Pityriasis Rubra Pilaris

Background

Pityriasis rubra pilaris (PRP) was first described in 1828 by Tarral and was named by Besnier in 1889. It is a chronic papulosquamous disorder of unknown etiology characterized by reddish-orange scaly plaques, palmoplantar keratoderma, and keratotic follicular papules.^[1] The disease may progress to erythroderma with distinct areas of uninvolved skin (the so-called islands of sparing).

Griffiths divided PRP into the following five types^{[2, 3]} :

• Classic adult (type I)
• Atypical adult (type II)
• Classic juvenile (type III)
• Circumscribed juvenile (type IV)
• Atypical juvenile (type V)

Subsequently, an HIV-associated type (type VI) was added to this classification system.^[4]  A few reports have also described pityriasis rubra pilaris associated with underlying malignancy.^{[5, 6, 7]}

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Pathophysiology

The etiology of PRP is unknown. A familial form of the disease exists, with an autosomal dominant inheritance pattern. Type V PRP has been linked to mutations in the gene CARD14.^{[8, 9]} Most cases of PRP are sporadic, however. It has been hypothesized that PRP may be related to an abnormal immune response to an antigenic trigger. Case reports have described PRP occurring after streptococcal infections.^[10]  PRP occurring after COVOD-19 vaccination has been reported, though the precise nature of the association remains to be defined.^[11]

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Epidemiology

The incidence of PRP has been reported to be 1 case in 3500-5000 patients presenting to dermatologic clinics in the United States. The familial form of PRP typically begins in early childhood and has an autosomal dominant inheritance pattern. The acquired form has a bimodal age distribution, with peaks in the first and fifth decades of life, but it can begin at any age. PRP occurs equally among men and women,^[12]  and persons of any race can be affected.

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Prognosis

Each type of PRP has its own prognosis. In general, the familial form of the disease may be persistent throughout life, and the acquired form of the disease may resolve spontaneously within 1-3 years. Patients with PRP can have painful and disabling palmoplantar keratoderma. Nail dystrophy and shedding may be present. However, most of the morbidity associated with PRP is associated with the erythroderma (see Complications).

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Patient Education

The PRP  Alliance is a nonprofit patient advocacy organization whose stated mission is to advocate for the timely and accurate diagnosis of PRP, the implementation of more effective and accessible treatment options, and an increase in PRP-specific research.

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History

The familial form of pityriasis rubra pilaris (PRP) has a gradual onset, whereas the acquired form has an acute onset. Various triggers have been described, including vaccination.^[13]  The disease typically spreads in a craniocaudal direction. Patients first notice redness and scales on the face and the scalp. This is often followed by redness and thickening of the palms and the soles (see the images below). The lesions may expand and coalesce to cover the entire body.

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Plantar keratoderma with orange hue on soles.

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Palmar keratoderma with orange hue on palms.

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Physical Examination

Skin

PRP is characterized by orange-red or salmon-colored scaly plaques with sharp borders, which may expand to involve the entire body (see the first image below). Often, areas of uninvolved skin, referred to as islands of sparing, are present. Follicular hyperkeratosis is commonly seen on the dorsal aspects of the proximal phalanges, the elbows, and the wrists (see the second image below). This pattern may be referred to as nutmeg grater papules. Palmoplantar keratoderma occurs in most patients and tends to have an orange hue. Painful fissures may develop in patients with palmoplantar keratoderma. Pruritus, though not a major symptom, may occur in the early stages of the disease.

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Reddish-orange plaques on trunk.

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Follicular hyperkeratosis seen on dorsal aspect of proximal phalanges.

Nails

Nail changes include distal yellow-brown discoloration, subungual hyperkeratosis, longitudinal ridging, nail-plate thickening, and splinter hemorrhages. Nail pitting is not typical.

Mucous membranes

Patients may complain of pain and irritation in the mouth. Mucous membrane changes include a diffuse whitish appearance of the buccal mucosa, lacy whitish plaques, grayish-white papules and plaques, erythema, and possible erosions.^[14]

Eyes

Patients with extensive disease may develop ectropion. Patients have also reported blurred vision and dryness.

Griffiths classification

Type I is classic adult PRP. This is the most common form, accounting for more than 50% of all cases of PRP. Onset is acute, and the features are classic, including erythroderma with islands of sparing, palmoplantar keratoderma, and follicular hyperkeratosis. This type of PRP has the best prognosis. Reportedly, about 80% of patients have remission in an average of 3 years. One reported case resolved spontaneously after 20 years.^[15] Scarring alopecia has been reported in this setting.^[16]

Type II is atypical adult PRP. This form accounts for about 5% of all cases of PRP. It is characterized by ichthyosiform lesions, areas of eczematous change, alopecia, and long duration (often 20 y or more).

Type III is classic juvenile PRP. This form accounts for about 10% of all cases of PRP. It is very similar to type I, but its onset is within the first 2 years of life. Remission can occur sooner than it does with type I, within an average of 1 year.

Type IV is circumscribed juvenile PRP. This form accounts for about 25% of all cases of PRP. It occurs in prepubertal children and is characterized by sharply demarcated areas of follicular hyperkeratosis and erythema of the knees and the elbows. The long-term outcome is unclear, with some reports of improvement in the late teenaged years. This form of PRP rarely progresses.

Type V is atypical juvenile PRP. This form accounts for about 5% of all cases of PRP. Most cases of familial PRP belong to this group. It has an early onset and runs a chronic course. It is characterized by prominent follicular hyperkeratosis, sclerodermalike changes on the palms and the soles, and infrequent erythema.

Type VI is HIV-associated PRP. Patients with HIV may have nodulocystic and pustular acneiform lesions. Elongated follicular plugs or lichen spinulosus–type lesions have also been reported to be present. This type tends to be resistant to standard treatments but may respond to antiretroviral therapies.

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Complications

Pityriasis rubra pilaris can cause painful and disabling palmoplantar keratoderma.

Nail dystrophy and shedding may occur.

Erythroderma is a reaction pattern of the skin that can occur in the setting of several different skin disorders, most commonly including psoriasis, eczema, lymphoma, drug reactions, and PRP. It is characterized by generalized erythema and scales, hair loss, and onycholysis. Systemic symptoms include malaise, fatigue, anorexia, fever, and chills. Patients with erythroderma may develop lymphadenopathy, hepatomegaly, splenomegaly, and electrolyte abnormalities due to increased transepidermal water loss. Cardiac failure may occur in patients with preexisting heart conditions.

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Laboratory Studies

No specific laboratory tests are available to confirm the diagnosis of pityriasis rubra pilaris (PRP). The diagnosis is usually made on the basis of a correlation between clinical findings and histologic findings.

Tests should be performed for electrolyte abnormalities, hypoalbuminemia, secondary bacterial infection in the skin, and possible sepsis.

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Procedures

Biopsy is indicated.

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Histologic Findings

Histologic features are not pathognomonic, but they are useful for ruling out other possible papulosquamous and erythrodermic disorders. Features on light microscopy include the following:

• Hyperkeratosis with alternating orthokeratosis and parakeratosis forming a checkerboard pattern in the stratum corneum
• Focal or confluent hypergranulosis
• Follicular plugging with perifollicular parakeratosis forming a shoulder effect
• Thick suprapapillary plates
• Broad rete ridges
• Narrow dermal papillae
• Sparse superficial dermal lymphocytic perivascular infiltration

Acantholysis has been reported as an additional histologic finding in PRP. Acantholysis may be restricted to adnexal epithelium. The presence of acantholysis, hypergranulosis, follicular plugging, and the absence of dilated capillaries and epidermal pustulation may help distinguish PRP from psoriasis.^[17]

Features on electron microscopy include the following:

• Decreased number of keratin filaments and desmosomes
• Enlarged intercellular spaces
• Parakeratosis with lipidlike vacuoles
• Large numbers of lamellar granules
• Focal split in the basal lamina at the dermoepidermal junction

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Medical Care

Topical therapy

Topical corticosteroids may provide some patient comfort, but they are believed to have little long-term therapeutic effect on pityriasis rubra pilaris (PRP).

Calcipotriol is a vitamin D analogue that has been used in the topical treatment of psoriasis. A report by Van Kerkhof et al described successful treatment in three patients with PRP; however, controlled studies are needed to further assess the usefulness of this agent in this setting.^[18]

The topical retinoid tazarotene has been used for topical treatment of psoriasis and acne. It has been reported to improve juvenile circumscribed PRP.^[19]

Emollients reduce fissuring and dryness, providing some patient comfort. Petroleum jelly or one of the many proprietary emollients may be used.

Biologics targeting tumor necrosis factor (TNF)-α; interleukins (ILs) 12, 17, and 23; and Th17 can produce remissions.^{[20, 21, 22, 23, 24, 25, 26]} Those targeting IL-12 and IL-23 are particularly helpful in early-onset disease related to CARD14 mutation.^{[27, 28, 29, 30, 31, 32]}

Phototherapy

Phototherapy can include narrowband phototherapy and extracorporeal photochemotherapy.

Nonresponsiveness to treatment with topical and systemic medications should prompt consideration of narrowband ultraviolet (UV) B (UVB) phototherapy. Narrowband UVB phototherapy uses a fluorescent bulb with a narrow emission spectrum that peaks at 311 nm (UVB spectrum, 290-320 nm). This selective and relatively longer wavelength may be more effective than broadband UVB for the treatment of PRP.^[33]

Extracorporeal photochemotherapy involves ex-vivo exposure of leukapheresed peripheral blood mononuclear cells to UVA in the presence of 8-MOP (a DNA-intercalating agent) and subsequent reinfusion of the treated cells. Successful treatment of a patient with PRP that was unresponsive to standard treatments has been reported.^[34] Further studies are needed.

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Long-Term Monitoring

PRP patients who have erythroderma should be monitored for electrolyte abnormalities, hypoalbuminemia, secondary bacterial infection in the skin, and possible sepsis.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Because of the rarity of this disease, therapy has been based on anecdotal reports.^[35] No large controlled trials have been performed.

A study of 12 patients by Dickens revealed that 80% of the patients had improvement from the use of oral retinoids. Clinical improvement can be expected within 4-6 months.^[36]

The use of monoclonal antibodies that suppress the immune system may improve the clinical aspects of the disease.^[37] A case series has compared infliximab with etanercept and found a more rapid onset of action with infliximab but roughly equal treatment duration required when compared with etanercept.^[38] Adalimumab has been added to the list.^[39]  Infliximab has been reported anecdotally to be of benefit, as has etanercept, ustekinemab, risankizumab, secukinumab, and ixekizumab.^{[25, 40, 41, 42, 43, 44, 45, 46, 47]}

Immunosuppressants inhibit cell growth and proliferation. They may also cause immunosuppression.^[48] Immunosuppressants inhibit key factors that regulate the immune system. Case reports have shown benefit in some patients with pityriasis rubra pilaris.^{[49, 50]}

Results from a small open-label, single-arm, 24-week clinical trial showed that ixekizumab, an interleukin 17A inhibitor, was safe and effective for treating pityriasis rubra pilaris.^[47] Seven of 11 subjects saw at least 50% improvement and four saw long-term remission.

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Acitretin (Soriatane)

• Dosing, Interactions, etc.

Clinical Context:  Acitretin is a metabolite of etretinate and related to both retinoic acid and retinol (vitamin A). Its mechanism of action is unknown. However, it is thought to exert therapeutic effects by modulating keratinocyte differentiation, keratinocyte hyperproliferation, and tissue infiltration by inflammatory cells. It is approved for the treatment of severe psoriasis.

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Isotretinoin (Amnesteem, Claravis, Sotret)

• Dosing, Interactions, etc.

Clinical Context:  Isotretinoin is a synthetic 13-cis isomer of the naturally occurring tretinoin (trans-retinoic acid). It is approved for use in severe recalcitrant nodular acne. A review by Allison et al revealed clearing in 5 of 6 pediatric patients with pityriasis rubra pilaris within 6 months.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

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Class Summary

These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes. They modulate keratinocyte differentiation.

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Cyclosporine (Neoral, Sandimmune)

• Dosing, Interactions, etc.

Clinical Context:  Cyclosporine is a cyclic polypeptide immunosuppressant agent produced as a metabolite by the fungus species Beauvaria nivea. It is approved for use in organ transplantation patients, rheumatoid arthritis, and psoriasis.

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Azathioprine (Azasan, Imuran)

• Dosing, Interactions, etc.

Clinical Context:  Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, which results in immunosuppression. It is approved for use in transplantation patients and patients with rheumatoid arthritis.

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Methotrexate (Rheumatrex)

• Dosing, Interactions, etc.

Clinical Context:  Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction. Successful treatment is reported. Follow the same guidelines as for use in psoriasis. Improvement may occur in 6 weeks, with a complete response after 3-4 months. Relapse may occur upon discontinuation.

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Class Summary

These agents inhibit cell growth and proliferation. They may also cause immunosuppression. Immunosuppressants inhibit key factors that regulate the immune system.

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Etanercept (Enbrel)

• Dosing, Interactions, etc.

Clinical Context:  Etanercept is a soluble p75 TNF receptor fusion protein (sTNFR-Ig). It inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses.

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Class Summary

The use of monoclonal antibodies that suppress the immune system may improve the clinical aspects of the disease.

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Vitamin A

• Dosing, Interactions, etc.

Clinical Context:  Improvement with vitamin A therapy has been reported; however, synthetic retinoids are more effective.

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Class Summary

Agents like vitamin A have been reported to improve the clinical aspects of the disease.

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Infliximab (Remicade)

• Dosing, Interactions, etc.

Clinical Context:  Infliximab is a chimeric monoclonal antibody that binds specifically to human tumor necrosis factor-alpha. It is approved for the treatment of rheumatoid arthritis, Crohn disease, ankylosing spondylitis, and psoriatic arthritis. Several reported cases describe adult-onset pityriasis rubra pilaris with excellent responses to infliximab.

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Adalimumab (Humira)

• Dosing, Interactions, etc.

Clinical Context:  Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF. It binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors. This interferes with cytokine-driven inflammatory processes. It also lyses surface TNF-expressing cells in vitro in the presence of complement, but it does not bind to TNF-beta (lymphotoxin).

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Ustekinumab (Stelara)

• Dosing, Interactions, etc.

Clinical Context:  Ustekinumab is a human monoclonal antibody directed against IL-12 and IL-23, thereby interfering with T-cell differentiation and activation and subsequent cytokine cascades.

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Class Summary

Monoclonal antibodies are genetically engineered chimeric murine-human immunoglobulins directed against tumor necrosis factor, which in turn interferes with cytokine driven inflammatory processes.

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