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Pityriasis rubra pilaris (PRP) is an inflammatory dermatologic disorder of unknown cause characterized by hyperkeratotic follicular papules combining into salmon-colored scaling plaques, palmoplantar hyperkeratosis, and sharply demarcated islands of spared skin.1 We report a case of refractory PRP treated with the immune modulator apremilast.
Report of a Case
A white man in his 70s presented with an 8-month history of scaling, pink, pruritic papules, originating on his back (Figure, A), which coalesced to encompass nearly his entire body surface. There was extensive erythema with scaling and waxy, hyperkeratotic scaling of the palms and soles.
Almost complete resolution is seen on the back of this elderly male patient.
A punch biopsy was performed for hematoxylin-eosin staining and demonstrated alternating parakeratosis and orthokeratosis with spongiosis and mild superficial lymphocytic infiltrate. Given these findings, PRP was diagnosed.
The patient started acitretin therapy and showed initial improvement, but after 4 months, his disease continued to progress. He was transitioned to methotrexate therapy with prednisone bridging. However, the methotrexate regimen was discontinued after 8 weeks owing to lack of response and was replaced with cyclosporine. After 4 weeks of marginal response with cyclosporine and prednisone, infliximab was added, based on literature reports of improvement of PRP with tumor necrosis factor (TNF) inhibition.2,3
The patient showed marked improvement after 1 infliximab infusion of 5mg/kg. Unfortunately, 4 weeks later, he was diagnosed with small-cell lymphocytic leukemia (SLL). Because TNF inhibitors have been associated with an increased risk of lymphoma,4 infliximab therapy was discontinued. The patient sought care for SLL, and rituximab and bendamustine chemotherapy was initiated. After completion of the chemotherapy, his PRP worsened.
The challenge was to identify a PRP-directed treatment in a patient with refractory disease and contraindication to TNF inhibitors. After exhausting therapeutic options, we considered apremilast (Otezla; Celgene Corporation). The patient started with a dose of 10 mg/d and titrated over 5 days to the recommended maintenance dose of 30 mg twice daily.
Four weeks later, the patient reported significant improvement in symptoms. He complained of mild gastrointestinal upset but denied other new symptoms. The most common adverse effects reported with apremilast are diarrhea, nausea, and headache.5 At 8- and 12-week follow-ups, he reported further decreases in body surface area involvement of PRP. At 6- and 8-month follow-ups, he showed nearly complete resolution of skin findings (Figure, B).
There is no unifying etiology to the pathogenesis of PRP. Current treatments are mainly empirical or based on case reports. Systemic retinoids and methotrexate are often used as first-line treatments. Other therapies include azathioprine, cyclosporine, fumaric acid, mycophenolate mofetil, vitamin D analogues, and phototherapy.1,2
Eastham et al3 demonstrated, in the most comprehensive analysis to date, that TNF inhibition is effective for refractory PRP. The patient in the present case responded well to infliximab but could not continue therapy because he developed SLL. Based on the proposed immune-driven mechanism of PRP, we explored novel treatments targeting regulation of inflammatory responses.
Apremilast is an oral, small-molecule inhibitor of phosphodiesterase 4 (PDE4) approved for treatment of moderate to severe plaque psoriasis and psoriatic arthritis.5 Expressed in various cell types including keratinocytes, PDE4 participates in regulation of immune and inflammatory processes by regulating intracellular cyclic adenosine monophosphate (cAMP) and downstream protein kinase A pathways and phosphorylating CREB (transcription factor cAMP-response element binding protein).6 Activation of this pathway results in downstream inhibition of proinflammatory cytokines, including TNF. Given our patient’s improvement with TNF inhibition, the choice of apremilast was a logical next step for the patient in the present case. The drug is appealing owing to its minimal adverse effects and monitoring requirements.6 At 12-month follow-up, the patient remained disease free.
Our experience suggests that apremilast may be an effective treatment for refractory PRP. Additional studies are necessary to further establish the role of PDE4 inhibitors as an option for refractory PRP.
Corresponding Author: Clara Curiel-Lewandrowski, MD, Department of Dermatology, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724 (firstname.lastname@example.org).
Published Online: November 4, 2015. doi:10.1001/jamadermatol.2015.3405.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We are indebted to Fangru Lian, MD, Department of Pathology, University of Arizona, Tucson, for providing the histopathologic analysis for the case. She did not receive any compensation for her contributions.
Krase IZ, Cavanaugh K, Curiel-Lewandrowski C. Treatment of Refractory Pityriasis Rubra Pilaris With Novel Phosphodiesterase 4 (PDE4) Inhibitor Apremilast. JAMA Dermatol. 2016;152(3):348–350. doi:10.1001/jamadermatol.2015.3405
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