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Pityriasis rubra pilaris: failure of combination treatment with acitretin and infliximab

  • Author(s): Lu, Rebecca
  • George, Saira J
  • Hsu, Sylvia
  • et al.
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Pityriasis rubra pilaris: failure of combination treatment with acitretin and infliximab
Rebecca Lu MD, Saira J George MD, Sylvia Hsu MD
Dermatology Online Journal 12 (4): 18

Department of Dermatology, Baylor College of Medicine, Houston, Texas. shsu@bcm.edu

Pityriasis rubra pilaris (PRP) is an uncommon papulosquamous disease that can be debilitating. Treatment is aimed at reducing the duration of disease and is often a challenge. A number of different therapeutic options have been reported in the literature with varying degrees of effectiveness [1]. We present a case of idiopathic classic adult pityriasis rubra pilaris unresponsive to acitretin (Soriatane) and infliximab (Remicade).


Clinical synopsis


Figure 1

A 56-year-old man was evaluated for a 9-week history of a diffuse erythematous rash that did not improve with a short course of oral prednisone. The patient reported severe exfoliation of the skin with associated bleeding and pain. He had no significant past medical history and was not taking any medications at that time.

Physical examination revealed confluent scaly, erythematous plaques with islands of sparing on his face, scalp, trunk, and extremities. There were thick scales on his palms and soles.

Laboratory data included a complete blood count, electrolyte profile, liver function tests, thyroid function studies, and prostate specific antigen. Except for a mild hyperglycemia, laboratory findings were within normal limits.

Histology of a biopsy specimen demonstrated a psoriasiform dermatitis with compact orthokeratosis alternating with parakeratosis in a vertical and horizontal array. The clinical and histopathologic findings were consistent with pityriasis rubra pilaris.

Treatment with acitretin (Soriatane®) 25 mg twice a day and infliximab (Remicade®) at 5mg/kg/dose was initiated after confirmation of laboratory results and a negative tuberculin skin test. The patient's symptoms did not improve after 4 infusions of infliximab (weeks 0, 2, 6, and 14), which was then discontinued. He has had no improvement of his symptoms with continued acitretin.


Discussion

PRP is an inflammatory disease characterized by coalescing scaly, salmon-colored plaques with islands of sparing in areas of normal-appearing skin [2, 3]. Most cases progress to a distinctive orange-hued exfoliative erythroderma [3]. Lesions tend to spread caudally, beginning in the scalp [4]. Palmoplantar keratoderma and follicular papules are characteristic findings [2, 3]. Ectropion can be observed in severe cases [3], and fingernail changes such as subungual hyperkeratosis, nail plate thickening, and splinter hemorrhages are not uncommon [5].

Five clinical variants, which were first described by Griffiths, vary in age at onset, distribution of lesions, and duration of disease [2]. Most common is Type I, the classic adult form, which accounts for greater than 50 percent of cases. Eighty percent of Type I cases spontaneously resolve within 3 years. Type II is a rare atypical adult variant and tends to be chronic in course. Types III to V are juvenile in onset and differ in clinical course and distribution of lesions [2, 6, 7]. Recently, some have proposed a new Type VI subset for HIV-associated cases [8].

Histopathology of PRP demonstrates psoriasiform hyperplasia with alternating orthokeratosis and parakeratosis in vertical and horizontal directions, with thick suprapapillary plates, broad rete ridges, and narrow dermal papillae [9, 10]. Acantholytic dyskeratosis, follicular plugging, and hypergranulosis are most predictive of PRP [9]. An inflammatory dermal infiltrate of eosinophils and plasma cells can also be observed [9].

The pathogenesis of PRP is not known. Initially thought to be due to a deficiency in vitamin A, many patients with PRP were later found to have normal serum levels of vitamin A [11] as well as retinol-binding protein [12, 13]. Magro et al proposed that an abnormal immune response to certain antigens may interfere with epidermal retinoid signaling pathways and disrupt keratinocyte terminal differentiation [9]. Others speculate that an infectious agent may be implicated in certain juvenile cases of PRP [14] and in HIV-associated PRP [15].

Treatment of PRP remains a challenge and results are variable. Synthetic oral retinoids have largely replaced toxic doses of vitamin A as first-line therapy. Isotretinoin has been effective in a number of patients [16, 17, 18]. In a large series, Dicken et al. found that 80 percent of patients had clearing of lesions within an average of 25 weeks of treatment with isotretinoin at a dose of approximately 1 mg/kg/day [17]. Allison et al. found isotretinoin to be the most effective in treating juvenile PRP [6]. Historically, etretinate [17, 18, 19, 20] had comparable rates of success, but was discontinued in 1998 and replaced by acitretin. Although there have been no large series of patients studied, treatment with acitretin at 1mg/kg/day alone or in combination with ultraviolet light have been reported with mixed results [21, 22, 23, 24, 25, 26].

Low-dose weekly methotrexate alone or in combination with retinoids can also be effective, although the results are inconsistent [2, 17, 18, 26]. Treatment with cyclosporine, azathioprine, stanozolol, topical calcipotriol, PUVA have all been reported with variable degrees of success [1, 3].

Because of its anti-inflammatory properties, inhibitors of tumor necrosis factor alpha (TNF-α) have recently been suggested as a therapeutic option for PRP. One such drug is infliximab, a chimeric monoclonal antibody against TNF-α approved by the FDA for the treatment of rheumatoid arthritis and Crohn's disease [27]. Successes in off-label usage for inflammatory skin diseases such as psoriasis [28, 29, 30], hidradenitis suppurativa [31], sarcoidosis, Behcet's disease, and collagen vascular diseases are growing in number [32]. The most data exist for psoriasis, and recent double-blinded, randomized controlled trials show that infliximab is effective for treating severe plaque-type psoriasis [29].

Generally well-tolerated, major side effects of infliximab include infusion reactions and infections [27, 33]. The most recognized infectious disease associated with infliximab is reactivation of tuberculosis, but cases of disseminated varicella [34, 35], disseminated Salmonella typhimurium [36], and atypical pneumonias [37] have also been reported. In rare instances infliximab has caused reversible lupus-like syndromes and neurologic disease [27]. The association of infliximab with congestive heart failure and malignancy require further investigation [27].

The efficacy of TNF-α inhibitors in the treatment of PRP is uncertain, and there have been no controlled studies. Only two reports describing the use of TNF-α inhibitors for PRP exist in the literature [23, 38]. In one case in which the patient had coexisting rheumatoid arthritis and PRP, treatment with a p55 TNF-α receptor immunoadhesin improved the patient's arthritic symptoms, but not the cutaneous symptoms associated with PRP [38]. In another study, a retrospective chart review demonstrated that three out of three patients with refractory PRP experienced marked improvement within 2 weeks of receiving two infusions of infliximab at 5 mg/kg/dose [23].

Infliximab is a new drug with potential for treating a number of inflammatory skin diseases. Although infliximab may improve PRP in some cases, it was not effective in our patient. We encourage further investigations to better ascertain if infliximab is feasible as a therapeutic option for this debilitating disease.

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