Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2022;12(4):e2022179 1 Apremilast in Psoriasis Patients With Serious Comorbidities: a Case Series and Systematic Review of Literature Aikaterini Tsentemeidou1, Elena Sotiriou1, Nikolaos Sideris1, Katerina Bakirtzi1, Ilias Papadimitriou1, Aimilios Lallas1, Dimitrios Ioannides1, Efstratios Vakirlis1 1 First Department of Dermatology and Venereology, School of Medicine, Aristotle University, Thessaloniki, Greece Key words: apremilast, comorbidities, medical dermatology, psoriasis, biologics Citation: Tsentemeidou A, Sotiriou E, Sideris N, et al. Apremilast in psoriasis patients with serious comorbidities: a case series and systematic review of literature. Dermatol Pract Concept. 2022;12(4):e2022179. DOI: https://doi.org/10.5826/dpc.1204a179 Accepted: March 18, 2022; Published: October 2022 Copyright: ©2022 Tsentemeidou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Elena Sotiriou, PhD, First Department of Dermatology and Venereology, School of Medicine, Aristotle University, 124 Delfon str, 54645, Thessaloniki, Greece, +302313308822, Email: elenasotiriou@yahoo.gr Introduction: Patients with serious comorbidities are traditionally excluded from clinical trials. Apremilast is not contraindicated in active infections, malignancy and serious hepatic or renal impair- ment, but real-life data is needed to support this recommendation. Objectives: The aim of this paper is to present our personal as well as literature-sourced real-world evidenced on apremilast use in psoriasis patients with serious baseline comorbidities. Methods: A case-series and systematic literature review were performed. The psoriasis archives of a tertiary-care hospital, four electronic databases (MEDLINE, ScienceDirect, Cochrane Library, Google scholar) and other sources were searched (January 2014 – July 2021). Identified records were consid- ered eligible, if they reported on the use of apremilast monotherapy in psoriasis patients with chronic infections, history of malignancy, serious liver, renal, psychiatric, or other disease(s). Results: At least 841 psoriasis patients with serious baseline diseases received apremilast. Only 3 cases of cancer progression and no infection reactivations or worsening of other diseases were documented. No increased frequency/severity of adverse events or reduced drug efficacy were noted. Main limita- tions of this study are the exclusion of a few reports due to inappropriately documented data and the fact that at least some patients might have been counted more than once. Conclusions: Apremilast is a safe and adequately efficacious option for psoriasis that cannot be treated/is challenging to treat with classic systemic agents and/or biologics. ABSTRACT 2 Review | Dermatol Pract Concept. 2022;12(4):e2022179 Introduction Psoriasis is a chronic cutaneous disease of inflammatory nature, with a worldwide prevalence ranging between 1-3%; it has a substantial negative effect on patient physical well- being and quality-of-life, as well as on national health expen- diture [1–3]. Apremilast (Otezla®, Amgen), a small molecular inhibitor of phosphodiesterase 4 (PDE4), has been used for the treatment of psoriatic arthritis and psoriasis since 2014 (first US Food and Drug Administration [FDA] approval). Contrary to biologics, it does not target any one specific component of the inflammatory process involved in the pathophysiology of psoriasis, but rather achieves some sort of equilibrium of pro-inflammatory and anti-inflammatory agents [4,5]. Apremilast comes with a set of favorable attributes, among which are the oral distribution, lower cost comparing to biologics and good safety profile [3,6]. It is not contrain- dicated in patients with active infections or serious liver im- pairment, nor is routine lab monitoring necessary. Similarly, it can be administered to patients with past or current ma- lignancy [8]. Patients with severe renal impairment can still receive a reduced dose of apremilast [9]. A pooled analysis (≥ 156 weeks) from the 2 apremilast-approving (ESTEEM) trials showed that serious infection rate was low among pa- tients receiving apremilast, while no serious opportunistic infections or cases of tuberculosis reactivation were noted [10]. However, as patients with chronic infections, cancers and serious co-existing diseases are traditionally excluded from clinical trials testing new drugs, conclusions regarding the use of said drugs in these occasions cannot always be safely drawn [7,11]. Objectives The purpose of this study is to present our five-year experi- ence in administering apremilast to psoriasis patients with serious comorbidities in the setting of a tertiary-care center in terms of drug safety and efficacy, as well as to concisely portray relevant real-life evidence sourced through a system- atic literature search. Methods Case Series The March 2016 (apremilast approval in Greece) to June 30th, 2021 archives of both the Psoriasis Outpatient Clinic and Afternoon Private Clinics of the First Dermatology Department, Aristotle University, Thessaloniki, Greece were consecutively searched for all psoriasis patients hav- ing received at least one dose of apremilast. Patients with an appropriately documented chronic/latent infection, recent (past 10 years) malignancy excluding basal cell carcinoma, serious kidney (stage IV and V) or liver (Child-Pugh C) dis- ease, severe psychiatric disorder or other serious illness as was defined by Kelley [12] were included in the study. The following data were retrieved by two collaborating authors (AT and NS): age, gender, comorbidity(-ies), year of comor- bidity diagnosis, apremilast dose, baseline Psoriasis Area and Severity Index (PASI), treatment outcome in terms of efficacy, duration of apremilast treatment (weeks) and ad- verse events (AEs) including adverse outcomes related to comorbidity(-ies) in question. Written informed consent was obtained by all participants. This project was designed and conducted based on the declaration of Helsinki and was ap- proved by the Ethics Committee of the Hospital of Venereal and Cutaneous Diseases, Thessaloniki, Greece. Systematic Review Eligibility Criteria We conducted this systematic review as stated by Meta-analyses Of Observational Studies in Epidemiology (MOOSE) statement. Published and unpublished prospec- tive or retrospective observational studies reporting on the use of apremilast for the treatment of psoriasis patients with serious baseline comorbidities (chronic/latent infections such as tuberculosis, hepatitis and HIV, cancer diagnosis within past ten years excluding basal cell carcinoma, stage IV and V chronic kidney disease hemodialysis, Child-Pugh class C liver disease, serious psychiatric disorders or other serious illness as was defined by Kelley [12]) were considered eligible for inclusion in our study. Clinical trials or studies not pre- senting real-life data, as well as studies reporting on combi- nation therapy of apremilast and other systemic agents aside from phototherapy, systemic corticosteroids or other medi- cation administered systemically for existing comorbidities were excluded from our review. Only studies performed after 2014 (apremilast first FDA approval) were considered. No language restrictions were placed. Information Sources Three electronic databases were searched (MEDLINE, ScienceDirect, and the Cochrane Library electronic data- bases). Google scholar (https://scholar.google.com/) was also browsed. Abstract compendia of the World Con- gresses of Dermatology, World Psoriasis and Psoriatic Ar- thritis Congresses, American Academy of Dermatology Annual Meetings and European Academy of Dermatology and Venereology Annual Congresses of the last five years were examined (online browsing). Last search date for all above mentioned platforms was July 4th, 2021. Amgen® was Review | Dermatol Pract Concept. 2022;12(4):e2022179 3 contacted and kindly asked to supply our team with any published or unpublished data abiding by our search criteria. The “Reference” section of studies included in our review was hand searched for additional eligible work. Search Strategy The following search strategy was used for MEDLINE data- base and modified accordingly for the rest of searched plat- forms: (apremilast[Title]) AND (psoriasis[Title/Abstract]) filtered by year of publication (2014 to 2021). The search was performed independently by two authors (AT and NS). Study Endpoints The primary endpoint of this study was the documentation of any safety-related outcomes in patients with serious co- morbidities having received apremilast (for example comor- bidity progression, AEs commonly related to apremilast use or other events). Secondary endpoint was treatment efficacy, without any limitations imposed on efficacy measures used. Selection Process and Data Collection Duplicate records were independently manually removed by two reviewers (NS and AT). Subsequently, two review- ers (AT and NS) independently screened titles and abstracts for relevance to the study objective. The full text of remain- ing records was read, and eligible studies were included in the review. AT and NS separately extracted the following data from included studies according to a pre-formulated sheet: first author, year of publication / research completion, comorbidity(-ies), age and gender of patient(-s), apremi- last dose, baseline PASI, AEs including comorbidity-related events. Any disagreements were resolved in consultation with a third author (ES). Quality Assessment Two authors (AT and ES) independently assessed included re- ports based on two different tools, namely the Joanna Briggs Institute (JBI) critical appraisal tool for case reports/case series and the JBI critical appraisal tool for analytical cross- sectional studies, each comprising eight questions (Supplement). Each study was assigned an overall rating of poor, good or fair, if 0-5, 6-7 or 8 criteria were met respectively. Results The psoriasis-archives search returned 16 eligible cases, one of which was not included in the analysis due to incom- pletely documented patient data (Table 1). No progression of malignancy, reactivation of chronic / latent infection or dete- rioration of already deficient renal or hepatic function were noted. Apremilast was generally well-tolerated and only mild transient AEs were reported in 6 patients. Patient compliance to treatment was high (three cases of temporary drug dis- continuation, < 14 days, due to Covid-19-related restrictions and consequent difficulties in drug prescription). Desired re- sponse (PASI50) was not achieved in 1 case and apremilast was therefore discontinued (primary drug failure). The systematic literature search yielded 52 studies eligi- ble for inclusion (Figure 1). One additional study was iden- tified after the last search date (published July 8th 2021) and does not appear in the flow diagram (Figure 1) [13]. A total of at least 826 psoriasis patients with serious comorbidities (various malignancies – at least 456 patients –, latent / past tuberculosis – 49 patients –, hepatitis B, C and HIV infec- tions – at least 83 patients –, serious renal – 7 patients – or liver impairment – at least 110 patients –, serious psychiatric disorders – 49 patients – or other serious illness as was defined by Kelley [12]) were prescribed apremilast twice or once daily (Table 2). The exact number of patients with se- rious comorbidities prescribed apremilast was not reported in a few studies, therefore, the numbers mentioned above are a conservative underestimation of the studied population. Included patients manifested all types of psoriasis and/or nail psoriasis. Overall, apremilast was hardly ever associated with negative comorbidity-related outcomes and reported AEs were apparently not more severe or frequent than those experienced by the average psoriasis patient. Sufficient re- sponse of psoriasis to apremilast was recorded in most cases. Overall, the quality of included studies was good (Table 3). Conclusions This case series and systematic review reports on the use of apremilast in 841 psoriasis patients with serious baseline comorbidities, which would have made the use of classic systemic agents and/or biologics inappropriate or challeng- ing. According to our study, the use of apremilast in this group of patients apparently neither leads to deterioration / exacerbation of severe pre-existing comorbidity(-ies) nor is it associated with an increased risk of adverse events. What is more, drug efficacy does not seem to be affected by the under- lying comorbidity, with cases of remarkable response even in erythrodermic patients with very serious underlying diseases. A drug safety profile, especially in the context of pre-existing comorbidities, is one of its major attributes to be taken into consideration, when deciding on a treatment regimen [14]. Psoriasis patients receiving apremilast, as op- posed to other systemic agents, seem to have a lower infec- tion risk [15]. Rates of herpes zoster infection were lowest for users of apremilast among a cohort of psoriasis patients treated with biologics and/or small molecules (5.4, 95% CI  1.7-12.6) [16]. Comparing to methotrexate (MTX), as investigated in a cohort of 2845 psoriasis patients treated 4 Review | Dermatol Pract Concept. 2022;12(4):e2022179 viral load, discussion with an infectious-disease specialist is warranted, with apremilast and acitretin being the preferred options [19]. Based on the same recommendations, the pre- ferred options for short-term systemic treatment of psoriasis patients with chronic hepatitis C infection are adalimumab and etanercept, as there is not enough evidence to support the use of other biologics and apremilast [19]. As far as chronic hepatitis B infection is concerned, ustekinumab, apremilast, cyclosporine and acitretin are preferred [19]. Apremilast has shown potential in the treatment of psoriasis patients with a history of malignancy. It may even help treat lung cancer, as PDE4 is expressed in lung cancer cells [20]. In the current pandemic era, it is important to examine a drug safety with regards to the COVID-19 infection. Accord- ing to the World Health Organization, psoriasis patients on with nine systemic agents in Spain, apremilast had a lower infection (incidence rate 0.3 [95% CI 0.1-0.9]) and malig- nant neoplasm risk (incidence rate 0.1 [95% CI 0-0.7]) [14]. Psoriasis may be more severe or difficult to treat in patients with HIV infection [17,18]. What is more, HIV-positive patients are immuno-compromised and prone to reactivation of latent infections [17]. According to the 2020 Belgian practical recommendations for the treatment of psoriasis in HIV-positive patients, apremilast and acitre- tin are considered first-line choices ]. Furthermore, many biologics (adalimumab, certolizumab pegol, etanercept, in- fliximab, ustekinumab, guselkumab, risankizumab, broda- lumab, secukinumab, ixekizumab) can be used in patients receiving highly active antiretroviral therapy (HAART) and having undetectable viral load [19]. In case of detectable Table 1. Cases of psoriasis patients with serious baseline comorbidities treated with apremilast. Case Sex Age Comorbidity (diagnosis) APR Dose Bas PASI Tx outcome APR duration AEs 1 M 69 Prostate cancer (2013) 30 mg bid 10.3 PASI50 week 16 53 (LOoE) None 2 M 76 Lung tuberculosis (1968) 30 mg bid 9 PASI50 week 16 52 (Lost to f/u) None 3 M 73 Latent tuberculosis 30 mg bid 13.4 PASI75 week 16 72 (LOoE) None 4 M 79a Lung cancer (2015) 30 mg bid 15.9 PASI50 not achieved 21 (LAoE) Abdominal pain 5 F 65 Breast cancer (2016), hepatitis B 30 mg bid 5.3 PASI100 24 weeks 35 (clear skin) Dyspepsia 6 M 63 Hepatitis C and liver fibrosis 30 mg bid 6.7 PASI50 week 16 37 (LOoE) None 7 M 44 Hemodialysis (Stage 5 Chronic kidney disease – IgA nephropathy) 30 mg od 13.2 PASI50 week 24 40 (LOoE) None 8 F 66 Lung tuberculosis (1980) 30 mg bid 11.1 PASI50 week 16 4 (AEs) Headache 9 M 33 HIV positive (2011) (CD4+ 602 cells/mm3) 30 mg bid 15.8 PASI75 week 16 149 (SoD) None 10 M 65 Urinary bladder cancer (2015), Stage 2 chronic kidney disease 30 mg bid 9.1 PASI50 week 16 31 (LOoE) None 11 F 56 Cervical cancer (2013) 30 mg bid 10.8 PASI75 week 24 154 (SoD) None 12 M 37 HIV positive (2009) (CD4+ 590 cells/mm3) 30 mg bid 24.5 PASI50 week 24 56 (SoD) Transient nausea 13 M 44 HIV positive (2002) (CD4+ 550 cells/mm3) 30 mg bid 33.6 PASI90q week 52 104 (SoD) Transient diarrhea 14 M 32 HIV positive (2009) (CD4+ 702 cells/mm3) 30 mg bid 19.3 PASI90 week 24 34 (SoD) Transient diarrhea 15 M 88 Hepatitis B 30 mg bid 28.6 PASI90 week 8 16 (SoD) None AEs = adverse events; APR = apremilast; Bas = baseline; F = female; f/u = follow-up; HIV = human immunodeficiency; LAoE = lack of efficacy; LOoE = loss of efficacy; M = male; o.d. = once daily; PASI = Psoriasis Area and Severity Index;; bid = twice daily (bis in die); PASI50  = 50% reduction of baseline PASI; PASI75 = 75% reduction of baseline PASI; virus; PASI90 = 90% reduction of baseline PASI; SoD = still on drug; Tx = treatment. aDeceased. Review | Dermatol Pract Concept. 2022;12(4):e2022179 5 IDENTIFICATION OF STUDIES VIA DATABASES AND OTHER SOURCES RECORDS IDENTIFIED FROM: MEDLINE (n=263) SCIENCEDIRECT (n = 161) COCHRANE LIBRARY (n = 207) GOOGLE SCHOLAR (n = 471) CONGRESSES (n = 129) AMGEN (n = 21) RECORDS SCREENED (n = 846) REPORTS SOUGHT FOR RETRIEVAL (n = 215) REPORTS NOT RETRIEVED (n = 12) REPORTS EXCLUDED DUE TO NOT MEETING INCLUSION CRITERIA AND/OR MEETING EXCLUSION CRITERIA: (n =151) REPORTS ASSESSED FOR ELIGIBILITY (n = 203) REPORTS SOURCED THROUGH REFERENCE SEARCH OF ELIGIBLE RECORDS (n= 0) REPORTS INCLUDED IN REVIEW (n = 52) RECORDS EXCLUDED (n = 631) RECORDS REMOVED BEFORE SCREENING: DUPLICATE RECORDS REMOVED (n = 405) RECORDS REMOVED FOR OTHER REASONS (n = 1) ID EN TI FI C A TI O N SC R EE N IN G IN C LU D ED Figure 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram detailing the number and origin of records identified, included in and excluded from this systematic review, as well as the reasons for exclusion. 6 Review | Dermatol Pract Concept. 2022;12(4):e2022179 Ta b le 2 . L it er at u re c as es o f ap re m il as t ad m in is te re d t o p so ri as is p at ie n ts w it h s er io u s b as el in e co m o rb id it ie s. R e p o rt C o m o rb id it y A g e /S e x A P R d o se B a s PA S I T x o u tc o m e A E s M u gh ed d u 2 0 2 0 [ 2 2 ] R ec u rr en t b ra in o li go d en d ro gl io m a u n d er te m o zo lo m id e an d p re d n is o n e 4 5 /M 3 0 m g b id 4 5 Im p ro ve m en t N /R C O V ID -1 9 p n eu m o n ia , f u ll r ec o ve ry M an fr ed a 2 0 1 9 [ 1 5 ] H IV p o si ti ve ( C D 4 + 6 2 8 c el ls /m m 3 ), H ep at it is B , d ru g ad d ic ti o n h is to ry 4 1 /M 3 0 m g b id 1 2 PA SI 9 0 W 2 4 N o n e, s ta b le C D 4 + c o u n t Z ar b afi an 2 0 1 9 [ 5 ] H IV p o si ti ve ( C D 4 + > 1 0 0 0 c el ls /m m 3 ) 5 4 /M 3 0 m g b id 1 0 .2 7 3 % P A SI re d u ct io n M 7 T ra n si en t d ia rr h ea , f re q u en t U R T Is , st ab le C D 4 + c o u n t R ed d y 2 0 1 7 [ 4 ] H IV p o si ti ve , H ep at it is C 4 6 /M 3 0 m g b id B SA 8 % B SA 1 .5 % M 5 N o n e Sh ah 2 0 1 9 [ 1 8 ] H IV p o si ti ve ( C D 4 + 7 4 2 /μ l) 3 5 /M 3 0 m g b id , th en o d 1 4 .7 PA SI 1 0 0 W 6 N o n e, s ta b le C D 4 + c o u n t Sa cc h el li 2 0 1 8 [ 3 2 ] H IV p o si ti ve ( 2 0 0 2 ) (C D 4 + 5 6 6 /m c) , p as t H ep at it is B a n d C 5 5 /M 3 0 m g b id 8 N A P SI q 2 1 PA SI 7 5 M 6 N A P SI 7 M 6 N o n e A p al la 2 0 1 9 [ 1 1 ] M et as ta ti c lu n g ad en o ca rc in o m a, s ta ge I II B ( 2 0 1 3 ) 6 7 /F 3 0 m g b id 1 8 PA SI 7 5 W 1 6 N o n e, c an ce r co u rs e n o t af fe ct ed b y A P R R ed d y 2 0 1 9 [ 1 7 ] H IV p o si ti ve ( C D 4 + 4 6 0 c el ls /m m 3 ) 5 0 /M 3 0 m g b id an d t h en o d B SA 1 0 % B SA 0 % M 3 N /R F o ti ad o u 2 0 1 8 [ 3 3 ] C h ro n ic h ep at it is B , u n d et ec ta b le v ir al l o ad 5 2 /F 3 0 m g b .i .d . 1 3 .2 PA SI 9 0 W 2 4 N o n e, n o rm al H B lo ad a n d L F T s Je o n 2 0 1 7 [ 3 4 ] A ct iv e h ep at it is C , d ec o m p en sa te d c ir rh o si s, m et as ta ti c H C C 5 5 /M 3 0 m g b id N /R PA SI 1 0 0 W 6 In it ia l n au se a G o n zá le z- C an te ro 2 0 1 8 [3 5 ] M al ig n an cy : 3 , l iv er d is ea se : 1 , a lc o h o li sm : 1 , in fe ct io u s d is ea se : 1 , r en al i n su ffi ci en cy : 1 , d em ye li n at in g d is ea se : 1 N /R N /R N /R N /R N o c h an ge s in t h e co u rs e o f co m o rb id it ie s G o tt li eb 2 0 2 1 [ 3 6 ] M al ig n an cy : 9 2 , s er io u s in fe ct io n : 5 3 N /R N /R N /R N /R N /R K ah n 2 0 1 9 [ 3 7 ] 1 . r en al c el l ca rc in o m a 2 . m el an o m a 6 3 , N /R 6 4 , N /R N /R B SA 1 0 % B SA 5 % N /R N o c li n ic al /r ad io gr ap h ic al s ig n s o f ca n ce r re cu rr en ce N ag at a 2 0 1 9 [ 3 8 ] H em o d ia ly si s 6 0 , M 3 0 m g o d P SS I 3 6 P SS I 1 0 W 1 2 N au se a (t ra n si en t) U va is 2 0 2 0 [ 3 9 ] B ip o la r af fe ct iv e d is o rd er 3 0 , F 3 0 m g/ d ay N /R N /R N /R V ic o -A lo n so 2 0 2 0 [ 4 0 ] C h ro n ic m ye lo id l eu k em ia u n d er i m at in ib , l at en t tu b er cu lo si s, a lc o h o li sm , s te at o h ep at it is 5 8 , M 3 0 m g b id 2 2 .4 PA SI 9 0 W 2 4 N o n e, s ta b le t u m o ra l st at e, n o rm al la b t es ts M el is 2 0 2 0 [ 4 1 ] M al ig n an cy ( ex cl . N M SC ): 1 3 ( b re as t, b la d d er , co lo re ct al ), s ev er e in fe ct io n : 7 ( H IV , H B V , H C V ), p sy ch ia tr ic d is o rd er : 6 , l iv er d is ea se : 3 , l at en t tu b er cu lo si s: 2 N /R 3 0 m g b id N /R N /R N /R P er ro n e 2 0 1 7 [ 4 2 ] C h ro n ic a n em ia a n d t h ro m b o cy to p en ia 7 1 , M N /R N /R N /R F an co n i Sy n d ro m e Review | Dermatol Pract Concept. 2022;12(4):e2022179 7 R e p o rt C o m o rb id it y A g e /S e x A P R d o se B a s PA S I T x o u tc o m e A E s C ar p en ti er i 2 0 2 0 [ 4 3 ] M al ig n an cy ( ex cl . N M SC ): 1 0 N /R N /R N /R M o st p at ie n ts sh o w ed im p ro ve m en t n o c li n ic al o r ra d io gr ap h ic re cu rr en ce o r p ro gr es si o n o f th ei r ca n ce r P ei ts ch 2 0 1 9 [ 4 4 ] M an te l ce ll l ym p h o m a u n d er r it u x im ab , h ep at ic an d p u lm o n ar y as p er gi ll o si s 6 0 , M 3 0 m g b id 1 7 .2 PA SI 9 0 M 5 N o n e, l ym p h o m a in r em is si o n T ak am a 2 0 2 0 [ 4 5 ] U ri n ar y b la d d er c an ce r u n d er p em b ro li zu m ab 7 4 , M 3 0 m g b id , th en o d 2 .9 PA SI 5 0 W 2 , PA SI 9 0 M 2 N au se a F o ti 2 0 2 1 [ 4 6 ] M el an o m a w it h l ym p h n o d e m et as ta si s u n d er n iv o lu m ab 6 2 , M 3 0 m g b id 4 4 PA SI 5 0 M 6 , PA SI 9 0 M 1 2 N o n e, n o w o rs en in g o f m el an o m a D i L er n ia 2 0 2 1 [ 4 7 ] M al ig n an cy : 3 c o lo re ct al , 2 G I st ro m al , 1 l eu k em ia , 1 l ym p h o m a, 1 k id n ey , 1 u te ru s an d t h yr o id , 2  m el an o m a, 1 u ri n ar y b la d d er ,1 m et as ta ti c SC C , 1  p ro st at e 5 F , 9 M (a ge N /R ) 3 0 m g b id N /R N /R D ia rr h ea , h ea d ac h e (3 p at ie n ts , d is c. A P R ), u ri n ar y b la d d er c an ce r an d m et as ta ti c SC C r ec u rr en ce a ft er A P R d is c. A ra go n -M ig u el 2 0 1 9 [4 8 ] M al ig n an cy h x : 6 , l at en t tu b er cu lo si s: 1 6 , h ep at it is C o r B ( ch ro n ic o r p as t) : 7 N /R N /R N /R N /R N /R N o i n fe ct io n r ea ct iv at io n s T am p o u ra tz i 2 0 1 9 [ 4 9 ] C h ro n ic h ep at it is B , u n d er e n te ca vi r 6 4 , M N /R N /R E x ce ll en t re sp o n se N o n e P ap ad av id 2 0 1 8 [ 5 0 ] M al ig n an cy h x : 1 , l at en t tu b er cu lo si s: 1 , c h ro n ic la te n t h ep at it is B : 1 N /R N /R N /R N /R N /R Sa h u q u il lo -T o rr al b a 2 0 2 0 [ 5 1 ] L at en t tu b er cu lo si s: 1 , a ct iv e h ep at it is B : 1 , sp o n ta n eo u s b ac te ri al p er it o n it is : 1 , i m m u n e h ep at it is : 1 N /R N /R N /R N /R N /R Si ci li an o 2 0 2 0 [ 5 2 ] M et as ta ti c m el an o m a (2 0 1 8 ) 7 5 , M 3 0 m g b id N /R Im p ro ve m en t N o n e, m el an o m a re m is si o n L an n a 2 0 2 0 [ 5 3 ] T u m o rs : 5 N /R N /R N /R N /R N /R L an n a 2 0 1 9 [ 5 4 ] H ep at it is E 5 5 , M 3 0 m g b id 1 8 PA SI 9 0 M 6 N o n e B al at o 2 0 2 0 [ 5 5 ] M al ig n an cy : 4 0 N /R N /R N /R N /R L o w er P A SI 5 0 a n d P A SI 7 5 r es p o n se ra te s Q u ei ro S il va 2 0 2 0 [ 2 1 ] H ai ry c el l le u k em ia 5 5 , M N /R N /R N /R Se ve re C O V ID -1 9 i n fe ct io n Ig h an i 2 0 1 8 ( 1 ) [5 6 ] M al ig n an cy h x : 1 5 , l iv er d is ea se : 8 , p sy ch ia tr ic d is o rd er : 9 N /R N /R N /R N /R N /R Ig h an i 2 0 1 8 ( 2 ) [5 7 ] M al ig n an cy h x : 3 1 , l iv er d is ea se : 2 7 , p sy ch ia tr ic d is o rd er : 2 9 N /R N /R N /R N /R N /R T ab le 2 c o n ti n u es 8 Review | Dermatol Pract Concept. 2022;12(4):e2022179 R e p o rt C o m o rb id it y A g e /S e x A P R d o se B a s PA S I T x o u tc o m e A E s Ig h an i 2 0 1 8 ( 3 ) [5 8 ] M al ig n an cy h x : 5 , l iv er d is ea se : 4 , p sy ch ia tr ic d is o rd er : 4 N /R N /R N /R N /R N /R P h an 2 0 2 0 [ 5 9 ] M al ig n an cy : 4 0 > 6 5 y N /R N /R N /R N /R Ig h an i 2 0 1 8 ( 4 ) [6 0 ] h ep at it is C : 2 , b re as t ca n ce r: 2 , r en al d is ea se (u n sp ec ifi ed ): 2 N /R N /R N /R N /R N /R M eg n a 2 0 2 0 [ 6 1 ] M al ig n an cy : 9 , h ep at it is C : 4 , l at en t tu b er cu lo si s: 3 N /R N /R N /R N /R N /R D el A lc áz ar 2 0 2 0 [ 6 2 ] L u n g ca n ce r: 2 0 , l at en t tu b er cu lo si s: 2 0 , h ep at it is C : 1 7 , h ep at it is B : 1 3 , h ep at it is B a n d C : 2 , m al ig n an cy h x : 9 2 , l iv er d is ea se : 3 3 N /R N /R N /R N /R N o c as es o f in fe ct io n r ea ct iv at io n o r ca n ce r re cu rr en ce F re m li n 2 0 1 7 [ 6 3 ] C as es o f al co h o l ex ce ss , a lc o h o li c li ve r d is ea se , p re vi o u s m al ig n an cy ( u n sp ec ifi ed n u m b er ) N /R N /R N /R N /R N /R F o u lk es 2 0 1 7 [ 6 4 ] C as es o f m al ig n an t m el an o m a an d H IV ( u n sp ec ifi ed n u m b er ) N /R N /R N /R N /R N /R M al ar a 2 0 1 8 [ 6 5 ] L at en t tu b er cu la r sk in i n fe ct io n : 2 , p re vi o u s h ep at it is : 1 , e n d o ca rd it is -r el at ed c ar d ia c va lv e fa il u re : 1 , m al ig n an cy : 4 N /R N /R N /R N /R N o n e D au d én 2 0 2 0 [ 1 4 ] M al ig n an cy h x : 1 4 ( 6 i n l as t 5 y ea rs ), h ep at it is B :1 2 , h ep at it is C : 5 , c h ro n ic l iv er d is ea se : 2 0 , r en al in su ffi ci en cy : 3 N /R N /R N /R N /R N /R K u n gu ro v 2 0 1 9 [ 6 6 ] H ep at it is B : 1 , c h ro n ic p an cr ea ti ti s, c h o le cy st it is an d c o li ti s: 1 , h ep at it is C : 1 4 7 , F 3 8 , F 3 1 , M N /R 2 7 .3 2 9 .9 3 3 PA SI 7 5 W 2 4 PA SI 7 5 W 6 PA SI 7 5 W 2 8 N o n e A ra go n -M ig u el 2 0 1 9 [6 7 ] b re as t ca n ce r: 1 , g al lb la d d er c an ce r: 1 , t re at ed la te n t tu b er cu lo si s: 3 N /R N /R N /R N /R N /R B u li c 2 0 1 9 [ 6 8 ] 1 . l ar yn ge al S C C ( 2 0 1 3 ) 2 . p ap il la ry t h yr o id c an ce r (2 0 1 4 ) 3 . l iv er c ir rh o si s (C h il d -P u gh B )/ p o rt al h yp er te n si o n / h ep at o ce ll u la r ca n ce r (p T 2 p N x p M x )/ li ve r tr an sp la n t (2 0 1 7 ) 4 . m el an o m a (p T 1 a, B re sl o w 0 .8 1 m m ) (2 0 1 3 ) 5 1 , M 5 0 , M 5 1 , M 5 8 , F N /R N /R N /R N o r ec u rr en cy o f m al ig n an cy o ve r a tw o -y ea r fo ll o w -u p F at to re 2 0 1 9 [ 6 9 ] N o n -m et as ta ti c n o n -s m al l- ce ll l u n g ca n ce r u n d er n iv o lu m ab 7 4 , F 3 0 m g b id N /R PA SI 1 0 0 W 6 T ra n si en t n au se a M ag d al en o 2 0 1 9 [ 7 0 ] C h ro n ic l iv er d is ea se : 1 3 , s ev er e in fe ct io n : 1 1 , p re vi o u s m al ig n an cy : 8 N /R N /R N /R N /R N /R Ta b le 2 . L it er at u re c as es o f ap re m il as t ad m in is te re d t o p so ri as is p at ie n ts w it h s er io u s b as el in e co m o rb id it ie s. ( co n ti n u ed ) Review | Dermatol Pract Concept. 2022;12(4):e2022179 9 R e p o rt C o m o rb id it y A g e /S e x A P R d o se B a s PA S I T x o u tc o m e A E s M ag d al en o -T ap ia l 2 0 1 9 [7 1 ] C h ro n ic a ct iv e al co h o li sm a n d h yp er -t ra n sa m in as em ia 6 1 , M N /R N /R N A P SI 3 2 PA SI < 5 M 6 N o s er io u s A E s G io e 2 0 2 1 [ 7 2 ] C h ro n ic h ep at it is B , b ip o la r d is o rd er , a cu te M R SA ee b ac te re m ia , p u lm o n ar y em b o lu s 3 4 , F N /R N /R ( > 9 5 % B SA ) B SA < 1 5 % M 1 N /R Ib ar gu re n 2 0 2 1 [ 7 3 ] 1 . S ta ge I V u ve al m el an o m a 2 . S ta ge I V l ar yn ge al c ar ci n o m a 3 . S ta ge I V s q u am o u s ce ll l u n g ca rc in o m a al l 3 u n d er n iv o lu m ab 5 0 , M 7 0 , M 6 0 , M 3 0 m g b id 1 2 1 3 .8 6 .4 PA SI 5 0 M 1 2 PA SI 7 5 ( ti m e N /R ) PA SI 5 0 n o t ac h ie ve d 1 . d ia rr h ea 2 . h ea d ac h e, c an ce r p ro gr es si o n a ft er 1 0 m o n th s 3 . c an ce r p ro gr es si o n a ft er 1 0 m o n th s K u ra ta 2 0 2 1 [ 7 4 ] C o lo re ct al c an ce r w it h in p as t ye ar 8 2 , F N /R 5 .5 N A P SI 7 7 PA SI 9 0 a n d N A P SI 5 0 W 8 γ- G T i n cr ea se a ft er 8 w ee k s & d ru g d is c. C o h en -S o rs 2 0 2 1 [ 1 3 ] H em at o lo gi c m al ig n an cy : 1 0 N /R N /R N /R N /R E vo lu ti o n o f p re vi o u sl y st ab le C L L (1 c as e) A E s = a d ve rs e ev en ts ; A P R = a p re m il as t; B as = b as el in e; b id = t w ic e d ai ly ; B SA = b o d y su rf ac e ar ea ; F = f em al e; C L L = c h ro n ic l ym p h o cy ti c le u k em ia ; d is c. = d is co n ti n u at io n ; H B V = h ep at it is B v ir u s; H C C  =   h ep at o ce ll u la r ca rc in o m a; H C V = h ep at it is C v ir u s; H IV = h u m an i m m u n o d ef ic ie n cy v ir u s; h x = h is to ry ; L F T s = l iv er f u n ct io n t es ts ; M = m al e; M = m o n th ; M R SA = m et h ic il li n r es is ta n t st ap h yl o co cc u s au re u s; N A P SI = n ai l p so ri as is s ev er it y in d ex ; N M SC = n o n -m el an o m a sk in c an ce r; N /R = n o t re p o rt ed ; o d = o n ce d ai ly ; P A SI = P so ri as is A re a an d S ev er it y In d ex ; P A SI 5 0 = 5 0 % r ed u ct io n o f b as el in e PA SI ; P A SI 7 5 = 7 5 % r ed u ct io n o f b as el in e PA SI ; PA SI 9 0 = 9 0 % r ed u ct io n o f b as el in e PA SI ; PA SI 1 0 0 = 1 0 0 % r ed u ct io n o f b as el in e PA SI ; P SS I = p so ri as is s ca lp s ev er it y in d ex ; SC C = s q u am o u s ce ll c ar ci n o m a; T x  =  t re at m en t; y = y ea rs o ld ; U R T Is = u p p er r es p ir at o ry t ra ct i n fe ct io n s; W = w ee k . 10 Review | Dermatol Pract Concept. 2022;12(4):e2022179 Ta b le 3 . M et h o d o lo gi ca l q u al it y as se ss m en t o f in cl u d ed r ep o rt s. R e p o rt M u g h e d d u 2 0 2 0 [2 2 ] M a n fr e d a 2 0 1 9 [ 1 5 ] Z a rb a fi a n 2 0 1 9 [ 5 ] R e d d y 2 0 1 7 [4 ] S h a h 2 0 1 9 [1 8 ] S a cc h e ll i 2 0 1 8 [ 3 2 ] A p a ll a 2 0 1 9 [1 1 ] R e d d y 2 0 1 9 [1 7 ] Fo ti a d o u 2 0 1 8 [ 3 3 ] Je o n 2 0 1 7 [3 4 ] Q u al it y F ai r F ai r F ai r F ai r F ai r F ai r F ai r F ai r F ai r F ai r R ep o rt G o n za le z- C an te ro 2 0 1 8 [ 3 5 ] G o tt li eb 2 0 2 1 [3 6 ] K ah n 2 0 1 9 [3 7 ] N ag at a 2 0 1 9 [3 8 ] U va is 2 0 2 0 [3 9 ] V ic o -A lo n so 2 0 2 0 [ 4 0 ] M el is 2 0 2 0 [4 1 ] P er ro n e 2 0 1 7 [4 2 ] C ar p en ti er i 2 0 2 0 [ 4 3 ] P ei ts ch 2 0 1 9 [4 4 ] Q u al it y G o o d G o o d G o o d G o o d G o o d F ai r G o o d F ai r G o o d F ai r R ep o rt T ak am a 2 0 2 0 [ 4 5 ] F o ti 2 0 2 1 [ 4 6 ] D i L er n ia 2 0 2 1 [ 4 7 ] A ra go n - M ig u el 2 0 1 9 [4 8 ] T am p o u ra tz i 2 0 1 9 [ 4 9 ] P ap ad av id 2 0 1 8 [ 5 0 ] Sa h u q u il lo - T o rr al b a 2 0 2 0 [5 1 ] Si ci li an o 2 0 2 0 [5 2 ] L an n a 2 0 2 0 [5 3 ] L an n a 2 0 1 9 [5 4 ] Q u al it y F ai r F ai r G o o d G o o d G o o d G o o d G o o d G o o d G o o d G o o d R ep o rt B al at o 2 0 2 0 [ 5 5 ] Q u ei ro S il va 2 0 2 0 [ 2 1 ] Ig h an i 2 0 1 8 (1 ) [5 6 ] Ig h an i 2 0 1 8 (2 ) [5 7 ] Ig h an i 2 0 1 8 (3 ) [5 8 ] P h an 2 0 2 0 [5 9 ] Ig h an i 2 0 1 8 (4 ) [6 0 ] M eg n a 2 0 2 0 [6 1 ] D el A lc az ar 2 0 2 0 [ 6 2 ] F re m li n 2 0 1 7 [6 3 ] Q u al it y G o o d G o o d G o o d G o o d G o o d G o o d G o o d G o o d G o o d G o o d R ep o rt F o u lk es 2 0 1 7 [ 6 4 ] M al ar a 2 0 1 8 [6 5 ] D au d én 2 0 2 0 [1 4 ] K u n gu ro v 2 0 1 9 [ 6 6 ] A ra go n - M ig u el 2 0 1 9 [6 7 ] B u li c 2 0 1 9 [6 8 ] F at to re 2 0 1 9 [6 9 ] M ag d al en o 2 0 1 9 [ 7 0 ] M ag d al en o - T ap ia l 2 0 1 9 [7 1 ] G io e 2 0 2 1 [7 2 ] Q u al it y G o o d G o o d G o o d G o o d G o o d G o o d G o o d G o o d G o o d G o o d R ep o rt Ib ar gu re n 2 0 2 1 [7 3 ] K u ra ta 2 0 2 1 [7 4 ] C o h en -S o rs 2 0 2 1 [ 1 3 ] Q u al it y G o o d G o o d G o o d C as e re p o rt s h av e b ee n a ss es se d t h ro u gh t h e JB I cr it ic al a p p ra is al c h ec k li st f o r ca se r ep o rt s. C ro ss -s ec ti o n al s tu d ie s h av e b ee n a ss es se d t h ro u gh t h e N IH q u al it y as se ss m en t to o l fo r o b se rv at io n al c o h o rt a n d cr o ss -s ec ti o n al s tu d ie s. E ac h r ep o rt h as b ee n a ss ig n ed a n o ve ra ll q u al it y m ar k in g o f p o o r, go o d o r fa ir . Review | Dermatol Pract Concept. 2022;12(4):e2022179 11 small molecules like apremilast are thought to be immuno- suppressed [6]. There have been reports of asymptomatic, as well as of fast and uneventful resolution of COVID-19 infec- tions in psoriasis patients under apremilast, even in the case of serious comorbidities [21-23 ]. What is more, it seems that apremilast use does not hinder the formation of antibodies against SARS-CoV-2 [6]. It is important to remember that common apremilast AEs like taste alteration and gastroin- testinal symptoms can mimic COVID-19 manifestations [6]. A relatively new, special population of psoriatic patients are those receiving therapy with immune checkpoint inhib- itors (ICPIs) for various types of cancer. ICPIs have revolu- tionized cancer treatment and their use expands constantly. They include monoclonal antibodies that target cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death ligand 1  (PD-L1) [24]. Due to the unique nature of ICPIs, a new category of AEs emerged concurrently with their clini- cal use  [24]. They are known as ‘‘immune-related adverse events’’ (irAEs) and although they can affect any organ, skin is the one most frequently involved [24]. Morbilliform ex- anthems, pruritus, vitiligo and lichenoid eruptions are by far the most common cutaneous irAEs [25,26]. Numerous others have been reported, among which newly occurring or exacerbating previous psoriasis. In the majority of cases, cutaneous irAEs are mild-to- moderate (grade 1-2) and anti-cancer treatment is not in- terrupted, although severity may vary, up to life-threatening Stevens-Johnson syndrome/toxic epidermal necrolysis [27,28]. Similarly, psoriasis is usually managed with topi- cal treatment [24,29]. In moderate/severe cases, treatment is more complicated since immunosuppression by anti-psoriatic drugs can theoretically lead to tumor escape. In those pa- tients, apremilast seems to be a relatively safe and effective choice, however its use is supported only by case reports/ small case series. Finally, an algorithm published recently by the ENCADO (European Network for Cutaneous Adverse Event to Oncologic Drugs) also suggests apremilast if the pa- tient does not respond to phototherapy and/or acitretin [30]. Our study is not without its limitations. A few large stud- ies like Armstrong and Levi were excluded from this review and potentially significant data was missed, because results were not reported separately for patients receiving apremi- last monotherapy and those receiving combination treatment or other systemic agents [31]. On the other hand, it is fairly possible that some patients included in this review have been counted more than once, as they might have been sourced from the same databases or research centers (eg  multiple publications by the same authors, Table 2). What is more, in studies reporting on multiple patients, efficacy and safety outcome measures were usually presented indistinguishably for all included patients and not individually, based on the comorbidity status, therefore the relevant fields of Table 2 could not be filled in. Last but not least, baseline comorbidity cases such as chronic infections were sometimes presented as a total number, without distinguishing among different types of eg infections. All in all, according to this case series and systematic review, real-life use of apremilast so far suggests that the latter is indeed a safe and adequately efficacious option for moderate-to-severe psoriasis that cannot be treated/ is challenging to treat with classic systemic agents and/or biologics. What is more, there seems to be no increased risk of COVID-19 infection in patients receiving apremilast, with evidence suggesting a smoother course of the disease. References 1. Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin. 2008;24(5):1529–1538. DOI:10.1185/030079908X301866. PMID: 18419879. 2. Shutty B, West C, Pellerin M, Feldman S. Apremilast as a treat- ment for psoriasis. Expert Opin Pharmacother. 2012;3(12): 1761-1770. DOI: 10.1517/14656566.2012.699959. PMID: 22712800. 3. Palfreeman AC, McNamee KE, McCann FE. New developments in the management of psoriasis and psoriatic arthritis: a focus on apremilast. Drug Des Devel Ther. 2013;7:201-210. DOI: 10.2147/ DDDT.S32713. PMID: 23569359. PMCID: PMC3615921. 4. Reddy SP, Shah V V., Wu JJ. Apremilast for a psoriasis pa- tient with HIV and hepatitis C. J Eur Acad Dermatol Vene- reol. 2017;31(11):e481–e482. DOI:10.1111/jdv.14301. PMID: 28449227. 5. Zarbafian M, Cote B, Richer V. Treatment of moderate to severe psoriasis with apremilast over 2 years in the context of long-term treated HIV infection: A case report. SAGE Open Med Case Rep. 2019;7:2050313X1984519. DOI:10.1177/2050313x19845193. PMID: 31105941. PMCID: PMC6503584. 6. Pacifico A, D’Arino A, Pigatto PDM, Malagoli P, Young D, Damiani G. COVID-19 vaccines do not trigger psoriasis flares in patients with psoriasis treated with apremilast. Clin Exp Dermatol. 2021;46(7):1344–1346. DOI:10.1111/ced.14723. PMID: 33969530. PMCID: PMC8239919. 7. Piaserico S, Messina F, Russo FP. Managing Psoriasis in Patients with HBV or HCV Infection: Practical Considerations. Am J Clin Dermatol. 2019;20(6):829–845. DOI:10.1007/s40257-019- 00457-3. PMID: 31222626. 8. Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, ran- domized controlled trial (ESTEEM 2). Br J Dermatol. 2015;173(6): 1387–1399. DOI:10.1111/bjd.14164. PMID: 26357944. 9. Liu Y, Zhou S, Assaf M, Nissel J, Palmisano M. Impact of Renal Impairment on the Pharmacokinetics of Apremilast and Metabolite M12. Clin Pharmacol Drug Dev. 2016;5(6):469–479. DOI:10.1002/ cpdd.256. PMID: 27870479. PMCID: PMC5132082. 10. Grekin SK, Robinson DM, Berk DR, Plc A, Ahluwalia G. Low serious infection rates in patients with psoriasis and psoriatic 12 Review | Dermatol Pract Concept. 2022;12(4):e2022179 Dermatol Venereol. 2020;34(8):e376-e378. DOI: 10.1111/jdv. 16625. PMID: 32385859. PMCID: PMC7272987. 23. Olisova OY, Anpilogova EM, Svistunova DA. Apremilast as a po- tential treatment option for COVID-19: No symptoms of infection in a psoriatic patient. Dermatol Ther. 2020;33(4):e13668. DOI: 10.1111/dth.13668. PMID: 32449265. PMCID: PMC7267080. 24. Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhib- itors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol. 2018;19(3):345-361. DOI: 10.1007/s40257-017-0336-3. PMID: 29256113. 25. Tattersall IW, Leventhal JS. Cutaneous toxicities of immune checkpoint inhibitors: The role of the dermatologist. Yale J Biol Med. 2020;93(1):123-132. PMID: 32226342. PMCID: PMC7087048. 26. Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint in- hibitor–related dermatologic adverse events. J Am Acad Derma- tol. 2020;83(5):1255-1268. DOI: 10.1016/j.jaad.2020.03.132. PMID: 32454097. PMCID: PMC7572894. 27. Ellis SR, Vierra AT, Millsop JW, Lacouture ME, Kiuru M. Dermatologic toxicities to immune checkpoint inhibitor therapy: A review of histopathologic features. J Am Acad Dermatol. 2020;83(4):1130–1143. DOI:10.1016/j.jaad.2020.04.105. PMID: 32360716. PMCID: PMC7492441. 28. Rovers J, Bovenschen H. Dermatological side effects rarely in- terfere with the continuation of checkpoint inhibitor immuno- therapy for cancer. Int J Dermatol. 2020;59(12):1485–1490. DOI:10.1111/IJD.15163. PMID: 32895923. 29. Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP. Dermatologic complications of anti-PD-1/PD-L1 immune check- point antibodies. Current Opinion in Oncology 2016;28(4): 254–263. DOI:10.1097/CCO.0000000000000290. PMID: 2713 6138. 30. Nikolaou V, Sibaud V, Fattore D, et al. 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