Pityriasis Rubra Pilaris (PRP) - Dermatology Notes

Definition: An uncommon, chronic papulosquamous disorder of keratinization characterized by follicular hyperkeratosis, confluent orange-red erythema with islands of sparing, and palmoplantar keratoderma.

Key Clinical Features:

• Demographics: Bimodal peaks – first to second decades (type III) and fifth to sixth decades (type I).

• Follicular papules: Keratotic, acneiform with spiny, nutmeg grater texture; these coalesce into erythematous plaques.

• Color: Characteristic salmon (waxy) orange-red or cayenne pepper hue.

• Islands of sparing: Pathognomonic – punched-out, normal skin islands within confluent erythema.

• Scale: Fine, branny (pityriasiform) on trunk; thick, waxy on palms and soles (keratoderma).

• Head and neck: Cenrifugal facial erythema with sparing of perioral and periorbital skin.

• Nails: Subungual hyperkeratosis, splinter hemorrhages, nail thickening, yellow-brown discoloration.

• Ectropion: Can occur with severe facial involvement.

• Pruritus: Variable from mild to severe.

Associated Conditions/Diseases:

• HIV infection: PRP can be atypical, severe, and treatment-resistant (type VI).

• Malignancy (paraneoplastic PRP): Associated with squamous cell carcinoma of lung, colon, breast, bladder, and hematologic malignancies (lymphoma, leukemia).

• Autoimmune disease: Rare associations including myasthenia gravis and hypothyroidism.

Types (Griffiths Classification – Board essential):

Type I is classic adult PRP. Onset is in adulthood (fifth to sixth decade). Course shows remission in 3 years in 80% of cases. Key features are typical findings with spontaneous resolution. No associated conditions.

Type II is atypical adult PRP. Onset is in adulthood. Course is chronic, lasting more than 20 years. Key features include eczematous or lichenoid features, alopecia, and sparse follicular papules. No associated conditions.

Type III is classic juvenile PRP. Onset is in childhood (first to second decade). Course shows remission in 1 year in 80% of cases. Key features are typical findings similar to type I. No associated conditions.

Type IV is circumscribed juvenile PRP. Onset is in childhood. Course is chronic. Key features include well-demarcated plaques on elbows and knees, no truncal erythema, and marked palmoplantar keratoderma. No associated conditions.

Type V is atypical juvenile PRP. Onset is in childhood. Course is chronic. Key features include linear or diffuse follicular hyperkeratosis, sclerodermatous changes, and familial inheritance. Associated conditions are familial (autosomal dominant) with CARD14 mutations.

Type VI is HIV-associated PRP. Onset is in adulthood (any age with HIV). Course is chronic and severe. Key features include fulminant presentation, nodulocystic lesions, and lichen spinulosus-like appearance. Associated condition is HIV infection with poor prognosis.

Prognosis:

• Type I and III have excellent prognosis – 80% remit within 3 years (adult) or 1 year (juvenile).

• Type II, IV, and V have poor prognosis – chronic, may persist for decades.

• Type VI has poor prognosis – severe, may be fatal if immune reconstitution is not achieved.

Differential Diagnosis:

• Psoriasis: Silvery-white scale (not branny), Auspitz sign positive, no islands of sparing, no follicular papules.

• Seborrheic dermatitis: Greasy yellow scale, involves scalp and nasolabial folds, no palmoplantar keratoderma.

• Lichen planus: Purple, polygonal, pruritic papules with Wickham striae, no follicular prominence.

• Darier disease: Greasy, crusted papules in seborrheic areas; nail changes (V-notches); histology shows acantholysis (not seen in PRP).

• Erythroderma (from psoriasis, atopic dermatitis, drug reaction): No islands of sparing, no follicular papules.

• Keratoderma blennorrhagicum (Reiter syndrome): Associated with urethritis, conjunctivitis, arthritis.

Management with Rationale:

• Topical therapy for mild to moderate disease: Emollients, keratolytics (salicylic acid, urea), topical retinoids (tazarotene), and topical corticosteroids (mild effect only).

• Systemic retinoids as first-line for moderate to severe disease: Acitretin at 0.5 to 1 mg/kg/day normalizes keratinocyte differentiation with response in 6 to 12 weeks. Isotretinoin is an alternative.

• Methotrexate at 7.5 to 25 mg weekly: Provides anti-inflammatory and antiproliferative effects; used if retinoids fail or are contraindicated.

• Biologics (emerging first-line for refractory disease): Anti-TNF agents (adalimumab, infliximab) give rapid response and are FDA-approved. Anti-IL-12/23 (ustekinumab) is highly effective. Anti-IL-17 (secukinumab, ixekizumab) shows promising results.

• Phototherapy: NB-UVB and PUVA may help but can exacerbate disease in some patients (caution required).

• Immunosuppressants: Cyclosporine for short-term rapid control.

• Supportive care: Emollients and antihistamines for pruritus.

Rationale for systemic retinoids: PRP is a disorder of retinoid metabolism with defective cellular retinoic acid-binding protein II (CRABP-II). Retinoids directly correct the keratinization defect.

Histopathology

1. FOUNDATIONS (First Principles)

• Normal follicular unit: The infundibulum (continuity with epidermis), isthmus, stem, and bulb. The infundibulum normally has a thicker granular layer and more compact keratin than interfollicular epidermis.

• Normal interfollicular epidermis: Stratified squamous epithelium with orthokeratosis.

• Langerhans cells: Antigen-presenting cells in suprabasal epidermis; may be increased in PRP.

• Keratinocyte differentiation: Progression from basal layer to spinous layer to granular layer to corneocyte. This process is regulated by retinoids via retinoic acid receptors (RAR and RXR).

  2. INITIATING EVENT

• Sporadic forms (types I, II, III, IV, VI): Unknown trigger – possibly infection, vaccination, or drugs. In type VI, HIV-induced immune dysregulation is the trigger.

• Familial form (type V): Gain-of-function mutations in CARD14 (caspase recruitment domain family member 14) on chromosome 17q25. CARD14 activates NF-κB in keratinocytes, leading to pro-inflammatory cytokine production (IL-17, TNF, IL-23).

• Defect: Abnormal keratinocyte differentiation and hyperproliferation driven by the Th17/IL-23 axis (similar to psoriasis but histologically distinct).

3. PATHOGENESIS

• CARD14 activation (or an unknown trigger in sporadic cases) leads to NF-κB nuclear translocation in keratinocytes.

• NF-κB upregulates IL-23, TNF, and IL-17 (from T cells and innate immune cells).

• IL-23 drives Th17 differentiation, producing IL-17A, IL-17F, and IL-22.

• IL-17 acts on keratinocytes, inducing hyperproliferation (acanthosis) and abnormal differentiation manifesting as parakeratosis alternating with orthokeratosis in both vertical and horizontal orientations.

• Retinoid signaling is disrupted due to CRABP-II deficiency, impairing granular layer formation.

• Follicular predilection: Infundibular keratinocytes are more sensitive to retinoid deficiency, so the earliest and most prominent changes occur at follicles.

• Islands of sparing: The mechanism is unknown – possibly residual normal keratinocyte clones resistant to the cytokine milieu.

4. HISTOPATHOLOGY EXPLAINED

Low power findings:

• Alternating orthokeratosis and parakeratosis in both vertical (stacked) and horizontal (shoulder-to-shoulder) orientation – this checkerboard pattern is the board exam hallmark.

• Follicular plugging (dilated follicles filled with keratotic material).

• Acanthosis (thickened epidermis) with broad, flattened rete ridges (not elongated and regular like psoriasis).

• Perifollicular lymphohistiocytic infiltrate (in early lesions).

High power findings:

• Parakeratosis shows retained nuclei in the stratum corneum.

• Orthokeratosis shows compact, anuclear keratin adjacent to parakeratotic areas – this alternating pattern is key.

• Granular layer is focally absent beneath parakeratotic areas and thickened beneath orthokeratotic areas (unlike psoriasis where the granular layer is uniformly thinned).

• Keratinocytes show mild spongiosis (intercellular edema) in some cases. No neutrophils are present in the stratum corneum (unlike psoriasis which shows Munro microabscesses).

• Follicles show lamellar follicular hyperkeratosis – concentric layers of keratin surrounding a dilated follicular ostium.

• Dermis shows a superficial perivascular lymphohistiocytic infiltrate; plasma cells may be present, especially in HIV-associated PRP.

Why this appearance:

• Checkerboard parakeratosis occurs because focal, rapid keratinocyte turnover with incomplete maturation alternates with normal turnover zones. This pattern is pathognomonic for PRP and is rarely seen in other conditions.

• Follicular plugging results from abnormal follicular keratinization identical to the epidermal defect.

• No neutrophils in the stratum corneum indicates that PRP is not driven by IL-17 to the same neutrophilic chemotactic degree as psoriasis.

5. NAMING LOGIC & TERMINOLOGY

• Pityriasis – Refers to branny (fine) scale, from the Greek word pityron meaning bran.

• Rubra – Meaning red, from Latin ruber.

• Pilaris – Relating to hair follicles, from Latin pilus meaning hair – follicular papules are the earliest and most characteristic feature.

• Checkerboard pattern – The alternating orthokeratosis and parakeratosis resembling a chessboard.

• Islands of sparing – Normal-appearing skin completely surrounded by erythematous PRP.

6. STAINING & MARKERS

• H&E is diagnostic when the checkerboard pattern and follicular plugging are present.

• Immunohistochemistry (not routine, primarily research): Ki-67 is increased in basal and suprabasal keratinocytes indicating hyperproliferation. K16 is positive as a hyperproliferation marker (also positive in psoriasis). K10 (differentiation marker) is reduced in parakeratotic areas. CARD14 staining is research only.

• No specific diagnostic immunohistochemical marker exists. Diagnosis is histologic and clinical.

7. TEMPORAL EVOLUTION

• Early lesion (follicular papule): Dilated follicle with lamellar hyperkeratosis and mild perifollicular inflammation. Minimal epidermal change.

• Established plaque: Acanthosis, checkerboard pattern of parakeratosis and orthokeratosis, follicular plugging, and superficial dermal infiltrate.

• Erythrodermic stage: Widespread confluent erythema; histology shows the same alternating pattern but may be subtler. Islands of sparing (seen clinically) are not visible histologically – biopsy must be taken from a red plaque.

• Chronic lesion: Thicker orthokeratosis with less parakeratosis. Follicular plugging remains prominent.

• Remission (treated or spontaneous): Return to normal histology. Residual follicular plugging may persist.

8. PATTERN RECOGNITION & DIAGNOSTIC LOGIC

• Pattern: Alternating orthokeratosis and parakeratosis (checkerboard) plus follicular hyperkeratosis plus psoriasiform hyperplasia.

Diagnostic pathway:

• If histology shows alternating orthokeratosis and parakeratosis with follicular plugging and no neutrophils in the stratum corneum, then diagnose PRP.

• If alternating orthokeratosis and parakeratosis with follicular plugging is seen in a patient with HIV risk factors, then diagnose type VI (HIV-associated) PRP.

• If uniform parakeratosis with elongated regular rete ridges and neutrophils in the stratum corneum (Munro microabscesses) is seen, then diagnose psoriasis.

• If alternating orthokeratosis and parakeratosis with acantholysis and corps ronds or grains is seen, then diagnose Darier disease.

• If parakeratosis with hypogranulosis and spongiosis and eosinophils is seen, then diagnose spongiotic dermatitis (eczema).

• If confluent parakeratosis with hypogranulosis and elongated rete ridges with suprapapillary plate thinning is seen, then diagnose psoriasis.

Key discriminator from psoriasis: PRP shows checkerboard pattern versus uniform parakeratosis in psoriasis; PRP shows follicular plugging versus absent in psoriasis; PRP shows no neutrophils in stratum corneum versus Munro microabscesses in psoriasis.

9. CLINICO-PATHOLOGICAL CORRELATION

• Salmon-orange color results from dermal vascular dilatation plus mild inflammation plus altered epidermal optical properties from alternating keratinization.

• Follicular papules (nutmeg grater texture) correspond to lamellar follicular hyperkeratosis palpable as rough, spiny papules.

• Palmoplantar keratoderma represents orthokeratotic hyperkeratosis with thick, waxy scale on acral skin.

• Islands of sparing represent foci of completely normal histology (orthokeratosis, intact granular layer) surrounded by diseased epidermis.

• Cenrifugal facial erythema with perioral sparing is a distinctive clinical pattern without a clear histologic explanation – possibly regional variation in retinoid metabolism.

• Ectropion results from severe acanthosis and inflammation causing skin shortening and outward pull.

10. EXAM-FOCUSED INSIGHTS

• The checkerboard pattern (alternating orthokeratosis and parakeratosis) is pathognomonic for PRP – if you see this on biopsy, think PRP.

• Follicular hyperkeratosis is an early and essential feature and may be the only finding in early disease.

• Islands of sparing are clinically pathognomonic – no other papulosquamous disorder has this finding.

• Type I (classic adult) is the most common form, with 80% remitting in 3 years.

• Type V (atypical juvenile) is familial with CARD14 mutation, is chronic, and responds poorly to treatment.

• Type VI (HIV-associated) is a board favorite – it is severe, nodulocystic, and treatment-resistant; think PRP in an HIV patient with erythroderma and follicular papules.

• Biologics (anti-TNF, anti-IL-12/23, anti-IL-17) are rapidly becoming first-line therapy, often more effective than retinoids for refractory disease.

• Do not confuse PRP with psoriasis – treatment differs. Retinoids are first-line for PRP, while methotrexate or biologics are first-line for psoriasis; topical steroids are less effective in PRP.

• Histology cannot reliably distinguish type I from type VI – clinical correlation with HIV status is required.

Must-Know Board Exam Questions & Answers

Q1: A 55-year-old man presents with salmon-orange erythema, follicular keratotic papules, and islands of normal-appearing skin on the trunk. His palms show thick, waxy keratoderma. What is the most likely diagnosis?

A: Pityriasis rubra pilaris (PRP), type I (classic adult).

Q2: What is the histopathological hallmark of PRP?

A: Alternating orthokeratosis and parakeratosis in a vertical and horizontal (checkerboard) pattern.

Q3: A 7-year-old child presents with well-demarcated plaques on the elbows and knees, thick palmoplantar keratoderma, and no truncal involvement. What type of PRP is this?

A: Type IV (circumscribed juvenile PRP).

Q4: What gene is mutated in familial PRP (type V)?

A: CARD14 (chromosome 17q25), encoding a protein that activates NF-κB in keratinocytes.

Q5: A patient with HIV presents with erythroderma, follicular papules, and nodulocystic lesions. What type of PRP is this, and what is the prognosis?

A: Type VI (HIV-associated PRP). The prognosis is poor, with severe and often treatment-resistant disease.

Q6: What is the first-line systemic treatment for moderate-to-severe PRP?

A: Acitretin (a systemic retinoid). Biologics including anti-TNF, anti-IL-12/23, and anti-IL-17 are increasingly used for refractory cases.

Q7: What histological feature distinguishes PRP from psoriasis?

A: PRP has alternating orthokeratosis and parakeratosis (checkerboard pattern) and follicular hyperkeratosis. Psoriasis has uniform parakeratosis, elongated regular rete ridges, and neutrophils in the stratum corneum (Munro microabscesses).

Q8: What are islands of sparing, and why are they clinically significant?

A: Islands of sparing are punched-out islands of normal skin within confluent erythema. They are pathognomonic for PRP and are not seen in psoriasis or other papulosquamous disorders.

Q9: A 60-year-old presents with new-onset PRP. What malignancy should be considered?

A: Paraneoplastic PRP – evaluate for underlying malignancy, especially squamous cell carcinoma of the lung, as well as colon, breast, bladder, and hematologic malignancies.

Q10: What is the expected prognosis for type I (classic adult) PRP?

A: 80% of patients achieve spontaneous remission within 3 years.