American Journal of Clinical Dermatology

, Volume 11, Issue 3, pp 157–170 | Cite as

Pityriasis Rubra Pilaris

A Review of Diagnosis and Treatment
Review Article Pityriasis Rubra Pilaris

Abstract

Pityriasis rubra pilaris (PRP) is a rare inflammatory dermatosis of unknown etiology, and finding a successful therapy can be challenging. PRP occurs equally in men and women. In some patients, associated autoimmune diseases, infections, or malignancies are possible trigger factors. PRP shows a bimodal age distribution, peaking in the first as well as in the fifth to sixth decade. Its classification into five subgroups is based on age at onset, clinical course, morphologic features, and prognosis. More than 50% of patients are best classified as type I with adult-onset PRP. This form is also characterized by high spontaneous remission rates (80%) within 1–3 years. Clinically, the classical adult (type I) and classical juvenile (type III) forms appear to be the same except for the patient’s age. Recently, the designation of a new category of PRP (type VI) has been proposed that is characterized by the presence of HIV infection with different clinical features and a poorer prognosis. Typical morphologic features of PRP are erythematosquamous salmon-colored plaques with well demarcated islands of unaffected skin. Often, keratoderma of the palms and soles is present. In patients with extensive disease, ectropion is a dreaded complication. Histology shows hyperkeratosis, alternating orthokeratosis and parakeratosis in a checkerboard pattern, and focal acantholytic dyskeratosis.

Descriptions and therapeutic experiences are mainly based on case reports. Mostly, systemic retinoids, methotrexate, and other immunosuppressive agents as well as UV light therapy are applied, with varying response rates. In recent years, treatment with so-called ‘biologics’ is becoming more and more popular for treating recalcitrant PRP.

We present a review of the clinical features, histopathologic findings, classification, differential diagnoses, and treatment of PRP.

Alphonse Devergie, a professor of dermatology in Paris, called this rare papulosquamous disorder ‘pityriasis pilaris’ for the first time in 1856.[1] Besnier[2] finally classified the disease as pityriasis rubra pilaris (PRP) when describing several cases in 1889. PRP is an idiopathic uncommon disorder of cornification characterized by follicular and palmoplantar hyperkeratosis and orange-red scaling plaques. The disease is subclassified into six types including both hereditary and acquired forms.[3] PRP affects both sexes similarly. It is seen in about 1 in 5000 new patients with skin disease in Great Britain.[4] In the US, a similar incidence of 1 in 3500–5000 patients presenting in dermatologic clinics has been reported.[5] There do not seem to be any geographic areas with high disease rates or racial groups with an abnormally high incidence of disease.

The differential diagnosis between PRP and psoriasis is often difficult, both clinically and histopathologically. In particular, hyperkeratosis, parakeratosis, and acanthosis are histologic features present in both PRP and psoriasis. Transitions from plaque psoriasis to PRP and vice versa have been observed in adult patients.[6]

Data for this review were identified by searches of MEDLINE, PubMed, and reference lists by means of the search term ‘pityriasis rubra pilaris’ up to January 2010.

1. Diagnosis

PRP often poses diagnostic problems, as it is commonly confused with other papulosquamous and erythrodermic disorders, particularly psoriasis. Diagnosis can only be confirmed by clinical presentation and histologic examination; no typical serologic markers exist for PRP.

1.1 Clinical Presentation

The clinical course of PRP is highly variable. The classic description of PRP found in the literature is of the most common type I PRP, with follicular hyperkeratosis as the elementary lesion.[7] Follicular keratotic papules or plaques may coalesce to form erythematous or salmon-colored plaques that develop scales (figure 1). A widespread distribution of lesions over the entire body is possible, and these are often accompanied by itching. Erythroderma may develop, representing a dreaded complication. The reported incidence of erythroderma varies considerably. Allison et al.[8] reported 17% of 30 children with PRP (mainly type III) developing erythroderma, whereas Dicken[9] stated that PRP “almost always progresses to a generalized erythroderma.” Albert and Mackool[10] reported that PRP frequently progresses to exfoliative erythroderma. However, Piamphongsant and Akaraphant[11] studied 168 people of Thai origin with PRP and found only 14 of those patients presenting with erythroderma. Therefore, specifications about the overall frequency of erythroderma in PRP or the variability among different subtypes are difficult.
Fig. 1

Pityriasis rubra pilaris in a 60-year-old woman: (a) with a widespread orange-tinged erythema and islands of non-involved skin known as ‘nappes claires;’ and (b) hyperkeratotic follicular papules on the forearm.

In adults, PRP typically starts on the face and scalp and spreads in a caudal direction, whereas in juvenile patients, the disease usually begins on the lower half of the body.[12] Intervening areas of uninvolved skin known as ‘islands of sparing’ or ‘nappes claires’ also represent a characteristic feature of PRP.[10] The papulosquamous rash may involve the oral mucosa.[13,14] The changes consist of white spots and lines, pale blue lines, and erythematous lesions covered with white streaks that affect the buccal mucosa, gingivae, and tongue. Lesions might resemble lichen planus, and patients may report pain and irritation of the tongue.

Palms and soles become hyperkeratotic and develop an orange hue. This condition is often painful when fissures develop (figure 2). Lymphadenopathy may occur if the cutaneous surface is affected to a large extent. Scaling is rather fine and powdery (pityriasiform) on the face and scalp and coarser on the lower half of the body. Follicular hyperkeratosis is often present, particularly on the dorsal aspects of the hands and fingers. Nail findings in PRP include thick nail plates with a rough surface or distal crumbling, yellow-brown discoloration, and subungual debris. In the case of prolonged facial erythroderma, ectropion may develop. Other ocular complications include peripheral ulcerative keratitis, corneal perforation, and dry eyes.[15] Features of PRP types other than type I are described in section 1.3.
Fig. 2

Palmar (a) and plantar (b) keratoderma with a prominent orange-yellow coloration.

1.2 Histologic Findings

Clinically, it may be difficult to distinguish PRP from psoriasis. Therefore, histopathologic examination remains an essential diagnostic criterion. Histologically, PRP shows an acanthotic epidermis with alternating orthokeratosis and parakeratosis in both vertical and horizontal directions. Focal or confluent hypergranulosis as well as thick suprapapillary plates and broad rete ridges are other helpful diagnostic features. Hair follicles are dilated, and a keratotic plug is present. An occasional distinctive change is ‘shoulder parakeratosis,’ in which parakeratosis is present adjacent to both sides of the keratin-plugged follicle. Superficial perivascular and perifollicular infiltrate of lymphocytes and macrophages is often present in the underlying dermis (figure 3). Microscopic examination of oral PRP shows features of nonspecific mucositis with inflammatory infiltrates, which are mainly composed of lymphocytes.[14] However, Kurzydlo and Gillespie[13] observed a thickened epithelium with acantholysis and dyskeratosis in a buccal biopsy.
Fig. 3

Skin biopsy showing alternating vertical and horizontal parakeratosis (‘checkerboard pattern’) and irregular hyperkeratosis, epidermal acanthosis, follicular plugging, a thin stratum granulosum, and lymphohistiocytic perivascular infiltrate in the underlying dermis typical for pityriasis rubra pilaris (hematoxylin and eosin stain, magnification ×20).

Braun-Falco et al.[16] conducted histologic, histochemical, and electron microscopic investigations in five patients with type I PRP and compared the results with findings in psoriasis vulgaris. PRP and psoriasis shared regular epidermal hyperplasia and hyperkeratosis. The stratum granulosum was partly thickened and always present in PRP but absent in psoriasis (figure 4). Vascular ectasia of the dermal papillary capillaries was seen in both PRP and psoriasis; however, the degree of vascular dilatation was significantly higher in psoriasis than in PRP. Both skin disorders showed inflammatory dermal infiltrates, which, in PRP, exclusively consisted of lymphocytes and monocytes. In contrast to psoriasis, polymorphonuclear leukocytes and Munro microabscesses were always absent in PRP. Irregular acanthosis seemed to be less pronounced in PRP than in psoriasis, and a moderate spongiosis could be occasionally observed. In contrast to psoriasis, enzyme histochemical investigations found the upper parts of the horny layer to be acid-phosphatase-negative in PRP, indicating orthokeratotic cornification. However, disturbances of the process of keratinization are suggested. Electron microscopy found decreased amounts of tonofilaments in the stratum granulosum of PRP skin, but an increased number of keratinosomes and a normal amount of keratohyalin granules. In pathologic disorders with disturbed keratinization, such as psoriasis, tonofilaments and keratohyalin granules are diminished.
Fig. 4

Skin biopsy of psoriatic skin showing hyperkeratosis, epidermal acanthosis, and papillomatosis with absence of the stratum granulosum. There is edema of the stratum papillare, and dilated capillaries with perivascular infiltrate. Intracorneal Munro microabscesses are pathognomonic for psoriasis (hematoxylin and eosin stain, magnification ×20).

Karneva et al.[17] investigated histologic changes of PRP under retinoid therapy. Electron microscopic features of PRP included decreased numbers of keratin filaments and desmosomes, enlarged intercellular spaces, parakeratosis with lipid-like vacuoles and a large number of lamellar granules, and a focal split of the basal lamina at the dermoepidermal junction. In four patients, treatment with etretinate led to a reduction of hyperkeratosis, whereas all other histologic signs of PRP persisted despite apparent clinical improvement. However, compared with untreated PRP, the number of cell organelles per keratinocyte decreased, indicating decreased cell activity.

Acantholytic foci have been reported several times in PRP with or without dyskeratosis.[18, 19, 20, 21] It remains unclear whether the concomitant finding of histologic features of both PRP and focal acantholytic dyskeratosis is incidental or whether it is a rare but definite histologic change in PRP. However, Magro and Crowson[22] found acantholytic dyskeratosis in 25 of 32 biopsies of PRP, which suggests that its presence is an important distinguishing feature of PRP. Many of the biopsies showed a significant dermal inflammatory infiltrate, which contained eosinophils and plasma cells resembling delayed-type hypersensitivity reactions. An abnormal immunologic response to antigenic triggers might thus be of pathogenetic importance. Other histologic features predictive of PRP versus psoriasis included an increased granular layer, follicular plugging, and the absence of psoriatic capillary alterations as already described by other authors.[23,24] All these findings indicate that PRP can be histologically distinguished from psoriasis.

1.3 Classification

In 1980, Griffiths[3,4] proposed five categories to classify PRP depending on age at onset, clinical course, and prognosis, and added a sixth category some years later. These categories are summarized in table I. In a group of 93 patients with PRP, 55% belonged to the classical adult type I PRP.[12] The classical adult-onset PRP usually starts with an erythematous macule on the upper half of the body. Within several weeks or a few months, further patches and follicular papules appear and coalesce in many areas of the trunk. The widespread yellow-orange erythema typically shows islands of spared skin. Erythroderma is a dreaded complication. Palmoplantar keratoderma is marked by a prominent orange-yellow color and appears usually within weeks or a couple of months, as does nail involvement. At its height, type I PRP is frequently accompanied by ectropion. This form of PRP carries the best prognosis. Despite the severe and often disabling course of the disease, more than 80% of these patients experience remission within 3 years.
Table I

Classification of pityriasis rubra pilaris (PRP) according to Griffiths[3,4]

Atypical adult type II PRP, which affects about 5% of PRP patients, is characterized by a long duration of 20 years or more as well as by atypical morphologic features. Clinical presentation resembles ichthyosis vulgaris, and patients may present with sparseness of the scalp hair. Palmoplantar hyperkeratosis is coarse and shows lamellated scales.

Classical juvenile type III PRP affects 10% of PRP patients and seems to be the counterpart of type I PRP with the age of onset as the only difference. Nevertheless, its clinical course is more favorable in children than in adults, since spontaneous clearing may be seen after 1 year. The onset of this form is usually between the ages of 5 and 10 years.[25]

Circumscribed or type IV PRP occurs in up to 25% of PRP patients, affecting prepubertal children and young adults. This type of PRP is characterized by well demarcated areas of erythema and follicular hyperkeratosis that predominantly appear on the knees and elbows, with less patchy erythema elsewhere. Palmoplantar involvement is characteristic of this subtype but it may also be absent.[26] The eruption is localized and does not progress into the widespread classical form. The 3-year remission rate of 32% for this subgroup is significantly less than that of classical adult PRP. The disease can be quite mild and localized, but the clinical course can also be marked by remissions and exacerbations. Gelmetti et al.[27] studied 29 children with PRP and proposed another classification, distinguishing type IV PRP on the basis of its duration: its acute form resolves in 6 months and the intermediate form in 1 year; the chronic form lasts for >1 year and may progress into an erythrodermic form (types I and III).

Atypical juvenile type V PRP occurs in up to 5% of patients and is characterized by an early age of onset and a chronic course.[28] It manifests as predominantly hyperkeratotic follicular lesions and shows ichthyosiform features. Some patients develop scleroderma-like changes on the palms and soles. Most cases of familial PRP belong to this category, whereas type III PRP with a positive familial background is reported in the literature.[12] Thomson and Moss[29] described a mother with type I PRP and her two daughters with type V PRP.

Miralles et al.[30] proposed a new type VI subset for HIV-associated cases, as these patients present with different clinical features and have a poorer prognosis than patients with type I PRP. PRP might be the initial manifestation of an HIV infection. It generally starts with erythematous desquamating follicular papules and prominent plugging distributed symmetrically over extensor body surfaces. Here, prominent follicular plugging with formation of spicules, which are rather uncommon in type I PRP, is a common finding. Involvement of nails, palms, and soles is highly variable or may be absent. Erythroderma is a frequent complication, also with typical islands of uninvolved skin. Unlike in type I PRP, plugs and spicules have little tendency to disappear. HIV-associated PRP can be associated with lesions of acne conglobata, hidradenitis suppurativa, and lichen spinulosus. Thus, this entity could be summarized under the term HIV-associated follicular syndrome.[31, 32, 33] Antiretroviral therapy may result in a complete response but relapses are frequent.

Not every case of PRP can be assigned with certainty to a specific type because of the possibility of intermediate forms and transitions from one type to another. Shahidullah and Aldridge[34] reported a child presenting with type III classical juvenile-onset PRP, who later developed type IV PRP. Furthermore, the percentage of different types of PRP is inconsistent. In a study of 30 children with PRP, 57% had type III classical PRP and 33% type IV circumscribed juvenile PRP.[8] The classical adult and juvenile types of PRP show great similarity and have the same disease processes that are arbitrarily divided according to the patient’s age at onset.[35] A further question is whether atypical adult PRP and the atypical juvenile form are truly PRP or present a more heterogeneous group of follicular ichthyosiform disorders.[36] A new classification was proposed by Piamphongsant and Akaraphant[11] in a study of 168 PRP patients of Thai origin (64 adults and 104 children aged ≤15 years). As they could not classify a residual group of their patients into any of Griffiths’ five or six types, they proposed a new classification of four types based only on physical (morphologic) findings. More than 50% of their patients belonged to the group presenting with palmoplantar keratoderma, circumscribed scaly erythematous patches on elbows and knees, and follicular plugging in the patches when first seen. However, PRP may present differently in patients of Thai origin compared with patients of Caucasian origin. To date, Griffiths’ classification into five or six well recognized groups remains the standard form for most studies.

1.4 Pityriasis Rubra Pilaris in Children

As described in section 1.3, children may present with type III, type IV, or type V PRP. In juvenile patients, PRP tends to start on the lower half of the body. In a series of 93 patients, children made up 45% of PRP patients,[12] and type IV circumscribed juvenile PRP was the most commonly observed type. Other authors reported the classical juvenile form (type III) to be the most common form of PRP.[8] Onset of the condition is gradual in the familial type and rapid in the acquired types. In children, hair and teeth are usually unaffected, but involvement of the mucous membranes has occasionally been observed.[25] The classical juvenile PRP histology is similar to that of classical adult PRP.

In 1983, Larrègue et al.[37] described a specific form of PRP with acute evolution in children and called it juvenile acute pityriasis rubra pilaris (JAPRP). According to Griffiths’ classification,[3,4] this form may be considered a reactive exanthema and as a subtype of type III PRP. JAPRP differs from other PRPs in its acute onset and self-limiting course.[38] Mediation of superantigens has been suggested as a possible trigger mechanism. In particular, preceding streptococcal infections and their bacterial toxins acting as superantigens seem to play a causative role.[39] JAPRP is initially seen as scarlatiniform erythema, followed by the appearance of follicular papules that may generalize. A desquamation period of 2–3 months is followed by complete resolution. Recurrences with nearly identical skin lesions may be provoked by new infections with the same bacteria.[39]

In a group of 42 neonates presenting with erythroderma, one infant had underlying PRP.[40] Ina study of PRP in 30 children by Allison et al.,[8] 17% had erythroderma, 13% had ectropion, and 33% had involvement of the nail plate. Palms, soles, and elbows were the most commonly affected sites. Recurrence rates of PRP have rarely been reported. Allison et al.[8] reported a 1-year recurrence rate of 17% in children with PRP who received treatment with isotretinoin, etretinate, and vitamin A (retinol). A 7-year-old boy with PRP showed complete clearing of skin lesions after 18 months of treatment with etretinate 10 mg daily and a relapse 15 years later. The eruption developed on the previous sites after an episode of acute gastroenteritis. After receiving etretinate 35 mg daily, he had complete resolution of the skin lesions 8 months later.[41] A possible association between HIV and PRP was also suggested by Menni et al.,[42] who reported a 4-year-old boy with diffuse palmar hyperkeratosis and hyperkeratotic plaques after an acute bronchopulmonary infection because of an altered immunologic status. Particularly in children, preceding infections and fever seem to play a pathogenic role.

Depending on age, possible treatments for PRP in children include retinoids, vitamin A, methotrexate, and azathioprine (see section 3). The tendency to relapse seems to be more common in juvenile PRP.[7] However, the prognosis seems to be more favorable in children, as Gelmetti et al.[27] reported a cure rate of 90% within 3 years.

1.5 Differential Diagnoses

PRP presenting as erythroderma frequently poses difficulties in establishing the diagnosis. On the other hand, diagnosis can be made with high certainty in the case of typical clinical features. However, PRP is often confused with psoriasis, particularly in the early stages. Here, histopathologic findings, clinical course, age at onset, and family history are useful diagnostic criteria. A poor response to phototherapy rather supports the diagnosis of PRP. Differential diagnoses of erythrodermic PRP include psoriasis, seborrheic dermatitis, T-cell lymphoma, erythroderma progressiva symmetrica, erythrokeratoderma variabilis, follicular eczema, follicular ichthyosis, generalized hypersensitivity reaction, and lichen planopilaris.[16,43] Localized forms of the disease, which can appear in type IV PRP, might be confused with Darier disease, pemphigus foliaceus, Grover disease,[22] or epidermal nevus.[26]

Particularly in children, in whom PRP may follow bacterial infection, differential diagnoses of JAPRP include streptococcal and staphylococcal scarlet fever, staphylococcal scalded skin syndrome, and Kawasaki disease.[38] Further common false diagnoses in children include Netherton syndrome, psoriasis, ichthyosis, and atopic dermatitis.[44]

2. Etiology and Associated Conditions

The etiology and pathogenesis of PRP remain unknown. A few possible mechanisms are considered in the literature, such as abnormal vitamin A metabolism in the skin, association with autoimmune diseases, internal malignancies, or infections, particularly HIV. Most patients have the acquired type, although familial forms of the disease with autosomal dominant inheritance have been described.[28,29] However, autosomal recessive inheritance has also been recorded;[45] thus, family history seems to be of minor importance. Acquired PRP peaks in the fifth or sixth decade of life, whereas familial PRP usually develops during childhood.[45]

Immunocytochemical or biochemical analyses of skin biopsy specimens are rarely conducted. Vanderhooft and Francis[28] performed these analyses in three of four individuals from one family and showed abnormal keratins with K6/16 expression and the possibility of an abnormal K14 and K16 by immunoblot analysis. Furthermore, immunohistochemistry showed suprabasal staining with monoclonal antibody AE1 (acidic keratins). These alterations are rather nonspecific findings that are often associated with abnormal epidermal differentiation. However, the presence of a 45 kD acidic keratin (most likely K17) not normally expressed in the epidermis may be related to the pathophysiology of PRP. Baran et al.[46] found increased p53 expression in PRP skin in comparison with the skin of healthy volunteers. p53 is a phosphoprotein induced by DNA damage that leads to cell cycle arrest and apoptosis in the case of ineffective DNA repair. The authors suggested that the cell cycle is disturbed in PRP epidermis, resulting in enhanced p53 expression.

Another postulated biochemical marker for PRP is defective synthesis of retinol-binding protein (RBP), a specific carrier protein of vitamin A. The RBP level was significantly lower in 11 patients with PRP than in the control group of healthy subjects.[47] The serum level of vitamin A is often normal in patients with PRP, and therapeutic administration of high doses of vitamin A is almost always ineffective.[48] In another study by Karneva et al.,[17] RBP and vitamin A levels were normal in three patients and remained unchanged during treatment with etretinate. Magro and Crowson[22] proposed that an abnormal immune response to certain antigens may interfere with epidermal retinoid signaling pathways and disrupt keratinocyte terminal differentiation.

The significance of associated infections, malignancies, or autoimmune disorders remains unclear. PRP has been observed after various infections and trauma, but most cases occur without any obvious preceding event.[10] Möhrenschlager and Abeck[39] described two children developing PRP shortly after streptococcal infection, which resolved spontaneously within several months. Bacteria-derived superantigens may play a causative role in triggering PRP in children. Reports[37,38] of an acute exanthematic form of juvenile PRP following an upper respiratory tract infection support the latter hypothesis. Here, PRP initially presented with features reminiscent of Kawasaki disease (e.g. widespread scarlatiniform erythema, swelling of the hands and feet, and mucous membrane involvement). Therefore, an immune system dysregulation with an abnormal response to antigenic triggers might be causative.[10,38] Other possible infectious triggers of PRP include cytomegalovirus[49] and varicella zoster virus.[50] Several cases of HIV-infected patients with PRP have been reported,[30, 31, 32,51] some with PRP as the first manifestation of infection.[52] Given its association with HIV and its response to antiretroviral therapy, a pathogenic role for HIV has been proposed.[30,53] Follicular inflammation secondary to infection of the follicle hair bulge by HIV was suggested by Misery et al.[53] An association of PRP with common hypogammaglobulinemia may result in chronic secondary bacterial infections of the skin.[54] Shvili et al.[55] recorded enhanced spontaneous activity of T-suppressor cells with an impairment of T-helper functions in a 6-year-old child with PRP. Circumscribed juvenile-onset PRP was recorded in two patients with Down syndrome, one of whom also had vitiligo.[56,57] A further patient with Down syndrome developed type III PRP at the age of 15 years.[58]

Several reports of PRP are associated with malignancies, including renal cell carcinoma,[59] Merkel cell carcinoma and multiple squamous cell carcinomas,[60] adenocarcinoma,[61] bronchogenic carcinoma,[13] hepatocellular carcinoma on a background of hepatitis C and cirrhosis,[62] laryngeal carcinoma,[63] metastases of the liver,[64] and other cutaneous malignancies.[21] Cutaneous malignancies in particular seem to be more aggressive when associated with PRP. A patient with a 5-year history of PRP developed metastatic Merkel cell carcinoma and, some months later, multiple rapidly growing squamous cell carcinomas.[60] Another patient with PRP developed multiple forms of cutaneous malignancy including Kaposi sarcoma, malignant melanoma, and multiple basal cell carcinomas.[21] Curing the neoplasm might improve PRP but, in some cases, PRP improved despite the deterioration of the malignancy. However, PRP and malignancies may occur coincidentally. A coincidence might be assumed for a patient with PRP preceding the diagnosis of a bronchogenic carcinoma after a long-standing smoking history.[13]

Eruptive seborrheic keratoses may appear in conjunction with erythrodermic flaring of PRP and involute and fall off on resolution of the erythroderma.[65,66] Cohen and Prystowsky[67] also reported prominent seborrheic keratoses in two patients with PRP, but no evidence was found for an underlying internal malignancy (Leser-Trélat sign). Further benign cutaneous disorders, including sebaceous and eccrine glandular disease, hidradenitis or dermatitis herpetiformis, as well as autoimmune diseases, such as lupus erythematosus and dermatomyositis, have been described in association with PRP.[7]

PRP has been reported to be accompanied by arthropathy.[68, 69, 70, 71, 72] While most PRP patients had associated seronegative arthritis,[69, 70, 71] Nakafusa et al.[72] described a patient with a rheumatoid factor that became positive. However, criteria for rheumatoid arthritis according to the American College of Rheumatology were not fulfilled. Some patients showed a clinical correlation between PRP and arthritis, and PRP as well as joint symptoms were observed to disappear with etretinate therapy.[69] Interestingly, one patient with PRP and rheumatoid arthritis showed dramatic improvement of joint symptoms with tumor necrosis factor (TNF)-α blockade (p55 TNFα receptor immunoadhesin), but his skin symptoms remained unchanged.[70] Thus, the role of TNFα in the pathogenesis of PRP remains unclear. However, clinical course and serologic findings in patients with PRP and arthropathy are rather non-homogeneous; thus, further studies are needed to show possible associations. Gül et al.[73] reported a case of PRP coexisting with both seronegative arthritis and autoimmune thyroiditis. As arthropathy is a typical complication in psoriasis, inflammatory processes attacking the bones may also play a role in PRP.

Dermatomyositis may present with atypical cutaneous involvement similar to PRP. This syndrome variant is also known as Wong dermatomyositis and PRP lesions may occur simultaneously, before, or after myositis. Histopathology shows features typical for PRP.[74,75] In the literature, about 20 cases of PRP-like eruptions have been reported in patients with dermatomyositis.[76] However, the pathophysiologic background remains to be elucidated. Another reported association of PRP is autoimmune hypothyroidism,[77,78] with thyroid hormone replacement allowing a rapid and complete remission of PRP. As thyroid hormone deficiency inhibits the transformation of carotene to vitamin A, and a disorder of vitamin A metabolism has been suggested in PRP, it may be responsible for the occurrence of PRP in these patients.

3. Therapy

PRP is often resistant to both topical and systemic therapies. Since spontaneous remission may occur in PRP, evaluating the true therapeutic value of any agent is difficult. Because of the relative rarity of PRP, it is difficult to conduct randomized, double-blind, placebo-controlled studies assessing treatment options. No randomized, controlled trials on PRP have been published in the literature, only case reports and case series. An overview of possible topical and systemic treatments in juvenile and adult PRP is given in table II.
Table II

Treatment of pityriasis rubra pilaris (PRP)

3.1 Topical Treatment

Topical treatment is often used in combination with systemic therapy to reduce the adverse effects of the latter. Topical therapy for PRP includes topical corticosteroids, keratolytics, emollients, tar, calcipotriene (calcipotriol), and topical tretinoin cream. Gregoriou et al.[81] successfully treated a young man with PRP on the scalp and face with pimecrolimus 1% cream. A 12-year-old girl with type IV PRP, unresponsive to topical corticosteroids and pimecrolimus cream, had complete and sustained resolution of all skin lesions with tazarotene gel 0.1% within 6 weeks of treatment.[44] Topical corticosteroids led to complete resolution in three juvenile patients with type III and type IV PRP.[79] In a study by Allison et al.,[8] three of four patients with type IV PRP had an excellent response to topical corticosteroids, one of three responded well to UVB phototherapy and tar (Goeckerman regimen), and one responded poorly to topical calcipotriene. In another study, Goeckerman treatment did not result in any significant improvement in 17 patients with type I PRP.[9] Several other reports with different topical treatment modalities have been published. Van de Kerkhof and Steijlen[80] successfully treated three patients with type II, III, and IV PRP with topical calcipotriene. These authors showed a reduction in the suprabasal expression of keratin 16 and the number of T lymphocytes, monocytes, and macrophages. However, resorption of vitamin D3 analogs has to be taken into consideration so that topical application is quantitatively limited.

Some patients experience severe pruritus resistant to antihistamines and topical treatment with potent corticosteroids. In these patients, topical capsaicin solution (0.03%) might result in significant relief from itching.[94] In case of oral involvement, corticosteroid mouth rinses may be useful.[14] For symptomatic relief, emollients, keratolytics, and systemic antihistamine therapy are beneficial.

Imiquimod, a toll-like receptor agonist and immune response modifier, plays an increasing role in the treatment of dermatologic diseases. Imiquimod is known to induce psoriasis.[107] Yang et al.[108] described a patient with exacerbated PRP during topical imiquimod treatment for actinic keratoses. Therefore, clinicians should be aware of such potential adverse effects.

3.2 Systemic Treatment

To date, systemic retinoids seem to be the most effective therapeutic agents. Several other therapies including phototherapy, psoralen plus UVA (PUVA), methotrexate, azathioprine, cyclosporine (ciclosporin), mycophenolate mofetil, fumaric acid, biologics, and extracorporeal phototherapy and their varying success have been reported. Systemic corticosteroids are not useful in PRP, and their discontinuation can even cause exacerbation of the disease.[109]

Isotretinoin and etretinate are synthetic vitamin A derivatives that modulate the growth and differentiation of epithelial tissues. Histologically, a decrease of hyperkeratosis occurs during etretinate therapy.[17] High dosages of vitamin A (150 000–300 000 units/day) do not seem to be beneficial in patients with type I PRP.[9] Potential adverse effects of systemic retinoids are liver toxicity, alopecia areata, lipid alterations, and dryness of mucous membranes. Teratogenicity and bony changes, such as hyperostosis or premature epiphyseal closure, particularly in prepubertal patients, are other important adverse effects. Isotretinoin is US FDA approved for children 12 years and older for the treatment of nodulocystic acne. Etretinate and acitretin are second-generation retinoids, but neither of these agents is approved for use in children. However, there is evidence for their off-label use in the pediatric population from a number of case reports and published clinical trials.[110,111] Children represent an important percentage of PRP patients, and systemic treatment is often required. The short-term use of oral retinoids in otherwise healthy children affected by severe PRP seems to be well tolerated and safe.[112]

An early multicenter study of adult and juvenile patients with PRP (disease type not specified) initiated isotretinoin therapy at dosages of 1–2 mg/kg/day for an average of 122 days. All 34 patients who remained under treatment for 12–16 weeks showed significant improvement.[88] In a further retrospective study, 10 of 15 patients (16–81 years of age, type I and III PRP) had complete clearing and two patients showed partial clearing after an average of 25 weeks of treatment with isotretinoin during which most patients received 1 mg/kg/day.[9] Selvaag et al.[79] successfully treated seven adult patients with PRP (six patients had type I PRP and one patient type II PRP) with retinoids with or without topical corticosteroids. A retrospective review of 18 patients treated with isotretinoin, etretinate, or both, suggested that etretinate was superior to isotretinoin in the treatment of adult-onset PRP (type not specified).[89] In adults, the recommended daily dose of etretinate is 0.5 mg/kg and of isotretinoin is 1 mg/kg for 3–6 months.[9,67,89] Abbott and Griffiths[113] treated an adult patient with type I PRP with varying dosages of etretinate (0.45–0.75 mg/kg/day) during 9 years with only modest improvement. After a period without any treatment besides emollients, his skin symptoms resolved spontaneously after 20 years. This unusual case shows that even after a long period of chronicity, complete remissions in PRP are possible. In a retrospective study of 30 children with PRP, five of six patients with type III PRP treated with daily oral isotretinoin at doses of 0.75–1.5 mg/kg showed 90–100% clearing within 6 months.[8] A dreaded complication of retinoids in children is the premature closure of epiphyses. A patient with a long history of PRP developed extensive extraspinal hyperostoses after 13 years of oral retinoid treatment. Discontinuation of acitretin led to severe exacerbation of PRP, but a good result was obtained with low-dose methotrexate therapy.[82]

Combined UVA1 radiation and acitretin therapy may be an alternative treatment,[93] but phototesting should be done before treatment because of reports on photoaggravated PRP. Kaskel et al.[114] reported a patient with evolving papules and infiltration in the UVB test fields (0.04 J/cm2) 4 days after irradiation that finally developed into generalized PRP. The same patient was then successfully treated with bath-PUVA. Oral retinoids and photochemotherapy with methoxsalen (8-methoxypsoralen) [Re-PUVA] may be a good therapeutic option.[94] Initial UVA doses should not exceed 0.3–0.5 J/cm2 with subsequent increments of 0.3 J/cm2 every third day. However, photoaggravation of PRP by UV exposure is well recognized.[115, 116, 117] Davidson et al.[118] reported, in a series of 57 PRP patients, that 26% showed exacerbation in the summer months. A 12-year-old girl with a 4-year history of PRP was successfully treated with narrow-band UVB in combination with acitretin commenced at a dosage of 0.75 mg/kg/day.[83] Acitretin alone led to relapses, and light-protected areas, such as the axillae, did not clear completely.[83] The authors supposed that narrow-band UVB has different biologic effects on the skin from those of broad-band UVB; for example, more immunosuppressive effects on lymphoproliferation and cytokine responses from peripheral blood cells. However, different response rates with phototherapy seem to reflect the heterogeneity of PRP, as some patients showed improvement with light therapy and others experienced exacerbation.

Whereas Griffiths[4] found that only 17 of 44 patients showed any response to methotrexate, Clayton et al.[90] had more promising results by adding methotrexate to oral retinoid therapy in patients with classic adult type I PRP with disabling involvement. They treated 22 PRP patients with either oral etretinate 25–75 mg/day or isotretinoin 40 mg twice daily. Six patients with extensive disease had low-dose methotrexate ranging from 5 to 30 mg/week started concurrently. Five patients had weekly methotrexate added at a later date. After 16 weeks of therapy, 8 of 11 patients receiving the combination treatment showed a 50–95% response. However, combination therapy with a retinoid and methotrexate may lead to increased hepatotoxicity. Dicken[9] also reported a favorable outcome in eight patients treated with low-dose weekly methotrexate for 6 months. Dosages ranged from 10 to 25 mg/week without occurrence of any significant adverse effects. In case of PRP-induced lower eyelid cicatricial ectropion, low-dose methotrexate may result in successful therapy, rendering surgical treatment superfluous.[119]

Because the same abnormal keratinization exists in type V juvenile PRP and in psoriasis, Coras et al.[6] decided to treat a 15-year-old boy with recalcitrant PRP since the first year of life with fumaric acid at increasing dosages. After 5 weeks of treatment, the boy showed dramatic improvement with almost complete clearing. The mechanism of action of fumaric acid is still not fully understood. It has immunomodulating activity, with inhibitory effects on keratinocyte proliferation and activation explaining the positive effect on PRP. Patients with PRP who do not respond to retinoids and methotrexate might be successfully treated with low-dose cyclosporine.[91] Particularly in children with recalcitrant PRP, low-dose short-term cyclosporine treatment is a possible option.[84] A further patient with type II PRP, who was unresponsive to fumaric acid, cyclosporine, narrow-band UVB, and bath-PUVA and had important contraindications to retinoid therapy, was successfully treated by extracorporeal photochemotherapy (ECP).[95] Hofer et al.[96] successfully treated two patients with type I PRP with a combination of acitretin and ECP and a combination of cyclosporine and ECP, respectively. Both patients were unresponsive to systemic retinoids, PUVA, and cyclosporine alone. Another patient with recalcitrant type II PRP showed significant improvement on intravenous immunoglobulins at a dosage of 2 g/kg (over 3 days) every 3 weeks.[97]

As PRP and psoriasis share clinical and histologic features, and infliximab has proved to be successful in psoriasis, TNFα inhibitors have recently gained attention in the treatment of PRP. Infliximab is a chimeric monoclonal antibody that binds to the proinflammatory cytokine TNFα, which may play a pathophysiologic role in PRP. Liao and Mutasim[98] successfully treated two patients with erythrodermic adult-onset PRP with infliximab 5 mg/kg added to their previous regimen of acitretin. Both patients showed marked improvement after 2 weeks of therapy and stayed on acitretin as maintenance therapy. The first patient had further infliximab infusions at weeks 4, 8, 14, and 22, and the second patient had one further infusion at week 2. Another patient with erythrodermic PRP, who did not respond to methotrexate, acitretin, fumaric acid, or mycophenolate mofetil, also received infliximab at a dose of 5 mg/kg, and improved significantly within 2 weeks. This patient received six infliximab infusions (weeks 2, 6, then at 8-week intervals), and her skin condition was still stable 4 months after the final infusion.[99] A further review reported three patients with refractory PRP who were treated with infliximab at a dose of 5 mg/kg. All patients showed >75% improvement in disease status within 3 days to 2 weeks after the first infusion.[100] Two patients with recalcitrant type I and type III PRP, respectively, were also successfully treated with infliximab.[101,102] Barth et al.[120] treated a patient with type I PRP, unresponsive to methotrexate alone, with the addition of infliximab 5 mg/kg as co-medication, since methotrexate reduces the risk of infliximab antibodies and higher levels of infliximab are achieved. After the second infusion of infliximab, skin lesions improved dramatically. However, Lu et al.[103] reported a patient with type I PRP unresponsive to a combination treatment of acitretin 50 mg/day and infliximab 5 mg/kg. The patient’s symptoms did not improve after four infusions of infliximab. In summary, nine patients with PRP have been successfully treated with infliximab so far, whereas one patient has shown no response.[104] Etanercept is a further biologic that binds to both TNFα and TNFβ receptors, rendering TNF biologically inactive. It was successfully administered subcutaneously at a dosage of 50 mg twice weekly in addition to acitretin 25 mg/day in a patient with extensive PRP who was resistant to acitretin alone, UVB light therapy, cyclosporine, and systemic corticosteroids.[105] After 7 months of this combination treatment, his skin lesions had nearly completely resolved. He remained on maintenance therapy of etanercept at a dosage of 50 mg every other week.[105] Furthermore, both Seckin et al.[106] and Cox et al.[85] successfully treated patients with type I PRP with etanercept. Since this drug has been recently approved in Europe for the treatment of chronic plaque psoriasis in children and adolescents (aged 8–17 years), it may be a promising treatment option in juvenile PRP.

Adalimumab is a monoclonal IgG-1 antibody with a high affinity for human TNF. It led to a remarkable improvement of PRP in a 72-year-old man with contraindications to any hepatotoxic or cholesterol-elevating drugs because of concurrent alcohol consumption and hypercholesterolemia.[86] We also successfully treated a 72-year-old man with type I PRP who was unresponsive to topical and systemic corticosteroids, PUVA and methotrexate, with adalimumab.[121] Controversial results exist for treatment with efalizumab. Gómez et al.[87] successfully treated a 10-year-old boy with recalcitrant PRP with efalizumab 1 mg/kg/week, but we observed a patient with adult PRP exacerbating while receiving this treatment.[122] Larger clinical studies are required to prove the efficacy of biologics in the treatment of PRP.

Patients with HIV-associated PRP may profit from antiretroviral therapy; in particular, zidovudine in combination with etretinate seems to be beneficial.[31] However, Miralles et al.[30] reported a case of an HIV-infected patient with PRP who developed erythroderma despite the administration of etretinate at a dosage of 1 mg/kg/day and zidovudine 600 mg/day. Finally, the patient died of septicemia, intravascular coagulation, and renal failure.

Because of their therapeutic efficacy, retinoids remain the first-line therapy for most patients with PRP. In comparison with etretinate, the shorter half-life of isotretinoin is favorable. The slow elimination of etretinate from the body produces a prolonged risk of teratogenicity. The combination of retinoids and PUVA therapy may be beneficial in some patients. When retinoids are not successful, methotrexate should be favored as second-line treatment. Biologics can be considered as an option in retractable PRP. However, larger clinical studies will be required to prove their efficacy. Treatment with cyclosporine, azathioprine, stanozolol, or systemic PUVA have been reported with varying degrees of success.[10,92]

4. Conclusion

Although PRP has been known as a distinctive entity since the 19th century, the pathogenesis of this rare disorder is still a matter for debate. Autoimmune diseases, infections, or malignancies are possible trigger factors. Other papulosquamous and erythrodermic disorders must be considered for clinical differential diagnosis. Histologic evaluation can often be helpful to rule out other disorders with similar clinical characteristics.

To date, no standardized treatment has been established. Topical corticosteroids, keratolytics, vitamin D3 analogs, and emollients are important for supporting systemic treatment or may even be sufficient for treating localized forms of PRP. Systemic retinoids have proven their efficacy in the treatment of PRP in several studies. In situations in which retinoids fail or cannot be used, methotrexate should be considered. Anti-TNFα inhibitors are a significant addition to the therapeutic armamentarium in a difficult-to-treat entity. However, the role of TNFα in the pathophysiology of PRP remains unclear and further studies are needed in this field.

Notes

Acknowledgments

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Annette Klein
    • 1
  • Michael Landthaler
    • 1
  • Sigrid Karrer
    • 1
  1. 1.Department of DermatologyUniversity of RegensburgRegensburgGermany

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