 %, 10 %, 50 %, and without dilution of
terbinafine in petrolatum. Patch test reading and
interpretation followed the International Contact
Dermatitis Research Group ( ICDRG ) scoring
system. In the ICDRG scoring system, 1+ represents erythema and edema; 2+ represents erythema, edema and vesicles, 3+ represents an
extreme reaction with bullous formation.21 At
the 72 hours reading, the result showed an
ICDRG 1+ reaction to undiluted terbinafine. All
other patch testing gave negative results.
DISCUSSION
Terbinafine is an antifungal agent that is
effective for the oral treatment of dermatophytes
causing onychomycosis and other dermatomycoses. Oral terbinafine causes adverse effects in
10.4 % of patients.22, 23 In a post marketing surveillance study performed in a cohort in the
U.K. (n = 10,361 patients), dermatological medical events were reported by 341 ( 3 % ) of the
patients.24 Most reactions were mild to moderate
rashes occurring in the first 2 weeks and resolving within 2 - 3 weeks after discontinuation of
terbinafine or despite continued treatment. The
most common cutaneous adverse effects associated with oral terbinafine are rash, pruritus and
urticaria. Generally, these manifestations are not
severe, requiring discontinuation of therapy in
only 1% of patients.22 With the increasing use of
oral antifungal agents, it is likely that severe
cutaneous adverse effects will be recognized
with a greater frequency. Less common cutaneous adverse effects reported with terbinafine
include erythema multiforme,2, 3 toxic epidermal
necrolysis / Stevens - Johnson syndrome,4 - 6 fixed
drug deruption, 7 erythema annulare centrifugum-like psoriatic drug eruption,14 and pustular psoriasiform eruption.19 Recently, there are
several reports linking terbinafine therapy with
development of psoriasis de novo15 or worsening
189
Table I. Differentiation between AGEP and pustular psoriasis
History of psoriasis
Causation
Onset
Duration
Systemic symptoms
Clincical appearance
Histology
AGEP 8-13
Possible
Usually drug
Shorter, < 1 week or weeks
Cleared spontaneously within 15 days
High fever, leukocytosis, seldom arthralgia
Erytheroderma with nonfollicular sterile
pustules, predominance in the folds.
Spongiform subcorneal/ intraepidermal
pustules,papillary dermal edema,
vasculitis, exocytosisof eosinophils,
single-cell necrosis of keratinocyts.
of pre-existing psoriasis.15-18 Terbinafine is also
reported to induce acute generalized exanthematous pustulosis 8-13 and one case was confirmed
by a positive patch-test result.13
The differential diagnosis of terbinafineindcued pustular eruption may include druginduced or drug-aggravated pustular psoriasis,1518
AGEP,8-13, 25, 26 or subcorneal pustular dermatosis (Snedden-Wilkinson disease),27 pustular vasculitis,28 IgA pemphigus, drug hypersensitivity
syndrome,29 and infections ( i.e. bacterial folliculitis, impetigo ). AGEP is characterized by
extensive formation of both follicular and nonfollicular sterile pustules on an erythematous
background combined with fever and peripheral
blood leukocytosis. 25 Five criteria have been
suggested for the definition of AGEP: a numerous small, non-follicular pustules arising on
edematous bases; b the pathological demonstration of intraepithelial or subcorneal pustules
associated with one or more of the followings:
dermal edema, vasculitis, perivascular
eosinophils; c fever > 38˚C; d blood neutrophil count above 7 x 109 / L; e acute course
with spontaneous resolution in 15 days.25 AGEP
and pustular psoriasis of the von Zumbusch type
have indistinguishable morphology. There are
still no clear-cut rules for the differentiation of
both entities until now. Table I is a summary of
differences between pustular psoriasis and
AGEP. The patient had a clinical course longer
than 15 days, no spontaneous resolution of pus-
190
Pustular psoriasis 15,18-20
Mostly
Infection>drug
Longer, <1 week to years.
Longer, can be recalcitrant or relapse
Often fever, leukocytosis, often arthralgia (~30%)
Generalized pustules on erythematous plaques,
may have nail change, more generalized.
Subcorneal/intraepidermal pustules,
papillomatosis, acanthosis, elongated rete,
parakeratosis.
tules, despite early discontinuance of the offending drug. His psoriatic history and response to
retinoid therapy also favor the diagnosis of generalized pustular psoriasis rather than AGEP.
Subcorneal pustular dermatosis is characterized
by larger flaccid blisters with hypopyon formation often arranged in a circinate distribution
pattern. 27 Pustular vasculitis is a variant of
leukocytoclastic vasculitis which is characterized by the development of many small pustules
localized mainly on the dorsa of hands.28 Drug
hypersensitivity syndrome, also called drug rash
with eosinophilia and systemic symptoms
(DRESS) may also show pustules. But it often
presents with eosinophilia, mononucleosis, and
more severe visceral involvement.29 The negative bacterial culture and sterile pustules did not
support infection as a cause of the skin lesions.
Reviewing the clinical course and histopathologic findings, all the above diagnosis except
pustular psoriasis are not likely in this patient.
In AGEP, the formation of sterile pustules
with neutrophil aggregation may be caused by
drug specific T cells. These T cells secrete high
amount of interleukin - 8, now also known as
CXC chemokine ligand 8 (CXCL8).30 Drug specific T cells from the blood and skin are activated and cytotoxic. Perforin / granzyme B and
Fas / FasL - mediated mechanism cause tissue
destruction and formation of vesicles. CXCL8
released from T cells and keratinocytes attracts
neutrophils to the vesicles and transform them
Dermatol Sinica, June 2004
terbinafine
to pustules.31 In drug induced pustular psoriasis,
similar mechanisms may be involved in the
pathogenesis of pustules. Drug specific T cells
in pustular psoriasis may release acute phase
cytokines, including IL-1, IL-6, CXCL8, and
TNF-α, that trigger flare-up of psoriasis and formation of generalized pustules.
The latency periods between the administration of different drugs and the exacerbation or
de novo appearance of psoriasis had been summarized by Gupta et al.15 The latency period of
terbinafine and nonsteroidal anti-inflammatory
drugs are denoted short ( less than 4 weeks );
antimalarials and angiotensin converting
enzyme inhibitors are intermediate (4-12
weeks); lithium and beta-blockers are long
(more than 12 weeks).15
Using systemic challenge test to identify
an offending drug in an suspected drug allergic
patient is unethical and sometimes dangerous.
Patch testing may be used as an alternative way
to identify the possible drug induced reactions.
The role of patch testing in confirming the
causative agent of AGEP has been well recognized in recent years.32 Wolkenstein et al. have
shown a 50 % sensitivity of patch testing in
cases of AGEP.32 In terbinafine-induced AGEP,
patch testing was reported to be positive by
Kempinaire et al.13 Therefore, some cases of
drug-induced generalized pustular eruption
could be due to type 4 reactions. We performed
patch testing in this case because of the similarity between AGEP and generalized pustular psoriasis both clinically and histopathologically.
Although the role of patch testing in most cases
of drug eruption is uncertain, the positive reaction to terbinafine in our case suggests that
delayed type hypersensitivity could play a role
in the pathogenesis of drug-induced generalized
pustular psoriasis as has been described previously.33
With the increasing administration of oral
antifungal agents, it is likely that severe cutaneous adverse effects will be recognized with a
greater frequency. This should be taken into
account when prescribing terbinafine for suspected onychomycosis without definite myco-
Dermatol Sinica, June 2004
logical evidence. In addition, the use of systemic antifungal agents makes interpretation of
subsequent mycological investigation difficult.
We propose fungal examinations be essential
before starting oral terbinafine for suspected
onychomycosis.
REFERENCES:
1. Villars VV, Jones TC: Special features of the clinical use of oral terbinafine in the treatement of fungal diseases. Br J Dermatol 126 (Suppl. 39): 6169, 1992.
2. McGregor JM, Rustin MHA: Terbinatinfe and erythema multiforme. Br J Dermatol 131: 587-588,
1994.
3. Todd P, Halpern S, Munro DD: Oral terbinafine
and erythema multiforme. Clin Exp Dermatol 20:
247-248, 1995.
4. Carstens J, Wendelboe P, Sogaard H, et al.: Toxic
epidermal necrolysis and erythema multiforme following therapy with terbinafine. Acta Derm
Venereol [Stockh] 74: 391-392, 1994.
5. White SI, Bowen-Johns D: Toxic epidermal necrolysis induced by terbinafine in a patient on longterm anti-epileptics. Br J Dermatol 134: 188-189,
1996.
6. Rzany B, Mockenhaupt M, Gehring W, et al.:
Stevens-Johnson syndrome after terbinafine. Arch
Dermatol 30: 509, 1996.
7. Munn SE, Russell Jones R: Terbinafine and fixed
drug eruption. Br J Dermatol 133: 815-816, 1995.
8. Dupin N, Gorin I, Djien V, et al.: Acute generalized erythematous pustulosis induced by
terbinafine. Arch Dermatol 132: 1253-1254, 1996.
9. Lombardo M, Cerati M, Pazzaglia A: Acute generalized exanthematous pustulosis induced by
terbinafine. J Am Acad Dermatol 49: 158-159,
2003.
10. Taberner R, Puig L, Gilaberte M, et al.: Acute
generalized exanthematous pustulosis induced by
terbinafine. Eur J Dermatol 13: 313-4, 2003.
11.Condon CA, Downs AMR, Archer CB:
Terbinafine-induced acute generalized exanthematous pustulosis. Br J Dermatol 138: 709-710,
1998.
12. Hall AP, Tae B: Acute generalized exanthematous
pustulosis associated with oral terbinafine. Austral
J Dermatol 41: 42-45, 2000.
13. Kempinaire A, De Raeve L, Merckx M, et al.:
Terbinafine-induced acute generalized exanthema-
191
tous pustulosis confirmed by a positive patch-test
result. J Am Acad Dermatol 37: 653-655, 1997.
14. Wach F, Stolz W, Rudiger R, et al.: Severe erythema annulare centrifugum-like psoriatic eruption
induced by terbinafine. Arch Dermatol 131: 960961, 1995.
15.Gupta AK, Sibbald Rg, Knowles SR, et al.:
Terbinafine therapy may be associated with the
development of psoriasis de novo or its exacerbation: four case reports and a review of druginduced psoriasis. J Am Acad Dermatol 36: 858862, 1997.
16.Gupta AK, Lynde CW, Lauzon GJ, et al.:
Cutaneous adverse effects associated with
terbinafine therapy: 10 case reports and a review
of the literature. Br J Dermatol 138: 529-532,
1998.
17. Tsankov N, Angelova I, Kazandjieva J: Drug induced psoriasis recognition and management.
Am J Clin Dermatol 1: 159-165, 2000.
18. Wilson NJ, Evans S: Severe pustular psoriasis provoked by oral terbinafine. Br J Dermatol 139: 168,
1998.
19. Papa CA, Miller OF: Pustular psoriasiform eruption with leukocytosis associated with terbinafine.
J Am Acad Dermatol 39: 115-117, 1998.
20. Bennett ML, Jorizzo JL, White WL.: Generalized
pustular eruptions associated with oral terbinafine.
Int J Dermatol 38: 596-600, 1999.
21. Rietschel RL, Fowler JF Jr.: Fisher's contact dermatitis, 5th edn. Philadelphia: Lippincott Williams
& Wilkins, 9-26, 2001.
22. Gupta AK, Sauder DN, Shear NH: Antifungal
agents: an overview. Part II. J Am Acad Dermatol
30: 911-933,1994.
23. Shear NH, Gupta AK: Terbinafine for the treatment of pedal onychomycosis: a foot closer to the
promised land of cured nails. Arch Dermatol 131:
937-942, 1995.
192
24. O'Sullivan DP, Needman CA, Banges A, et al.:
Postmarketing surveillance of oral terbinafine in
the UK: report of a large cohort study. Br J Clin
Pharmacol 42: 559-565, 1996.
25. Roujeau JC, Bioulac-Sage P, Bourseau C, et al.:
Acute generalized exanthematous pustulosis.
Analysis of 63 cases. Arch Dermatol 127: 13331338, 1991.
26. Sidoroff A, Halevy S, Bavinck JNB, et al.: Acute
generalized exanthematous pustulosis (AGEP)-A
clinical reaction pattern. J Cutan Pathol 28: 113119, 2001.
27. Mandel EH, Gonzales V.: Subcorneal pustular dermatosis (Sneddon-Wilkinson). Arch Dermatol
99:246-247, 1963.
28. Strutton G, Weedon D, Robertson I.: Pustular vasculitis of the hands. J Am Acad Dermatol 32:192198, 1995.
29. Descamps V, Valance A, Edlinger C, et al.:
Association of human herpesvirus 6 infection with
drug reaction with eosinophilia and systemic
symptoms. Arch Deramtol 137: 301-304, 2001.
30. Britschgi M, Steiner UC, Schmid S, et al.: T-cells
involvement in drug-induced acute generalized
exanthematous pustulosis. J Clin Invest 107: 14331441, 2001.
31. Schmid S, Kuechler PC, Britschgi M, et al.: Acute
generalized exanthematous pustulosis: role of
cytotoxic T cells in pustule formation. Am J
Pathol 161: 2079-2086, 2002.
32. Wolkenstein P, Chosidow O, Flechet M-L, et al.:
Patch testing in severe cutaneous adverse drug
reaction including Stevens-Johnson syndrome and
toxic epidermal necrolysis. Contact Dermatitis 35:
234-236, 1996.
33. Whittam LR, Wakelin SH, Barker JN: Generalized
pustular psoriasis or drug-induced toxic pustoloderma? The use of patch testing. Clin Exp
Dermatol 25: 122-124, 2000.
Dermatol Sinica, June 2004