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Long-Term Clearance of Linear Porokeratosis With Tacrolimus, 0.1%, Ointment

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Long-Term Clearance of Linear Porokeratosis With Tacrolimus, 0.1%, Ointment

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hadi firman
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Clinical Review & Education

The Cutting Edge

Long-term Clearance of Linear Porokeratosis With


Tacrolimus, 0.1%, Ointment
Ashley C. Parks, MD; Kelly J. Conner, MD; Cheryl A. Armstrong, MD

Porokeratosis is a disorder of abnormal keratinization with mul- only a few very faint reticulated pale-brown macules (Figure 2), thus
tiple clinical variants. It is often difficult to achieve complete reso- demonstrating the long-term efficacy of treatment with topical be-
lution of porokeratosis even with a variety of therapies that have been tamethasone and tacrolimus.
reported to have some efficacy.
Discussion
Report of a Case Porokeratosis is a disorder of abnormal keratinization character-
A woman in her 40s with no significant medical history was re- ized by at least 5 known clinical variants: porokeratosis of Mibelli,
ferred for evaluation of a painful dermatitis on her left arm. Approxi- disseminated superficial actinic porokeratosis, linear porokerato-
mately 1 year earlier, a painful, pruritic, erythematous papule had de- sis, punctate porokeratosis, and porokeratosis palmaris et plan-
veloped on her left arm, which subsequently spread into a linear array taris disseminata. The varying clinical presentations of porokerato-
of papules extending from her left wrist up her arm to her neck, as- sis are unified by the classic histologic finding of the cornoid lamella,
sociated with pruritus, paresthesias, and pain; 3- to 10-mm erythem- which is thought to correlate with the hyperkeratotic ridge found
atous papules with overlying scales were arranged in a linear pat- clinically and is the result of hyperproliferation of keratinocytes. Al-
tern extending up the ventral part of her arm, across her shoulder though its exact pathogenesis remains unknown, porokeratosis may
to the left side of her neck and chest (Figure 1). Several lesions ex- be triggered by immunosuppression, exposure to UV radiation, or
hibited an outer hyperkeratotic rim. She had similarly shaped areas genetic predisposition.
of hyperpigmentation without overlying epidermal change on her Linear porokeratosis was first described as a distinct clinical en-
left arm and on the left side of her chest and neck. tity in the 1970s.1 Lesions typically arise in infancy or childhood and
A skin biopsy sample revealed a vertical column of parakerato- consist of annular papules and plaques with a hyperkeratotic bor-
sis within the stratum corneum, an absent granular layer underly- der, similar to classic porokeratosis. The lesions characteristically fol-
ing the column, and a focal lymphohistiocytic infiltrate underlying low the lines of Blaschko and are most commonly found on the ex-
the epidermal change. The clinical and histopathologic features con- tremities. Linear porokeratosis is particularly difficult to treat because
firmed a diagnosis of linear porokeratosis. The patient had been of its widespread distribution, but it is particularly important to treat
treated with betamethasone dipropionate, 0.05%, ointment for sev- because of its risk of malignant degeneration. Although the rate of
eral months with minimal improvement; oral acitretin treatment was malignant transformation for porokeratosis overall is 7.5%, the rate
subsequently started at 25 mg/d. After 3 months of acitretin treat- for linear porokeratosis is 19%.2 Therefore, treatment approaches
ment, she had no improvement of the lesions on her arm but had that effectively clear these lesions may decrease the risk of local ma-
adverse effects, including scaling of her palms and soles and dry- lignant degeneration.
ness of her lips and face. Although many treatment options have been reported to im-
We continued daily treatment with betamethasone dipropio- prove porokeratosis, achieving complete resolution of lesions is no-
nate, 0.05%, ointment and added tacrolimus, 0.1%, ointment, ad- toriously difficult. Because of the varied clinical presentations of po-
ministered twice daily, to the patient’s treatment regimen. Oral ac- rokeratosis, treatment options must be tailored based on the size
itretin treatment was discontinued because it had caused adverse and location of the lesions and the amount of distress experienced
effects with no skin improvement. With the combination of beta- by the patient. Many patients may be treated conservatively with
methasone and tacrolimus, the skin lesions improved rapidly and dra- sun protection, emollients, and observation for malignant degen-
matically. At the 2-month follow-up examination, the patient had hy- eration.
perpigmented macules and patches in a linear pattern up the ventral A variety of reported treatments have demonstrated some de-
side of her left arm and across the shoulder to her neck on the left gree of success, including topical retinoids, fluorouracil cream, 5%
side, consistent with postinflammatory hyperpigmentation. The in- imiquimod cream, and topical vitamin D analogues. Treatment with
flammation had completely cleared. In addition to improved skin le- oral retinoids has also proved beneficial, yet disease often recurs af-
sions, the patient reported complete resolution of associated pain, ter discontinuation of therapy.3 Destructive options more appro-
pruritus, and paresthesia. priate for local variants include excision, cryotherapy with liquid ni-
The patient was followed up at 3- to 6-month intervals for 2½ trogen, dermabrasion, and chemical peels. In addition, a variety of
years, during which her skin showed continued improvement. Ta- laser therapies and photodynamic therapy have shown variable ef-
crolimus treatment was tapered down to once-daily administra- ficacy. These destructive, surgical, and laser therapies are not suit-
tion to areas of postinflammatory hyperpigmentation and any new able for widespread disease, however, because they cause scarring
lesions, with betamethasone used only on new lesions. At 2½-year and pain. Because recurrence is common with the treatment op-
follow-up, the daily tacrolimus treatment was discontinued. At ex- tions currently available for disseminated disease, alternative thera-
amination, the patient’s skin was essentially back to baseline, with pies are necessary, and because several of the conventional treat-

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The Cutting Edge Clinical Review & Education

Figure 1. Linear Porokeratosis Before Successful Treatment Figure 2. Linear Porokeratosis After Successful Treatment

Examination at 2½-year follow-up showed long-term clearance of lesions after


treatment with tacrolimus, 0.1%, and betamethasone dipropionate, 0.05%,
ointments.

mal efficacy of topical pimecrolimus in a 25-year-old woman with


facial porokeratosis.4 Calcineurin inhibition results in downregula-
tion of T-cell activity and disturbance of cytokine transcription. Cur-
rently, topical calcineurin inhibitors are used to treat atopic derma-
titis by interrupting proinflammatory cytokines of the early immune
response and potentially acting on other cells important to the patho-
physiologic mechanism of this condition, such as dendritic cells, mast
cells, keratinocytes, basophils, and eosinophils.5
Treatment of porokeratosis with calcineurin inhibitors seems
contradictory because of the potent immunosuppressive action on
T cells, but a newly proposed pathophysiologic mechanism might
This case of linear porokeratosis was refractory to standard treatment methods explain the effectiveness of tacrolimus in porokeratosis. Low con-
(betamethasone dipropionate, 0.05%, ointment and oral acitretin). centrations of a calcineurin inhibitor, pimecrolimus, enhanced ex-
pression of activation markers of the innate immune system in hu-
man keratinocytes.6 Specifically, pimecrolimus enhances expression
ments for porokeratosis had been tried without success in our of cathelicidin, CD14, and human β-defensin 2 and 3 in response to
patient, we tried using a novel therapy. toll-like receptor 2/6 ligands.6 Keratinocytes rely on toll-like recep-
To our knowledge, there are no previous reported cases of suc- tors to detect breaches in the skin barrier and activate the innate im-
cessful treatment of any clinical variant of porokeratosis with a cal- mune response. Further results suggest that pimecrolimus can am-
cineurin inhibitor, such as tacrolimus. One report described mini- plify innate immune responses in keratinocytes.6 Therefore, we

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Clinical Review & Education The Cutting Edge

hypothesize that tacrolimus similarly amplifies the innate immune its rapid and dramatic response to tacrolimus. We hypothesize that
response in keratinocytes, prevents the proliferation of abnormal topical tacrolimus was the treatment primarily responsible for the
keratinocytes, and thus improves the lesions of porokeratosis. This resolution of her porokeratosis, given that her lesions had not pre-
may also explain why imiquimod leads to improvement of porokera- viously responded to betamethasone or acitretin monotherapy.
tosis by inducing inflammation through activation of toll-like recep- However, acitretin was still present in her body, and its role in asso-
tors. Because systemic immunosuppression potentially increases the ciation with betamethasone and tacrolimus cannot be deter-
risk of porokeratosis, this highlights the distinct regulation of in- mined.
nate and adaptive immunity. In conclusion, tacrolimus may be an effective and safe alterna-
This is the first report, to our knowledge, of linear porokerato- tive to conventional treatments for porokeratosis. However, con-
sis successfully treated with topical tacrolimus. The report is unique trolled studies with more patients and long-term follow-up are
because of both the linear appearance of our patient’s disease and needed to evaluate its true effectiveness.

ARTICLE INFORMATION REFERENCES 4. Lee Y, Choi EH. Exclusive facial porokeratosis:


Author Affiliations: Department of Dermatology, 1. Rahbari H, Cordero AA, Mehregan AH. Linear histopathologically showing follicular cornoid
University of Arkansas for Medical Sciences, Little porokeratosis: a distinctive clinical variant of lamellae. J Dermatol. 2011;38(11):1072-1075.
Rock. porokeratosis of Mibelli. Arch Dermatol. 5. Simpson D, Noble S. Tacrolimus ointments.
Corresponding Author: Ashley C. Parks, MD, 1974;109(4):526-528. Drugs. 2005;65(6):827-858.
Department of Dermatology, University of Arkansas 2. Sasson M, Krain AD. Porokeratosis and 6. Büchau AS, Schauber J, Hultsch T, Stuetz A,
for Medical Sciences, 4301 West Markham St, Slot cutaneous malignancy: a review. Dermatol Surg. Gallo RL. Pimecrolimus enhances TLR2/6-induced
576, Little Rock, AR 72205 (ashleycerone@gmail 1996;22(4):339-342. expression of antimicrobial peptides in
.com). 3. Goldman GD, Milstone LM. Generalized linear keratinocytes. J Invest Dermatol.
Accepted for Publication: September 10, 2013. porokeratosis treated with etretinate. Arch 2008;128(11):2646-2654.

Conflict of Interest Disclosures: None reported. Dermatol. 1995;131(4):496-497.

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