DR [page 8] [Dermatology Reports 2016; 8:6599] Erythrodermic psoriasis treated with apremilast John Arcilla,1 Daniel Joe,1 Johnathan Kim,1 Yohanan Kim,1 VuAnh N. Truong,1 Navin Jaipaul1,2 1Department of Medicine, Loma Linda University School of Medicine and 2Department of Medicine, VA Loma Linda Healthcare System, Loma Linda, CA, USA Abstract Erythroderma is a rare potentially deadly exfoliative dermatitis characterized by diffuse cutaneous erythema which may be associated with multi-organ dysfunction. Therefore, it is imperative to recognize and treat it promptly. Erythrodermic psoriasis is the most common form of erythroderma. Management of this condition is largely based on aggressive sup- portive care and the use of anti-inflammatory immunosuppressive and biologic agents. We describe a case of psoriatic erythroderma which was triggered by withdrawal from sys- temic steroids and successfully treated with apremilast and cyclosporine. Apremilast induced atrial fibrillation limited its continued use after the initial response period. Introduction We report a case of a 79 year old man with erythrodermic psoriasis successfully treated during the initial response phase with the novel oral small-molecule phosphodiesterase-4 inhibitor apremilast. Case Report A 79-year-old man with hypertension and psoriasis was hospitalized for severe sepsis associated with a generalized and painful ery- thematous rash. He had been diagnosed with psoriasis affecting <1% body surface area (BSA) three months before this presentation and was treated with topical ketoconazole and fluocinolone. Two weeks before hospitaliza- tion, he received a five day oral prednisone taper prescribed by a family physician for skin rash. Following this, he developed a confluent, erythematous, scaling rash covering >50% BSA. Methotrexate was started for presumed psoriatic erythroderma; however, his symp- toms worsened to include progressive skin involvement, fever, and hypotension which led to hospitalization.Physical exam revealed ten- der erythematous plaque with scale from head to toe, most prominently involving the head, neck, chest, back, upper arms, abdomen, but- tocks, groin, and proximal thighs (Figure 1). Laboratory evaluation was remarkable for leukocytosis of 23.8×103/µL and pre-renala- zotemia. Intravenous fluids, empiric antibi- otics, topical steroids, and emollient moisturiz- er were started. Infectious work-up was nega- tive; yet fevers, leukocytosis, and cutaneous pain symptoms persisted. Dermatology per- formed a punch biopsy which demonstrated evolving pustular psoriasis (Figure 2). Apremilast was started for treatment of ery- throdermic psoriasis. The patient’s rash and systemic features began to improve by day 10. Though BSA involvement was essentially unchanged, psoriasis plaques demonstrated reduced erythema and scaling with marked improvement in cutaneous pain symptoms (Figure 3). As a result, Psoriasis Area and Severity Index score improved from 44.0 on admission to 26.4 after initiating apremilast treatment. However, the patient subsequently developed new-onset atrial fibrillation attrib- uted to apremilast which was discontinued and switched to cyclosporine. The patient contin- ued to improve and was discharged on cyclosporine. Dermatology Reports 2016; volume 8:6599 Correspondence: Navin Jaipaul, VA Loma Linda Healthcare System, 11201 Benton St. 111N, Loma Linda, CA 92357, USA. Tel.: +1.909.583.6090 - Fax: +1.909.777.3858. E-mail: Navin.Jaipaul@va.gov Key words: Erythroderma; Psoriasis; Erythrodermic psoriasis; Apremilast. Contributions: the authors contributed equally. Conflict of interest: the authors declare no poten- tial conflict of interest. Received for publication: 13 May 2016. Accepted for publication: 17 August 2016. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). ©Copyright J. Arcilla et al., 2016 Licensee PAGEPress, Italy Dermatology Reports 2016; 8:6599 doi:10.4081/dr.2016.6599 Figure 1. Skin findings on day one of hospitalization demonstrating (A) well defined generalized erythema and scaling most promi- nently involving the head, neck, chest, back, upper arms, abdomen, buttocks, groin, and proximal thighs and (B) magnified view of the erythema and scaling. No n c om me rci al us e o nly [Dermatology Reports 2016; 8:6599] [page 9] Discussion Erythroderma is a rare potentially deadly exfoliative dermatitis which may result from systemic infection, drug hypersensitivity, malignancy (e.g. cutaneous T cell lymphoma), and inflammatory conditions such as Stevens Johnson syndrome, pityriasis rubra pilaris, and erythrodermic psoriasis.1 Initial manage- ment for severe cases includes fluid resuscita- tion, empiric antibiotics, and diligent diagnos- tic evaluation. Erythrodermic psoriasis is the most com- mon form of erythroderma and accounts for 25% of all cases.2 When associated with psori- asis, the erythrodermic variant represents less than 1.5% of cases and manifests with well- defined erythematous plaques and overlying silvery scale.3 It generally affects the entire body and may be associated with life-threaten- ing complications such as sepsis, hypovolemic shock, and acute kidney injury secondary to cutaneous fluid loss.2 Erythrodermic psoriasis may result from uncontrolled dermatosis, abrupt withdrawal of anti-psoriatic drugs such as steroids or methotrexate, drug reaction, sys- temic infection, ultraviolet burns, alcoholism, and emotional stress.2 Our patient’s withdraw- al from oral steroids likely triggered his ery- throderma. Skin biopsy may be helpful in diag- nosis as erythroderma may develop acutely or gradually from any variant of psoriasis.2 Treatment is largely based on aggressive sup- portive care and the use of anti-inflammatory immunosuppressive and biologic agents. High quality evidence-based treatment recommen- dations for erythordermic psoriasis are lacking due to the rarity of the condition. Most ran- domized clinical trials on psoriasis treatments have excluded less common variants such as the erythrodermic and pustular subtypes.4 In light of this, first-line agents that have been used with variable efficacy include cyclosporine, infliximab, acitretin, and methotrexate.5 Etanercept and combination therapies are second-line alternatives.5 Recently, biologics including ustekinumab and golimumab have also been used with reported efficacy in the treatment of erythrodermic pso- riasis.6,7 Systemic corticosteroids and ultravio- let light therapy are not recommended due to risks of disease exacerbation and photosensi- tivity.5 Choice of therapy should be based on disease severity and patient comorbidities. For example, we chose to treat our patient with apremilast due to the presence of pre-renal acute kidney injury which is a relative con- traindication to use of the other aforemen- tioned first-line agents. Apremilast is a novel small-molecule oral medication which selec- tively inhibits phosphodiesterase 4 and has been shown to downregulate the production of pro-inflammatory cytokines while upregulat- ing anti-inflammatory cytokines.8 It is approved for treatment of psoriatic arthritris and moderate to severe plaque psoriasis. The efficacy of apremilast was demonstrated in a phase III randomized controlled trial that showed a statistically and clinically significant reduction versus placebo in the baseline Psoriasis Area and Severity Index score in patients with moderate to severe plaque psori- asis.9 However, a search of the published liter- ature resulted in no reports describing the use of apremilast in erythrodermic psoriasis. Our Case Report Figure 2. Skin biopsy demonstrating mild psoriasiform hyperplasia and rare intracorneal pustules with mild superficial perivascular mixed inflammation consistent with evolving pustular psoriasis. Figure 3. Skin findings on day ten of hospitalization demonstrating reduced intensity of erythema and scaling in response to apremilast treatment. No n c om me rci al us e o nly [page 10] [Dermatology Reports 2016; 8:6599] patient improved on apremilast; however, he developed new-onset atrial fibrillation which was attributed to the medication so it was dis- continued. When compared with placebo, apremilast treatment has been associated with an increased, albeit low, incidence of tach- yarrhythmia, most frequently atrial fibrillation.9 Once the patient’s renal function improved, he was started on cyclosporine and his erythroderma eventually resolved. Conclusions Erythroderma associated with psoriasis may be triggered by withdrawal from systemic steroids. It is a rare and potentially fatal exfo- liative dermatitis which needs to be recog- nized and treated promptly. The mainstay of treatment is founded on aggressive supportive care and use of anti-inflammatory immuno- suppressive drugs, including newer biologic agents. We also observed encouraging results in treating erythrodermic psoriasis using the novel oral small-molecule phosphodiesterase-4 inhibitor apremilast. Its continued use in our patient, however, was limited after the initial response period by the development of atrial fibrillation which was attributed to the medica- tion. References 1. Rothe MJ, Bernstein ML, Grant-Kels JM. Life-threatening erythroderma: diagnos- ing and treating the red man. Clin Dermatol 2005;23:206-17. 2. Stinco G, Errichetti E. Erythrodermic pso- riasis: current and future role of biologi- cals. Bio Drugs 2015;29:91-101. 3. Raychaudhuri SK, Maverakis E, Raychaudhuri SP. Diagnosis and classifi- cation of psoriasis. Autoimmun Rev 2014;13:490-5. 4. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: sections 1,3,4,5. Overview of psoriasis and guide- lines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008;58:826-50. 5. Rosenbach M, Hsu S, Korman NJ, et al. Treatment of erythrodermic psoriasis: from the medical board of the National Psoriasis Foundation. J Am Acad Dermatol 2010;62:655-62. 6. Kim YS, Kim JH, Lee S, et al. Erythrodermic psoriasis improved by ustekinumab: a report of two cases. Ann Dermatol 2016;28:121-2. 7. Lee WK, Kim GW, Cho HH, et al. Erythrodermic psoriasis treated with goli- mumab: a case report. Ann Dermatol 2015;27:446-9. 8. Kelly JB, Foley P, Strober BE. Current and future oral systemic therapies for psoria- sis. Dermatol Clin 2015;33:91-109. 9. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moder- ate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol 2015;73:37-49.A) Case Report No n c om me rci al us e o nly