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| A Novel Case of Recalcitrant Juvenile Pityriasis Rubra Pilaris with
Response to Bexarotene |
| Andrew P. Word*, Mahir Patel and Alan Menter M |
| Baylor University Medical Center, Department of Dermatology, Dallas, TX, USA |
| *Corresponding author: |
Dr. Andrew P. Word
Department of Dermatology
Baylor
University Medical Center
Baylor Medical Pavilion, 3900 Junius St., Suite
145, Dallas, TX 75146, USA
Tel: 940-887-9158
Fax: 972-715-1469
E-mail: andrew.p.word@gmail.com |
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| Received September 23, 2011; Accepted November 02, 2011; Published November 06, 2011 |
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| Citation: Word AP, Patel M, Menter AM (2011) A Novel Case of Recalcitrant
Juvenile Pityriasis Rubra Pilaris with Response to Bexarotene. J Clin Exp Dermatol
Res 2:131. doi:10.4172/2155-9554.1000131 |
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| Copyright: © 2011 Word AP, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited. |
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| Abstract |
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| Pityriasis rubra pilaris (PRP) is generally treated with single or combination regimens of topical agents, systemic
retinoids, methotrexate, biologics, various other immunosuppressant agents, and light therapy; however, cases of
PRP that are not amenable to these therapies can be challenging to control. We present the case of a male with
biopsy-proven juvenile PRP followed for ten years, with failure to respond to all traditional treatment regimens.
Significant improvement in the patient's cutaneous and rheumatological symptoms occurred when the patient was
treated with bexarotene (Targretin®). To our knowledge, this represents the first reported successful treatment of PRP
with bexarotene. Thus, treatment with bexarotene may represent a beneficial option for cases of PRP recalcitrant to
traditional treatment modalities. |
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| Keywords |
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| Bexarotene; Pityriasis rubra pilaris; Targretin |
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| Abbreviations |
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| PRP: Pityriasis Rubra Pilaris |
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| What’s already known about this topic? |
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| . First-line systemic treatments of pityriasis rubra pilaris (PRP)
include retinoids and methotrexate, with various biologics and other
immunosuppressants used as second-line regimens. Phototherapy
may be used as monotherapy or in combination with these agents. |
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| What does this study add? |
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| . For cases of PRP recalcitrant to traditional therapies, bexarotene
(Targretin®) should be considered. |
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| Report of a Case |
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| A 6-year-old Caucasian male presented to our psoriasis clinic with
bilateral scaling and fissuring of the palms and soles and a persistent
rash involving the elbows, knees, and scalp present for over a year.
Prior topical therapies had little effect. The patient reported a strong
family history of pityriasis rubra pilaris (PRP) with both his father
and grandfather having a history of the disorder. On exam, there
was a moderate degree of scaling on the scalp and ears. Follicular
erythematous hyperkeratotic papules were noted on the elbows
and knees bilaterally. Most prominent was confluent inflammatory
hyperkeratosis of the palms and soles bilaterally with fissuring. |
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| Biopsies were performed on lesions of the patient's right posterior
axilla and right knee, confirming a diagnosis of PRP (Figure 1). Over
the ensuing years, the patient developed multiple erythrodermic
episodes covering major portions of his body surface area. |
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| For many years, the patient had been treated with a multitude of
systemic treatments, including isotretinoin, acitretin, methotrexate,
cyclosporine, prednisone, etanercept, adalimumab, and efalizumab.
All regimens provided only mild relief of cutaneous symptoms. The
patient also developed joint pain and stiffness, especially of the fingers,
wrists, knees, and ankles. Additionally, the patient was seen by a growth
specialist and was shown to have a bone age of seven years when he was
eleven years old. The psychological effect of the patient's unremitting
disorder led to development of depression, insomnia, and ultimately,
a threatened suicide attempt. After approximately seven years of
these multiple failed treatment regimens, the patient was started on
bexarotene (Targretin®). |
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| At follow-up after two years of continuous bexarotene treatment,
the now 16-year-old patient's cutaneous condition had improved
dramatically. The severity and frequency of erythrodermic flares and
joint complaints had decreased. Relative to previous exams, a decrease
in hyperkeratosis and scaling of the patient's scalp were noted.
Erythematous plaques with scaling and islets of sparing were noted
on the patient's trunk, back, and upper and lower extremities (Figure
2). There was also a significantly reduced hyperkeratosis of the hands
(Figure 3a and Figure 3b) and feet bilaterally, leading to significant
improvement in his quality of life relating to daily activities. In addition
to these improvements of his PRP signs and symptoms, the patient had experienced dramatic changes in his confidence and outlook on life.
The patient continues on bexarotene treatment. |
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Figure 1: Biopsy from area of involvement on patient’s back showing classic
horizontal and vertical alternations of orthokeratosis and parakeratosis. |
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Figure 2: Erythematous plaques with overlying scale on patient’s back, with
“island of sparing.” |
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Figure 3: Palms before and after bexarotene treatment. A) Before treatment,
confluent inflammatory hyperkeratosis with sparse fissuring. B) After treatment,
reduced hyperkeratosis without fissuring or inflammation. |
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| Discussion |
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| Pityriasis rubra pilaris (PRP) is a rare inflammatory papulosquamous
disorder of unclear etiology [1,2]. PRP occurs in three distinct peaks,
during the first decade, second decade, or in adulthood (40-60 years)
[1,3]. Most commonly, PRP develops as an acquired disorder [1,3];
however, it has been estimated that, as in our case, 6.5% of PRP cases
are due to familial inheritance [1]. The inheritance pattern is generally
autosomal dominant with variable expressivity, though an autosomal
recessive pattern has also been reported [3]. |
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| Various hypotheses explaining the pathophysiology of PRP have been proposed. PRP has been reported in association with various
malignancies, immunologic abnormalities infections, and trauma [1-4].
When associated with such inciting events, PRP may develop because
of an abnormal immune response elicited against an antigenic trigger
[3-4]. Because of the efficacy of retinoids in treating PRP, vitamin A
and retinol binding protein deficiencies have been postulated to play a
role in PRP [1-4]. These proposed mechanisms have yet to be validated. |
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| There are well-described characteristic clinical findings of PRP that
aid in its diagnosis. Follicular hyperkeratosis with an erythematous
background and islands of skin sparing are key features of PRP [1-6]. Follicular keratotic papules have a characteristic "nutmeg grater"
roughened surface [1-3] and commonly develop on the trunk,
extremities, and dorsa of the fingers. Coalescence of papules may
occur, leading to plaques with overlying scale. PRP generally begins on
the face and scalp of adults while the lower body is typically involved
initially in children [2]. When palms and soles become involved, an
orange-red waxy keratoderma is present, oftentimes with associated
fissuring. Scaling of the scalp and nail changes are also common in
PRP. Rheumatologic associations have been reported with PRP, with
seronegative arthritis and dermatomyositis being the most commonly
associated disorders [6]. Patients with PRP, especially children, may
also experience psychosocial issues because of the stigmatizing nature
of their disorder as was seen in our patient. |
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| Histopathology is helpful in confirming a diagnosis of PRP,
especially when differentiating from psoriasis. Nonfollicular lesions
may demonstrate alternating orthokeratosis and parakeratosis in
vertical and horizontal directions (e.g., "checkerboard pattern"),
hypergranulosis, thick suprapapillary plates, narrow dermal papillae,
broad rete ridges, and sparse lymphocytic perivascular infiltrate [1,4,5].
Follicular lesions also show dilated hair follicles with follicular plugging
by cornified cells and irregular acanthosis [1,5]. Parakeratosis may be
present on both sides of the plugged follicle, a situation referred to as
"shoulder parakeratosis" [2]. |
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| PRP has been categorized into six categories by the age of
occurrence and clinical presentation, which are summarized in (Table
1). The most common form of PRP, occurring in approximately 55%
of affected individuals and presenting with classic clinical findings,
is classical adult (type I) PRP. Atypical adult (type II) PRP follows a
chronic course and is characterized by ichthyosiform scale of the legs,
areas of dermatitis, keratoderma of the palms and soles with lamellated
scaling, and areas of alopecia [1,2,4]. Classical juvenile (type III) PRP
presents very similarly to type I PRP and generally affects children of
five to ten years of age [1,2]. Juvenile circumscribed (type IV) PRP is
the most common form of PRP in the juvenile population and presents
as discrete areas of follicular hyperkeratosis with keratotic plugging,
most often occurring on the knees and elbows [1,2]. Atypical juvenile
(type V) PRP is marked by follicular hyperkeratosis and keratoderma
[1,2]. HIV-associated (type VI) PRP can be the initial manifestation
of an HIV infection with associated acne conglobata and hidradenitis
suppuritiva [2]. Inherited forms of PRP are most commonly reported
as types II and V PRP; both are atypical in presentation and the only
forms of PRP that generally follow a chronic course. Our patient likely
falls into the PRP type V classification. |
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Table 1: Modified Griffiths classification of PRP (adapted from Klein et al. [2] and Chan et al. [3]). |
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| Because of the uncommon nature of PRP and its unknown etiology
and spontaneously remitting nature, treatment is largely empiric,
with efficacy often difficult to assess. Methotrexate, TNF-α inhibitors,
azathioprine, cyclosporine, systemic corticosteroids, stanozolol (a
testosterone-derived anabolic steroid), systemic and additive UV
therapy, and various topical applications have shown varying degrees of efficacy [1,2]. Retinoids, derivatives of vitamin A, affect growth and
differentiation of epithelial tissues [2,7] and significantly decrease the
hyperkeratosis [2]. Thus, oral retinoids, especially isotretinoin and
etretinate, have become the mainstay of PRP treatment. |
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| Retinoids enact their effects by binding to two subfamilies of
receptors: retinoid acid receptors (RARs) and retinoid X receptors
(RXRs) [7]. There are three subtypes in each subfamily, specifically
RARa, RARb, RARg, and RXRa, RXRb, and RXRg [8]. Each retinoid
shows specific affinity and activation for the retinoid receptor
subtypes, representing receptor-ligand specificity [8]. These
receptors homodimerize and bind DNA to affect the function of
genes downstream of retinoid acid response elements (RAREs) [7].
Additionally, RXRs have the unique capacity to heterodimerize with
other classes of nuclear receptors, including RARs, vitamin D receptor
(VDR), thyroid receptor (TR), and peroxisome proliferation activating
receptors (PPARs) [8,9]. Therefore, retinoids that bind RXRs, also
known as "rexinoids," can affect a variety of cellular pathways. |
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| There are different expression patterns of retinoid receptors
throughout the body. In the skin, there are five times as many RXRs
as there are RARs [8]. Here, RXRa is the predominant subtype, with
RARg also highly expressed [8]. Thus, gene expression resulting from
RXRa-RARg heterodimerization is thought to be a major way in which
rexinoids enact their effects in the skin [8]. Additionally, VDR is also
highly expressed in the skin, making RXR-VDR heterodimerization
and its effects another important product of rexinoid treatment [8]. |
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| Bexarotene is a novel synthetic oral rexinoid that has been used
predominantly for cutaneous T-cell lymphoma and non-small cell lung
cancer therapy. Bexarotene differs from older synthetic retinoids, such
as isotretinoin and etretinate, which only activate the RAR pathway
[7,10], in that it possesses approximately 100 times the potency for
activating RXRs as compared to RARs [11]. It can activate all three
RXR subtypes [8]. Bexarotene is capable of suppressing cell growth
through interactions with a multitude of growth-regulatory pathways,
including cyclin D1, Cox-2, AP1, IGF-BP6, and RARb [12]. This
rexinoid is especially promising as an antineoplastic agent because
of its efficacy in inhibiting cell cycle progression, angiogenesis, and
metastasis, as well as inducing apoptosis and cell differentiation [7].
Pertinent to hyperproliferative cutaneous conditions, bexarotene has
antikeratinizing activity as a topical agent and has been shown to cause
thinning of the stratum corneum in the rhino mouse model [8]. It has
also been hypothesized that bexarotene decreases inflammation through
interaction with PPARs, which may reduce inflammatory cytokine
expression [8,9]. Bexarotene can also inhibit T-cell accumulation in
CTCL [8]. |
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| As with all retinoids, side effects of bexarotene, including liver
toxicity, alopecia, and mucocutaneous issues, often warrant dose
reduction or discontinuation of treatment [1,2]. Additionally, bexarotene treatment carries a significant potential of developing
hypertriglyceridemia, hypercholesterolemia, and hypothyroidism
[13]. These events can be managed with careful dosing of
bexarotene and concomitant treatment with lipid-lowering agents
for hypertriglyceridemia and hypercholesterolemia and thyroxine
for hypothyroidism [13]. Leukopenia has also been reported more
frequently with bexarotene treatment than with other retinoids [14]. |
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| Our patient presented with severe, recalcitrant atypical juvenile
(type V) PRP of ten years' duration with associated arthritis. Though no
other combinations of various systemic and topical regimens resulted
in significant clinical improvement, our patient showed significant
improvement in cutaneous, rheumatological, and psychological aspects
of the disease after treatment with bexarotene. To our knowledge, no
other cases of any form of PRP, with or without associated arthritis, have
been treated to date with bexarotene. Considering the aforementioned
discussion of its mechanisms of action, it can be concluded that, when
compared to older retinoids, bexarotene's more potent antineoplastic,
anti-keratinizing, and anti-inflammatory characteristics make it a more
effective option for the treatment of severe cutaneous proliferative and
inflammatory rheumatologic symptoms of PRP, as in our patient.
This case is presented to highlight that bexarotene has the potential to
provide a beneficial therapeutic option for cases of PRP that are chronic
in duration, recalcitrant to other systemic medications, or associated
with rheumatologic abnormalities. |
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| References |
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