Pityriasis Rubra Pilaris and variants (Devergie's disease, lichen acuminatus, lichen psoriasis, lichen ruber acuminatus, lichen ruber pilaris, pityriasis pilaris)

Are You Confident of the Diagnosis?

What you should be alert for in the history

The diagnosis of PRP can best be made using several well-described clinical features of the most common form, type 1 or classic adult. Patients describe rough, perifollicular, erythematous papules that coalesce to form large, scaly plaques. Patients present with a generalized eruption that is often asymptomatic, but patients may complain of pruritus or burning. PRP commonly begins in the scalp and progresses caudally; inquire about increasing fine scalp scale associated with pruritus or erythema. The palms and soles are frequently involved with an orange-red, waxy keratoderma. Patients may complain of stiff hands or painful fissures.

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There are five variants of PRP: classic adult, (type I), representing 55% of PRP cases; atypical adult, (type II), 5%; classic juvenile, (type III), 10%; circumscribed juvenile, (type IV), 25%; and atypical juvenile, (type V), 5%. A sixth variant has been proposed for PRP in HIV patients.

Characteristic findings on physical examination

On physical examination, classic adult PRP is characterized by perifollicular hyperkeratosis (Figure 1) with an erythematous base. Commonly seen on the dorsum of the hands and wrists, the papules frequently give the appearance of a nutmeg grater. On the trunk, the papules often coalesce into red-orange plaques with a fine scale (Figure 2) and characteristic, sharply demarcated islands of sparing (normal appearing skin) (Figure 3). The plaques may progress to an exfoliative erythroderma and a waxy, orange-red hued keratoderma frequently develops on the palms and soles (Figure 4). Keratoderma with a coarser and lamellated scale is seen in types II and V, the atypical adult and atypical juvenile variants.

Sharply demarcated follicular hyperkeratosis.

Orange-red, waxy palmoplantar keratoderma.

Scalp involvement with erythema and a fine, diffuse scale resembling seborrheic dermatitis may be the presenting clinical manifestation (Figure 5), and a rapid progression to erythroderma can occur in several weeks. Severe ectropion may develop with prolonged facial erythroderma. Alopecia may be seen in either adult form. Ichthyosiform lesions and areas of eczematous dermatitis, especially in the lower extremities, may be seen in the atypical adult and atypical juvenile variants.

PRP Scalp Involvement may mimic seborrheic dermatitis.

Nail changes are frequent and include nail plate thickening, yellow-brown discoloration, and splinter hemorrhages (Figure 6). The mucous membranes are rarely involved, but may resemble oral lichen planus with diffuse, lacy whitish plaques and papules on the buccal mucosa.

Nail plate thickening and discoloration.

The classification of PRP is summarized in Table I.

Clinical Type	I – classic adult	II – atypical adult	III – classic juvenile	IV – circumscribed juvenile	V – atypical juvenile	VI – HIV associated
Age of Onset	Adult		Juvenile			Adult
Clinical Findings	– perifollicular hyperkeratosis (nutmeg grater)- red-orange plaques with islands of sparing- waxy palmoplantar keratoderma- exfoliative erythroderma	– ichthyosiform scale- eczematous dermatitis- more course, lamellated keratoderma & scale- occasional alopecia	– similar findings to type I	– elbows, knees, bony prominences- erythematous follicular papules- onset prepuberty	– similar findings to type II- Note: most familial forms	– nodulocystic, pustular, acneiform lesions- elongated follicular plugs
Course	Majority clear within 3 years	Chronic	Majority clear within 3 years, sooner than type I	Variable	Chronic	Variable
Distribution	Generalized			Focal	Generalized
% of PRP Cases	55%	5%	10%	25%	5%	Unknown

Type II PRP, atypical adult, differs from the classic form with ichthyosiform lesions, eczematous scaling, and a coarser, lamellated keratoderma and follicular hyperkeratosis. Type II also has a longer duration with a more chronic course, as well as occasional alopecia. Only 20% of type II patients achieve clinical resolution within 3 years, whereas a majority resolve in this time frame with the classic type.

Type III, classic juvenile, is the juvenile form of PRP that closely resembles type I, classic adult. As with type I, type III also typically clears within 3 years of onset. Remission of classic PRP occurs sooner in children than adults, often occurring within 1 year.

Type IV, circumscribed juvenile, is the most common form in children, often seen in prepubescents. Type IV is the only variant of PRP with focal involvement rather than a generalized eruption. There are sharply demarcated areas of erythema and follicular hyperkeratosis mainly on the elbows, knees, and bony prominences. This form of PRP rarely progresses.

Type V, atypical juvenile, closely resembles type II, atypical adult, with more ichthyosiform scaling and prominent follicular hyperkeratosis. Type V patients also present with the course, lamellated keratoderma of the palms and soles. Onset is typically within the first few years of life and these patients have a more chronic course. The rare familial forms of PRP fall within this group.

Type VI is a proposed group for PRP associated with HIV. These patients present with nodulocystic or pustular acneiform lesions with elongated follicular plugs. They often have a clinical picture resembling lichen spinulosus or hidradenitis suppuritiva. This form of PRP is often recalcitrant to conventional therapy, but may respond to highly active antiretroviral therapy (HAART).

Expected results of diagnostic studies

Laboratory studies should be directed at ruling out electrolyte abnormalities, hypoalbuminemia, and bacterial skin infections. No specific laboratory tests are needed to diagnose PRP as correlating the clinical picture and histological findings makes the diagnosis.

A biopsy is often important in making the diagnosis of PRP. The histological features are not pathognomonic and many are non-specific, but they may be useful in ruling out other papulosquamous and erythrodermoid disorders. On histology, an alternating vertical and horizontal ortho and parakeratosis forming a checkerboard pattern in the stratum corneum with a psoriasiform dermatitis is distinctive, but not pathognomonic.

Hypergranulosis of the interfollicular epidermis with follicular plugging, acanthosis and acantholysis of the adnexal epithelium, and broad rete ridges with narrow dermal papillae are also seen. A sparse, perivascular lymphohistiocytic infiltrate is present with a focal split in the basal lamina at the dermal-epidermal junction (Figure 7).

Hypergranulosis with perivascular infiltrate.

Direct immunofluorescence is not very helpful as IgG, IgA, IgM, and C3 are all negative. There is little value in imaging studies.

Diagnosis confirmation

PRP is often mistaken for other papulosquamous and erythrodermic disorders, most often psoriasis. The two may be differentiated by histological evaluation, but this effort may too be equivocal. The presence of epidermal acantholysis and focal acantholytic dyskeratosis, hypergranulosis, shorter and thicker rete pegs, limited vascular dilation in the dermal papillae, and the absence of both neutrophilic migration towards the epidermis and Munro microabscesses favor a diagnosis of PRP. Nail changes such as pitting, oil drops, and marginal onycholysis favor a diagnosis of psoriasis.

In addition to psoriasis, other disorders in the differential diagnosis include the following:

generalized hypersensitivity reaction
cutaneous T-cell lymphoma (CTCL)
erythrokeratoderma variabilis
follicular eczema
follicular ichthyosis
lichen planopilaris
seborrheic dermatitis (early PRP may mimic seborrheic dermatitis, but PRP is much more recalcitrant to conventional therapy)
subacute cutaneous lupus erythematosus
erythema gyratum repens (EGR or and EGR-like pattern may occur in resolving PRP if the patient has been taking systemic retinoids or high dose Vitamin A. Only 5 cases of this extremely rare phenomenon have been reported in the literature, and all patients had been previously treated, or were currently being treated with systemic retinoids or high dose Vitamin A. PRP has also only occasionally been associated with an underlying malignancy, whereas EGR is associated with an underlying malignancy in 80% of cases.
oral lichen planus (mucous membrane involvement is much rarer in PRP, and the cutaneous signs are significantly different)
ichthyoses/atopic dermatitis (types II and V, the atypical forms, have many overlapping features but PRP typically has the additional papulosquamous component)
symmetric erythrokeratoderma
Kawasaki disease (especially in children with acute-onset PRP)
erythroderma of other etiology
secondary syphilis (has distinctive ham-colored papulosquamous lesions of the palms and soles)

Who is at Risk for Developing this Disease?

Type I, the classic adult form of PRP, is the most common. PRP is a rare disorder with the reported incidence ranging from 1 in 3,500-5,000 new patient visits in the United States to 1 in 50,0000 new patient visits in India. There is no gender or ethnic bias, with incidence peaking during the first and second decade, and again during the fifth and sixth decade. Most cases are sporadic, but familial forms have been reported, usually autosomal dominant in inheritance and atypical in presentation.

What is the Cause of the Disease?

Etiology

The etiology of PRP is largely unknown. A vitamin A deficiency was originally proposed but has since not been substantiated. Systemic retinoids help, so an as yet unidentified dysfunction in keratinization of Vitamin A metabolism may still exist.

An immune system dysregulation and abnormal response to antigenic triggers has also been proposed stemming from reports of infections, (including HIV and streptococcal infections), ultraviolet exposure, or various other minor traumas preceding the onset of PRP. Reported associations with hypothyroidism, reactive arthritis, dermatomyositis, celiac sprue, vitiligo, and myasthenia gravis suggest an autoimmune component.

Pathophysiology

While an antigenic trigger has not been identified, the inflammatory cascade is somehow initiated causing a marked hyperproliferation of inflammatory cells and the ensuing dermal inflammation creates the characteristic lesions of PRP. Owing to the success of some biologic therapeutics, it is likely that TNF-a and IL-12/23 play important roles in the recruitment of inflammatory cells and keratinocyte hyperproliferation.

Recently CARD 14 mutations have been identified in both familial and sporadic cases of PRP. CARD 14 encodes member 14 of the caspase recruitment domain family and is highly expressed in the skin. Although the precise signaling pathway regulated by CARD 14 remains to be elucidated, CARD 14 is known to activate the transcription factor nuclear factor-kappa B (NF- B), which plays a central role in cell proliferation, apoptosis and inflammation. The importance of NF- B in the pathogenesis of PRP may have future therapeutic implications.

Systemic Implications and Complications

Systemic manifestations such as malaise, fatigue, fever, and chills may accompany an acute onset of PRP. The systemic implications of PRP are mostly attributed to erythroderma and include lymphadenopathy, hepatosplenomegaly, and electrolyte abnormalities stemming from increased transepidermal water loss. In patients with preexisting cardiac conditions, cardiac failure can occur with erythroderma and they may have difficulty regulating temperature. With prolonged facial erythroderma, ectropion may develop leading to visual problems. Arthritis has also been reported in some PRP patients.

Upon diagnosing PRP, it is important to rule out dermatomyositis as the presence of PRP defines the Wong type variant of that disease. Patients with this rare form of dermatomyositis have the erythematous, hyperkeratotic follicular papules seen with classic adult PRP on the extremities, particularly the dorsal hand and wrists. The scalp, forehead, and posterior neck may also be involved. These patients do not show other common PRP clinical findings however, such as the waxy orange-red discoloration, palmoplantar keratoderma, or exfoliative erythroderma.

Treatment Options

As a unifying etiology has yet to be established and there have been few large scale, randomized trials given the paucity of patients, there is no definitive treatment strategy for PRP. Many different regimens have been reported and the strategy is primarily empiric based on anecdotal reports. Treatment options are summarized in Table II.

Medical Options	Physical Modalities	Surgical Options
TOPICAL	Phototherapy (Narrow-band UVB, UVA1, or PUVA*)	May be required for a severe ectropion.
Keratolytics
Topical Steroids
Emollients
Calcipotriol
Imiquimod
SYSTEMIC
Systemic Retinoids
Methotrexate
Cyclosporine
Adalimumab
Infliximab
Etanercept
Ustekinumab
Azathioprine
Anakinra
Systemic Steroids

*PUVA, psoralen plus ultraviolet A.

The goal remains primarily to prevent complications and reduce morbidity, especially considering the natural course of the disease for many patients is spontaneous resolution.

Optimal Therapeutic Approach for this Disease

While the etiology is unclear and regimens remain largely empiric, PRP is generally considered an acute disorder and first-line treatment is systemic. A review of the literature reveals no good randomized controlled trials detailing treatment options, so much of the regimens are anecdotal or from limited case series.

Systemic retinoids, such as isotretinoin (0.5-2 mg/kg, start 1-1.5 mg/kg), acitretin (25-50 mg/day), etretinate (25-50 mg/day), and alitretinoin (0.5 mg/kg/day) are first-line therapy. Isotretinoin has been shown to induce significant clearing within 3-6 months, and the recurrence rate has been reported at 17%. Due to the ease with which a patient may receive acitretin, the authors tend to prescribe this retinoid for the appropriate patients, as personal experience and the scientific literature do not clearly demonstrate that isotretinoin is superior. The effects of retinoids on familial forms are unclear.

Methotrexate has also been used with success in PRP. Doses ranging from 10-25 mg/week have been reported to clear PRP in 3-6 months. Myelosuppression and hepatotoxicity are well-known potential side effects of methotrexate, especially with concomitant systemic retinoid use (both can be given at the onset of therapy in severe cases). Monitor laboratory studies at baseline, after 1 month, and periodically as indicated if starting methotrexate.

Other immunosuppressive options include azathioprine (1 mg/kg/day orally for 6-8 weeks, increase by 0.5 mg every 4 weeks until response, not to exceed 2.5 mg/kg/day), and cyclosporine (2.5-5 mg/kg/day).

For patients with acute flares, erythroderma, or significant systemic symptoms, systemic steroids (prednisone, start 1 mg/kg/day) can be used. With more focal disease, topical keratolytics (such as salicylic acid 6% as a lotion or cream) may help relieve the follicular hyperkeratosis, topical steroids may relieve more symptomatic lesions, and all patients should be given an emollient. In patients with palmar keratoderma and fissuring, emollients and potent (betamethasone 0.05%) or ultrapotent (clobetasol 0.05%) topical steroids can be given. These patients may also need analgesia.

A number of studies have shown success with biologics, with reports detailing use of infliximab (intravenous infusion induction 5 mg/kg at 0, 2, and 6 weeks, then 5 mg/kg every 6-8 weeks, increase to 10 mg/kg if diminishing response, consider discontinuing by week 14 if no response), adalimumab (40 mg subcutaneously every 2 weeks), etanercept (50 mg subcutaneously weekly), and ustekinumab (using the approved dosing for psoriasis patients). These biologic agents have been used either alone or in combination with systemic retinoids or methotrexate in refractory cases. Recently, a patient with refractory PRP and having a contraindication for TNF-a inhibitors was successfully treated with apremilast, a phosphodiesterase 4 inhibitor, at standard psoriasis dosing. While these reports and series have shown encouraging therapeutic successes, the reports are limited and use of these drugs in PRP needs to be further evaluated. Precautions and monitoring should resemble those associated with the treatment of psoriasis patients.

More recently some reports have documented the use of topical imiquimod with PRP. The practicality of this approach is limited when a large body surface area is affected. As with the biologics, this modality needs to be further evaluated.

Phototherapy with narrow-band ultraviolet (UV) B, UVA1, or psoralen plus UVA (PUVA) does benefit many patients, (especially when used with a systemic retinoid), but may exacerbate disease severity.

For the classic juvenile form of PRP, less toxic regimens are recommended given the high frequency of spontaneous resolution of disease. Topical tazarotene (1% gel) may also be effective for the treatment of juvenile PRP.

Inquire as to functional disability of the patient, as milder cases of more cosmetic concern can be managed less aggressively.

Patient Management

Explain to the patient the natural history of PRP before starting therapy. For many, this condition resolves spontaneously within 3-5 years. Advise them also that PRP is typically not a life-threatening disease. There are number of PRP support groups available as well. Patients with erythroderma should be monitored regularly for electrolyte abnormalities, hypoalbuminemia, bacterial infections of the skin, and sepsis. Many of the therapeutics require regular laboratory monitoring.

Unusual Clinical Scenarios to Consider in Patient Management

Severe forms of PRP with nodular and pustular acneiform lesions have been seen in HIV patients. This form of PRP is often resistant to standard therapy, but may respond to highly active antiretroviral therapy (HAART).

PRP is associated with dermatomyositis, known as the Wong variant of this disease. These patients typically have follicular hyperkeratosis especially on the extremities, but rarely have the orange-red discoloration, palmoplantar keratoderma, or exfoliative erythroderma. Ask patients about muscle pain or weakness and perform the appropriate laboratory analyses to evaluate for the presence of dermatomyositis.

PRP has occasionally been reported with a number of solid and hematologic malignancies, but true paraneoplastic PRP is an uncommon condition. The cutaneous findings of paraneoplastic PRP are typical in morphology for the classic adult form, but progression may be unusually rapid, often in as little as 2 weeks. In several reports, the skin findings resolved upon treatment of the underlying neoplasm, while in others the skin lesions improved despite a deteriorating condition of the malignancy. Only one report described an atypical presentation for PRP, with prominent mucosal involvement, filiform facial hyperkeratosis, and sparing under pressure areas (eye glasses and bra strap).

PRP has been associated with the following: laryngeal squamous cell carcinoma, hepatocellular carcinoma, renal-cell carcinoma, bronchogenic carcinoma, metastatic carcinoma with unknown primary, leukemia, and Merkel-cell carcinoma. Underlying malignancy should be considered in patients with unusually rapid progression of PRP.

Familial forms of PRP are rare but have been reported. The inheritance pattern is autosomal dominant, and these patients typically present in the first few years of life and ultimately have a much more chronic course. Consider treatment regiments accordingly as these patients will likely require long term therapy.

What is the Evidence?

Albert, MR, Mackool, BT. “Pityriasis rubra pilaris”. Int J Dermatol. vol. 38. 1999. pp. 1-11. (An outstanding review of PRP including etiology, histopathology, and clinical findings. While providing an excellent background of PRP and treatment options, this article does not include the newest additions to the therapeutic arsenal.)

Chan, H, Liu, FT, Naguwa, S. “A review of pityriasis rubra pilaris and rheumatologic associations”. Clin Dev Immunol. vol. 11. 2004. pp. 57-60. (The authors found eight case reports of PRP associated with new-onset arthritis. They also describe a case of seronegative mono-arthritis preceding cutaneous lesions of PRP by two years. This article also gives and excellent review of the clinical presentation, classification, treatment modalities, and rheumatologic associations of PRP. It is important to rule out rheumatologic conditions such as dermatomyositis in all patients with PRP.)

Shenefelt, PD. “Pityriasis Rubra pilaris”. eMedicine Online Journal. 2010 May. (A concise, but thorough and up-to-date review of the disorder and treatment options. The format is accessible for quick review.)

Griffiths, WA. “Pityriasis rubra pilaris”. Clin Exp Dermatol. vol. 5. 1980. pp. 105-112. (The first paper to thoroughly detail the epidemiology and background of PRP, as well the clinical and histopathologic findings. In this paper Griffiths establishes the original and still-used classification scheme for this disease.)

Miralles, ES, Nunez, M, De Las Heras, ME, Perez, B, Moreno, R, Ledo, A. “Pityriasis rubra pilaris and human immunodeficiency virus infection”. Br J Dermatol. vol. 133. 1995. pp. 990-3. (PRP in HIV patients, including those not significantly immunosuppressed, may present with slightly different morphology, including nodulocystic, acneiform, and lichen spinulosus-like lesions. This subpopulation has a poor prognosis and is often recalcitrant to conventional therapy, although HAART may be effective. This paper also proposes that these patients be classified as a sixth variant within the original classification scheme by Griffiths.)

Cohen, PR, Prystowsky, JH. “Pityriasis rubra pilaris: a review of diagnosis and treatment”. J Am Acad Dermatol. vol. 20. 1989. pp. 801-7. (A detailed review of the histopathologic features of PRP, a discussion of pathogenesis, and the relationship to Vitamin A. This is an excellent overview of the disease and treatment modalities, but does not include the newest therapeutic options.)

Magro, CM, Crowson, AN. “The clinical and histomorphological features of pityriasis rubra pilaris. A comparative analysis with psoriasis”. J Cutan Pathol. vol. 24. 1997. pp. 416-4. (This review explores the clinical features, associated background illnesses, and some potential triggers of PRP. This paper also represents an outstanding detail of the histomorphologic spectrum culled from a massive chart review. Histomorphologic features predictive of PRP include follicular plugging, an increased granular cell layer, and acantholysis.)

Bletloch, I, Ramon, R, Silvestre, JF, Carnero, L, Albares, MP, Banuls, J. “Acute juvenile pityriasis rubra pilaris: a superantigen mediated disease?”. Pediatr Dermatol. vol. 18. 2001. pp. 411-4. (A case report and description of juvenile circumscribed PRP. This is an excellent description of this unique form of PRP, and delves into the possibility that PRP may be a superantigen mediated disorder.)

Alexis, AH, Strober, BE. “Off-label dermatologic uses of anti-TNF-a therapies”. J Cutan Med Surg. vol. 9. 2005. pp. 296-302. (Tumor necrosis factor-alpha is a proinflammatory cytokine that plays an immunomodulatory role in a variety of systemic and dermatologic diseases. Psoriasis is the main dermatologic condition indicated for these medications, and this paper thoroughly reviews all reported off-label uses for other inflammatory dermatologic conditions. This paper reviews the pathology, and gives insight into the use of biologics in treating PRP.)

Ruiz Villaverde, R, Sanchez Cano, D. “Successful treatment of type 1 pityriasis rubra pilaris with ustekinumab therapy”. Eur J Dermatol. vol. 20. 2010. pp. 630-1. (A case report demonstrating successful use of ustekinumab, an anti-IL-12 and IL-23, in the treatment of PRP. By showing successful treatment of this disorder by focusing on these cytokines, this report further details the pathogenesis of PRP.)

Inoue, N, Dainichi, T, Fujisawa, A, Nakano, H, Sawamura, D, Kabashima, K. “CARD14 Glu138 mutation in familial pityriasis rubra pilaris does not warrant differentiation from familial psoriasis”. J Dermatol. vol. 43. 2016. pp. 187-189. (A case report of familial pityriasis rubra pilaris with CARD 14 genetic mutation with a brief review on CARD 14 and the NF- B pathway.)

Eastham, AB, Femia, AN, Qureshi, A, Vleugels, RA. “Treatment options for pityriasis rubra pilaris including biologic agents: a retrospective analysis from an academic medical center”. JAMA Dermatol.. vol. 150. 2014. pp. 92-4. (The largest and most comprehensive retrospective analysis on treatment of pityriasis rubra pilaris including biologic agents.)

Krase, IZ, Cavanaugh, K, Curiel-Lewandrowski, C. “Treatment of refractory pityriasis rubra pilaris with novel phosphodiesterase 4 (PDE4) inhibitor apremilast”. JAMA Dermatol.. vol. 152 (3). 2016. pp. 348-50. (A case report demonstrating success of using apremilast in the treatment of refractory PRP in a patient with contraindication to biologics, further demonstrates that there is an up-regulation of various inflammatory cytokines in pathogenesis of PRP.)

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Pityriasis Rubra Pilaris and variants (Devergie's disease, lichen acuminatus, lichen psoriasis, lichen ruber acuminatus, lichen ruber pilaris, pityriasis pilaris)

Are You Confident of the Diagnosis?

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