10.5826/dpc.1204a179
Introduction: Patients with serious comorbidities are traditionally excluded from clinical trials. Apremilast is not contraindicated in active infections, malignancy and serious hepatic or renal impairment, 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 (2014 – July 2021). Identified records were considered 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 limitations 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.
text/xml
2160-9381
2205
en
Efstratios Vakirlis
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
biologics
Apremilast in psoriasis patients with serious comorbidities: a case series and systematic review of literature
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2022-10-31
2021-11-27
2022-10-31
2022-12-01
e2022179
Dermatol Pract Concept
Introduction: Patients with serious comorbidities are traditionally excluded from clinical trials. Apremilast is not contraindicated in active infections, malignancy and serious hepatic or renal impairment, 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 (2014 – July 2021). Identified records were considered 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 limitations 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.
Efstratios Vakirlis
2022/10/31
10.5826/dpc.1204a179
e2022179
First Department of Dermatology and Venereology, School of Medicine, Aristotle University, Thessaloniki, Greece
2160-9381
biologics
en
e2022179
Kurata M, Ohyama M. Long-term remission of severe nail psoriasis after discontinuation of apremilast in a colorectal cancer survivor. J Dermatol 2021;48:e248–9doi:10.1111/1346-8138.15831.
Apremilast in psoriasis patients with serious comorbidities: a case series and systematic review of literature
https://dpcj.org/index.php/dpc/article/download/2205/1831
          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




  ABSTRACT              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.




Review | Dermatol Pract Concept. 2022;12(4):e2022179                                                                                     1
Introduction                                                      an appropriately documented chronic/latent infection, recent
                                                                  (past 10 years) malignancy excluding basal cell carcinoma,
Psoriasis is a chronic cutaneous disease of inflammatory          serious kidney (stage IV and V) or liver (Child-Pugh C) dis-
­nature, with a worldwide prevalence ranging between 1-3%;        ease, severe psychiatric disorder or other serious illness as
it has a substantial negative effect on patient physical well-    was defined by Kelley [12] were included in the study. The
being and quality-of-life, as well as on national health expen-   following data were retrieved by two collaborating authors
diture [1–3]. Apremilast (Otezla®, Amgen), a small molecular      (AT and NS): age, gender, comorbidity(-ies), year of comor-
inhibitor of phosphodiesterase 4 (PDE4), has been used for        bidity diagnosis, apremilast dose, baseline Psoriasis Area
the treatment of psoriatic arthritis and psoriasis since 2014     and Severity Index (PASI), treatment outcome in terms of
(first US Food and Drug Administration [FDA] approval).           efficacy, duration of apremilast treatment (weeks) and ad-
Contrary to biologics, it does not target any one specific        verse events (AEs) including adverse outcomes related to
component of the inflammatory process involved in the             comorbidity(-ies) in question. Written informed consent was
pathophysiology of psoriasis, but rather achieves some sort       obtained by all participants. This project was designed and
of equilibrium of pro-inflammatory and anti-inflammatory          conducted based on the declaration of Helsinki and was ap-
agents [4,5].                                                     proved by the Ethics Committee of the Hospital of Venereal
    Apremilast comes with a set of favorable attributes,          and Cutaneous Diseases, Thessaloniki, Greece.
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-   Systematic Review
pairment, nor is routine lab monitoring necessary. Similarly,
it can be administered to patients with past or current ma-       Eligibility Criteria
lignancy [8]. Patients with severe renal impairment can still     We conducted this systematic review as stated by
receive a reduced dose of apremilast [9]. A pooled analysis       Meta-analyses Of Observational Studies in Epidemiology
(≥ 156 weeks) from the 2 apremilast-approving (ESTEEM)            (MOOSE) statement. Published and unpublished prospec-
trials showed that serious infection rate was low among pa-       tive or retrospective observational studies reporting on the
tients receiving apremilast, while no serious opportunistic       use of apremilast for the treatment of psoriasis patients with
infections or cases of tuberculosis reactivation were noted       serious baseline comorbidities (chronic/latent infections such
[10]. However, as patients with chronic infections, cancers       as tuberculosis, hepatitis and HIV, cancer diagnosis within
and serious co-existing diseases are traditionally excluded       past ten years excluding basal cell carcinoma, stage IV and
from clinical trials testing new drugs, conclusions regarding     V chronic kidney disease hemodialysis, Child-Pugh class C
the use of said drugs in these occasions cannot always be         liver disease, serious psychiatric disorders or other serious
safely drawn [7,11].                                              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-
Objectives                                                        nation therapy of apremilast and other systemic agents aside
                                                                  from phototherapy, systemic corticosteroids or other medi-
The purpose of this study is to present our five-year experi-
                                                                  cation administered systemically for existing comorbidities
ence in administering apremilast to psoriasis patients with
                                                                  were excluded from our review. Only studies performed after
serious comorbidities in the setting of a tertiary-care center
                                                                  2014 (apremilast first FDA approval) were considered. No
in terms of drug safety and efficacy, as well as to concisely
                                                                  language restrictions were placed.
portray relevant real-life evidence sourced through a system-
atic literature search.
                                                                  Information Sources
                                                                  Three electronic databases were searched (MEDLINE,
Methods                                                           ScienceDirect, and the Cochrane Library electronic data-
                                                                  bases). Google scholar (https://scholar.google.com/) was
Case Series                                                       also browsed. Abstract compendia of the World Con-
The March 2016 (apremilast approval in Greece) to June            gresses of Dermatology, World Psoriasis and Psoriatic Ar-
30th, 2021 archives of both the Psoriasis Outpatient Clinic       thritis Congresses, American Academy of Dermatology
and Afternoon Private Clinics of the First Dermatology            Annual Meetings and European Academy of Dermatology
Department, Aristotle University, Thessaloniki, Greece
­                                                                 and Venereology Annual Congresses of the last five years
were consecutively searched for all psoriasis patients hav-       were examined (online browsing). Last search date for all
ing received at least one dose of apremilast. Patients with       above mentioned platforms was July 4th, 2021. Amgen® was



2                                                                            Review | Dermatol Pract Concept. 2022;12(4):e2022179
contacted and kindly asked to supply our team with any                 transient AEs were reported in 6 patients. Patient compliance
published or unpublished data abiding by our search criteria.          to treatment was high (three cases of temporary drug dis-
The “Reference” section of studies included in our review              continuation, < 14 days, due to Covid-19-related restrictions
was hand searched for additional eligible work.                        and consequent difficulties in drug prescription). Desired re-
                                                                       sponse (PASI50) was not achieved in 1 case and apremilast
Search Strategy                                                        was therefore discontinued (primary drug failure).
The following search strategy was used for MEDLINE data-                  The systematic literature search yielded 52 studies eligi-
base and modified accordingly for the rest of searched plat-           ble for inclusion (Figure 1). One additional study was iden-
forms: (apremilast[Title]) AND (psoriasis[Title/Abstract])             tified after the last search date (published July 8th 2021) and
filtered by year of publication (2014 to 2021). The search             does not appear in the flow diagram (Figure 1) [13]. A total
was performed independently by two authors (AT and NS).                of at least 826 psoriasis patients with serious comorbidities
                                                                       (various malignancies – at least 456 patients –, latent / past
Study Endpoints                                                        tuberculosis – 49 patients –, hepatitis B, C and HIV infec-
The primary endpoint of this study was the documentation               tions – at least 83 patients –, serious renal – 7 patients – or
of any safety-related outcomes in patients with serious co-            liver impairment – at least 110 patients –, serious p
                                                                                                                           ­ sychiatric
morbidities having received apremilast (for example comor-             disorders – 49 patients – or other serious illness as was
bidity progression, AEs commonly related to apremilast use             ­defined by Kelley [12]) were prescribed apremilast twice or
or other events). Secondary endpoint was treatment efficacy,           once daily (Table 2). The exact number of patients with se-
without any limitations imposed on efficacy measures used.             rious comorbidities prescribed apremilast was not reported
                                                                       in a few studies, therefore, the numbers mentioned above are
Selection Process and Data Collection                                  a conservative underestimation of the studied population.
                                                                       Included patients manifested all types of psoriasis and/or
Duplicate records were independently manually removed
                                                                       nail psoriasis. Overall, apremilast was hardly ever associated
by two reviewers (NS and AT). Subsequently, two review-
                                                                       with negative comorbidity-related outcomes and reported
ers (AT and NS) independently screened titles and abstracts
                                                                       AEs were apparently not more severe or frequent than those
for relevance to the study objective. The full text of remain-
                                                                       experienced by the average psoriasis patient. Sufficient re-
ing records was read, and eligible studies were included in
                                                                       sponse of psoriasis to apremilast was recorded in most cases.
the review. AT and NS separately extracted the following
                                                                       Overall, the quality of included studies was good (Table 3).
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-              Conclusions
last dose, baseline PASI, AEs including comorbidity-related
                                                                       This case series and systematic review reports on the use of
events. Any disagreements were resolved in consultation
                                                                       apremilast in 841 psoriasis patients with serious baseline
with a third author (ES).
                                                                       comorbidities, which would have made the use of classic
                                                                       systemic agents and/or biologics inappropriate or challeng-
Quality Assessment
                                                                       ing. According to our study, the use of apremilast in this
Two authors (AT and ES) independently assessed included re-
                                                                       group of patients apparently neither leads to deterioration /
ports based on two different tools, namely the Joanna Briggs
                                                                       ­exacerbation of severe pre-existing comorbidity(-ies) nor is it
Institute (JBI) critical appraisal tool for case reports/case series
                                                                       associated with an increased risk of adverse events. What is
and the JBI critical appraisal tool for analytical cross-­sectional
                                                                       more, drug efficacy does not seem to be affected by the under-
studies, each comprising eight questions ­(Supplement). Each
                                                                       lying comorbidity, with cases of remarkable response even in
study was assigned an overall rating of poor, good or fair, if
                                                                       erythrodermic patients with very serious underlying diseases.
0-5, 6-7 or 8 criteria were met respectively.
                                                                          A drug safety profile, especially in the context of
                                                                       pre-existing comorbidities, is one of its major attributes to

Results                                                                be taken into consideration, when deciding on a treatment
                                                                       regimen [14]. Psoriasis patients receiving apremilast, as op-
The psoriasis-archives search returned 16 eligible cases, one          posed to other systemic agents, seem to have a lower infec-
of which was not included in the analysis due to incom-                tion risk [15]. Rates of herpes zoster infection were lowest
pletely documented patient data (Table 1). No progression of           for users of apremilast among a cohort of psoriasis patients
malignancy, reactivation of chronic / latent infection or dete-        treated with biologics and/or small molecules (5.4, 95%
rioration of already deficient renal or hepatic function were          CI 1.7-12.6) [16]. Comparing to methotrexate (MTX), as
noted. Apremilast was generally well-tolerated and only mild           investigated in a cohort of 2845 psoriasis patients treated



Review | Dermatol Pract Concept. 2022;12(4):e2022179                                                                                 3
         Table 1. Cases of psoriasis patients with serious baseline comorbidities treated with apremilast.
                                                                           Bas                                 APR
    Case     Sex   Age    Comorbidity (diagnosis)          APR Dose        PASI        Tx outcome            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       None
                                                                                                          f/u)
    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            21 (LAoE)         Abdominal
                                                                                    achieved                                pain
    5        F     65    Breast cancer (2016),            30 mg bid          5.3    PASI100 24            35 (clear         Dyspepsia
                         hepatitis B                                                weeks                 skin)
    6        M     63    Hepatitis C and liver            30 mg bid          6.7    PASI50 week 16        37 (LOoE)         None
                         fibrosis
    7        M     44    Hemodialysis (Stage 5            30 mg od         13.2     PASI50 week 24        40 (LOoE)         None
                         Chronic kidney disease –
                         IgA nephropathy)
    8        F     66    Lung tuberculosis (1980)         30 mg bid        11.1     PASI50 week 16        4 (AEs)           Headache
    9        M     33    HIV positive (2011)              30 mg bid        15.8     PASI75 week 16        149 (SoD)         None
                         (CD4+ 602 cells/mm3)
    10       M     65    Urinary bladder cancer           30 mg bid          9.1    PASI50 week 16        31 (LOoE)         None
                         (2015),
                         Stage 2 chronic kidney
                         disease
    11       F     56    Cervical cancer (2013)           30 mg bid        10.8     PASI75 week 24        154 (SoD)         None
    12       M     37    HIV positive (2009)              30 mg bid        24.5     PASI50 week 24        56 (SoD)          Transient
                         (CD4+ 590 cells/mm3)                                                                               nausea
    13       M     44    HIV positive (2002)              30 mg bid        33.6     PASI90q week 52       104 (SoD)         Transient
                         (CD4+ 550 cells/mm3)                                                                               diarrhea
    14       M     32    HIV positive (2009)              30 mg bid        19.3     PASI90 week 24        34 (SoD)          Transient
                         (CD4+ 702 cells/mm3)                                                                               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.
a
Deceased.




with nine systemic agents in Spain, apremilast had a lower             viral load, discussion with an infectious-disease specialist is
infection (incidence rate 0.3 [95% CI 0.1-0.9]) and malig-             warranted, with apremilast and acitretin being the preferred
nant neoplasm risk (incidence rate 0.1 [95% CI 0-0.7]) [14].           options [19]. Based on the same recommendations, the pre-
        Psoriasis may be more severe or difficult to treat             ferred options for short-term systemic treatment of psoriasis
in patients with HIV infection [17,18]. What is more,                  patients with chronic hepatitis C infection are adalimumab
HIV-positive patients are immuno-compromised and prone                 and etanercept, as there is not enough evidence to support the
to reactivation of latent infections [17]. According to the            use of other biologics and apremilast [19]. As far as chronic
2020 Belgian practical recommendations for the treatment               hepatitis B infection is concerned, ustekinumab, apremilast,
of psoriasis in HIV-positive patients, apremilast and acitre-          cyclosporine and acitretin are preferred [19]. Apremilast has
tin are considered first-line choices ]. Furthermore, many             shown potential in the treatment of psoriasis patients with a
biologics (adalimumab, certolizumab pegol, etanercept, in-             history of malignancy. It may even help treat lung cancer, as
fliximab, ustekinumab, guselkumab, risankizumab, broda-                PDE4 is expressed in lung cancer cells [20].
lumab, secukinumab, ixekizumab) can be used in patients                    In the current pandemic era, it is important to examine a
receiving highly active antiretroviral therapy (HAART) and             drug safety with regards to the COVID-19 infection. Accord-
having undetectable viral load [19]. In case of detectable             ing to the World Health Organization, psoriasis patients on



4                                                                                   Review | Dermatol Pract Concept. 2022;12(4):e2022179
                       IDENTIFICATION OF STUDIES VIA DATABASES AND OTHER SOURCES



                    RECORDS IDENTIFIED FROM:
   IDENTIFICATION



                     MEDLINE (n=263)                                               RECORDS REMOVED BEFORE
                     SCIENCEDIRECT (n = 161)                                       SCREENING:
                     COCHRANE LIBRARY (n = 207)                                     DUPLICATE RECORDS
                     GOOGLE SCHOLAR (n = 471)                                       REMOVED (n = 405)
                     CONGRESSES (n = 129)                                           RECORDS REMOVED FOR
                     AMGEN (n = 21)                                                 OTHER REASONS (n = 1)




                    RECORDS SCREENED (n = 846)                                     RECORDS EXCLUDED (n = 631)




                    REPORTS SOUGHT FOR                                             REPORTS NOT RETRIEVED
                    RETRIEVAL (n = 215)                                            (n = 12)
  SCREENING




                    REPORTS ASSESSED FOR                                           REPORTS EXCLUDED DUE
                    ELIGIBILITY (n = 203)                                          TO NOT MEETING INCLUSION
                                                                                   CRITERIA AND/OR MEETING
                                                                                   EXCLUSION CRITERIA: (n =151)

                    REPORTS SOURCED THROUGH
                    REFERENCE SEARCH OF ELIGIBLE
                    RECORDS (n= 0)
 INCLUDED




                    REPORTS INCLUDED IN REVIEW
                    (n = 52)


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.




Review | Dermatol Pract Concept. 2022;12(4):e2022179                                                                               5
6
                                                                               Table 2. Literature cases of apremilast administered to psoriasis patients with serious baseline comorbidities.
                                                               Report                             Comorbidity                      Age/Sex   APR dose       Bas PASI     Tx outcome                     AEs
                                                       Mugheddu 2020 [22]      Recurrent brain oligodendroglioma under              45/M     30 mg bid         45       Improvement    N/R
                                                                               temozolomide and prednisone                                                                             COVID-19 pneumonia, full recovery
                                                       Manfreda 2019 [15]      HIV positive (CD4+ 628 cells/mm3), Hepatitis B,      41/M     30 mg bid         12       PASI90W24      None, stable CD4+ count
                                                                               drug addiction history
                                                       Zarbafian 2019 [5]      HIV positive (CD4+ >1000 cells/mm3)                  54/M     30 mg bid        10.2      73% PASI       Transient diarrhea, frequent URTIs,
                                                                                                                                                                        reduction M7   stable CD4+ count
                                                       Reddy 2017 [4]          HIV positive, Hepatitis C                            46/M     30 mg bid       BSA 8%     BSA 1.5% M5    None
                                                       Shah 2019 [18]          HIV positive (CD4+ 742/μl)                           35/M     30 mg bid,       14.7      PASI100 W6     None, stable CD4+ count
                                                                                                                                              then od
                                                       Sacchelli 2018 [32]     HIV positive (2002) (CD4+ 566/mc), past Hepatitis    55/M     30 mg bid         8        PASI75M6       None
                                                                               B and C                                                                      NAPSIq 21   NAPSI 7 M6
                                                       Apalla 2019 [11]        Metastatic lung adenocarcinoma, stage IIIB (2013)    67/F     30 mg bid         18       PASI75 W16     None, cancer course not affected by
                                                                                                                                                                                       APR
                                                       Reddy 2019 [17]         HIV positive (CD4+ 460 cells/mm3)                    50/M      30 mg bid     BSA 10%     BSA 0% M3      N/R
                                                                                                                                             and then od
                                                       Fotiadou 2018 [33]      Chronic hepatitis B, undetectable viral load         52/F     30 mg b.i.d.     13.2      PASI90 W24     None, normal HBload and LFTs
                                                       Jeon 2017 [34]          Active hepatitis C, decompensated cirrhosis,         55/M     30 mg bid        N/R       PASI100 W6     Initial nausea
                                                                               metastatic HCC
                                                       González-Cantero 2018   Malignancy: 3, liver disease: 1, alcoholism: 1,      N/R         N/R           N/R       N/R            No changes in the course of
                                                       [35]                    infectious disease: 1, renal insufficiency: 1,                                                          comorbidities
                                                                               demyelinating disease: 1
                                                       Gottlieb 2021 [36]      Malignancy: 92, serious infection: 53                N/R         N/R           N/R       N/R            N/R
                                                       Kahn 2019 [37]          1. renal cell carcinoma                             63, N/R      N/R         BSA 10%     N/R            No clinical/radiographical signs of
                                                                               2. melanoma                                         64, N/R                  BSA 5%                     cancer recurrence
                                                       Nagata 2019 [38]        Hemodialysis                                         60, M     30 mg od       PSSI 36    PSSI 10 W12    Nausea (transient)
                                                       Uvais 2020 [39]         Bipolar affective disorder                           30, F    30 mg/day        N/R       N/R            N/R
                                                       Vico-Alonso 2020 [40]   Chronic myeloid leukemia under imatinib, latent      58, M    30 mg bid        22.4      PASI90 W24     None, stable tumoral state, normal
                                                                               tuberculosis, alcoholism, steatohepatitis                                                               lab tests
                                                       Melis 2020 [41]         Malignancy (excl. NMSC): 13 (breast, bladder,        N/R      30 mg bid        N/R       N/R            N/R
                                                                               colorectal), severe infection: 7 (HIV, HBV, HCV),
                                                                               psychiatric disorder: 6, liver disease: 3, latent
                                                                               tuberculosis: 2
                                                       Perrone 2017 [42]       Chronic anemia and thrombocytopenia                  71, M       N/R           N/R       N/R            Fanconi Syndrome




Review | Dermatol Pract Concept. 2022;12(4):e2022179
                                                               Report                              Comorbidity                         Age/Sex     APR dose     Bas PASI     Tx outcome                    AEs
                                                       Carpentieri 2020 [43]    Malignancy (excl. NMSC): 10                              N/R         N/R          N/R      Most patients   no clinical or radiographic
                                                                                                                                                                           showed          recurrence or progression of their
                                                                                                                                                                           improvement     cancer
                                                       Peitsch 2019 [44]        Mantel cell lymphoma under rituximab, hepatic           60, M      30 mg bid      17.2     PASI90 M5       None, lymphoma in remission
                                                                                and pulmonary aspergillosis
                                                       Takama 2020 [45]         Urinary bladder cancer under pembrolizumab              74, M      30 mg bid,     2.9      PASI50 W2,      Nausea
                                                                                                                                                    then od                PASI90 M2
                                                       Foti 2021 [46]           Melanoma with lymph node metastasis under               62, M      30 mg bid      44       PASI50 M6,      None, no worsening of melanoma
                                                                                nivolumab                                                                                  PASI90 M12
                                                       Di Lernia 2021 [47]      Malignancy: 3 colorectal, 2 GI stromal, 1 leukemia,     5 F, 9 M   30 mg bid      N/R      N/R             Diarrhea, headache (3 patients, disc.
                                                                                1 lymphoma,1 kidney, 1 uterus and thyroid,             (age N/R)                                           APR), urinary bladder cancer and
                                                                                2 melanoma,1 urinary bladder,1 metastatic SCC,                                                             metastatic SCC recurrence after APR
                                                                                1 prostate                                                                                                 disc.




Review | Dermatol Pract Concept. 2022;12(4):e2022179
                                                       Aragon-Miguel 2019       Malignancy hx: 6, latent tuberculosis: 16, hepatitis     N/R         N/R          N/R      N/R             N/R
                                                       [48]                     C or B (chronic or past): 7                                                                                No infection reactivations
                                                       Tampouratzi 2019 [49]    Chronic hepatitis B, under entecavir                    64, M        N/R          N/R      Excellent       None
                                                                                                                                                                           response
                                                       Papadavid 2018 [50]      Malignancy hx: 1, latent tuberculosis: 1, chronic        N/R         N/R          N/R      N/R             N/R
                                                                                latent hepatitis B: 1
                                                       Sahuquillo-Torralba      Latent tuberculosis: 1, active hepatitis B: 1,           N/R         N/R          N/R      N/R             N/R
                                                       2020 [51]                spontaneous bacterial peritonitis: 1, immune
                                                                                hepatitis: 1
                                                       Siciliano 2020 [52]      Metastatic melanoma (2018)                              75, M      30 mg bid      N/R      Improvement     None, melanoma remission
                                                       Lanna 2020 [53]          Tumors: 5                                                N/R         N/R          N/R      N/R             N/R
                                                       Lanna 2019 [54]          Hepatitis E                                             55, M      30 mg bid      18       PASI90 M6       None
                                                       Balato 2020 [55]         Malignancy: 40                                           N/R         N/R          N/R      N/R             Lower PASI50 and PASI75 response
                                                                                                                                                                                           rates
                                                       Queiro Silva 2020 [21]   Hairy cell leukemia                                     55, M        N/R          N/R      N/R             Severe COVID-19 infection
                                                       Ighani 2018 (1) [56]     Malignancy hx: 15, liver disease: 8, psychiatric         N/R         N/R          N/R      N/R             N/R
                                                                                disorder: 9
                                                       Ighani 2018 (2) [57]     Malignancy hx: 31, liver disease: 27, psychiatric        N/R         N/R          N/R      N/R             N/R
                                                                                disorder: 29

                                                                                                                                                                                                                 Table 2 continues




7
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                                                                           Table 2. Literature cases of apremilast administered to psoriasis patients with serious baseline comorbidities. (continued)
                                                               Report                                 Comorbidity                          Age/Sex   APR dose    Bas PASI    Tx outcome                   AEs
                                                       Ighani 2018 (3) [58]       Malignancy hx: 5, liver disease: 4, psychiatric           N/R        N/R         N/R      N/R           N/R
                                                                                  disorder: 4
                                                       Phan 2020 [59]             Malignancy: 40                                            >65 y      N/R         N/R      N/R           N/R
                                                       Ighani 2018 (4) [60]       hepatitis C: 2, breast cancer: 2, renal disease           N/R        N/R         N/R      N/R           N/R
                                                                                  (unspecified): 2
                                                       Megna 2020 [61]            Malignancy: 9, hepatitis C: 4, latent tuberculosis: 3     N/R        N/R         N/R      N/R           N/R
                                                       Del Alcázar 2020 [62]      Lung cancer: 20, latent tuberculosis: 20, hepatitis       N/R        N/R         N/R      N/R           No cases of infection reactivation or
                                                                                  C: 17, hepatitis B: 13, hepatitis B and C: 2,                                                           cancer recurrence
                                                                                  malignancy hx: 92, liver disease: 33
                                                       Fremlin 2017 [63]          Cases of alcohol excess, alcoholic liver disease,         N/R        N/R         N/R      N/R           N/R
                                                                                  previous malignancy (unspecified number)
                                                       Foulkes 2017 [64]          Cases of malignant melanoma and HIV (unspecified          N/R        N/R         N/R      N/R           N/R
                                                                                  number)
                                                       Malara 2018 [65]           Latent tubercular skin infection: 2, previous             N/R        N/R         N/R      N/R           None
                                                                                  hepatitis: 1, endocarditis-related cardiac valve
                                                                                  failure: 1, malignancy: 4
                                                       Daudén 2020 [14]           Malignancy hx: 14 (6 in last 5 years), hepatitis          N/R        N/R         N/R      N/R           N/R
                                                                                  B:12, hepatitis C: 5, chronic liver disease: 20, renal
                                                                                  insufficiency: 3
                                                       Kungurov 2019 [66]         Hepatitis B: 1, chronic pancreatitis, cholecystitis       47, F      N/R         27.3     PASI75 W24    None
                                                                                  and colitis: 1, hepatitis C: 1                            38, F                  29.9     PASI75 W6
                                                                                                                                            31, M                   33      PASI75 W28
                                                       Aragon-Miguel 2019         breast cancer: 1, gallbladder cancer: 1, treated          N/R        N/R         N/R      N/R           N/R
                                                       [67]                       latent tuberculosis: 3
                                                       Bulic 2019 [68]            1. laryngeal SCC (2013)                                   51, M      N/R         N/R      N/R           No recurrency of malignancy over a
                                                                                  2. papillary thyroid cancer (2014)                        50, M                                         two-year follow-up
                                                                                  3. liver cirrhosis (Child-Pugh B)/portal                  51, M
                                                                                  hypertension/ hepatocellular cancer (pT2pNxpMx)/          58, F
                                                                                  liver transplant (2017)
                                                                                  4. melanoma (pT1a, Breslow 0.81mm) (2013)
                                                       Fattore 2019 [69]          Non-metastatic non-small-cell lung cancer under           74, F    30 mg bid     N/R      PASI100 W6    Transient nausea
                                                                                  nivolumab
                                                       Magdaleno 2019 [70]        Chronic liver disease: 13, severe infection: 11,          N/R        N/R         N/R      N/R           N/R
                                                                                  previous malignancy: 8




Review | Dermatol Pract Concept. 2022;12(4):e2022179
                                                                 Report                                   Comorbidity                              Age/Sex         APR dose           Bas PASI         Tx outcome                           AEs
                                                        Magdaleno-Tapial 2019 Chronic active alcoholism and                                         61, M              N/R             N/R           PASI<5 M6            No serious AEs
                                                        [71]                  hyper-transaminasemia                                                                                  NAPSI 32
                                                        Gioe 2021 [72]               Chronic hepatitis B, bipolar disorder, acute MRSAee             34, F             N/R          N/R (>95%        BSA< 15% M1          N/R
                                                                                     bacteremia, pulmonary embolus                                                                     BSA)




Review | Dermatol Pract Concept. 2022;12(4):e2022179
                                                        Ibarguren 2021 [73]          1. Stage IV uveal melanoma                                     50, M          30 mg bid             12          PASI50 M12           1. diarrhea
                                                                                     2. Stage IV laryngeal carcinoma                                70, M                               13.8         PASI75 (time         2. headache, cancer progression after
                                                                                     3. Stage IV squamous cell lung carcinoma                       60, M                                6.4         N/R)                 10 months
                                                                                     all 3 under nivolumab                                                                                           PASI50 not           3. cancer progression after 10
                                                                                                                                                                                                     achieved             months
                                                        Kurata 2021 [74]             Colorectal cancer within past year                              82, F             N/R             5.5           PASI90 and           γ-GT increase after 8 weeks & drug
                                                                                                                                                                                     NAPSI 77        NAPSI50 W8           disc.
                                                        Cohen-Sors 2021 [13]         Hematologic malignancy: 10                                      N/R               N/R               N/R         N/R                  Evolution of previously stable CLL
                                                                                                                                                                                                                          (1 case)

                                                       AEs = adverse events; APR = apremilast; Bas = baseline; bid = twice daily; BSA = body surface area; F = female; CLL = chronic lymphocytic leukemia; disc. = discontinuation; HBV = hepatitis B virus;
                                                       HCC = ­hepatocellular carcinoma; HCV = hepatitis C virus; HIV = human immunodeficiency virus; hx = history; LFTs = liver function tests; M = male; M = month; MRSA = methicillin resistant staphylococcus
                                                       aureus; NAPSI = nail psoriasis severity index; NMSC = non-melanoma skin cancer; N/R = not reported; od = once daily; PASI = Psoriasis Area and Severity Index; PASI50 = 50% reduction of baseline PASI; PASI75
                                                       = 75% reduction of baseline PASI; PASI90 = 90% reduction of baseline PASI; PASI100 = 100% reduction of baseline PASI; PSSI = psoriasis scalp severity index; SCC = squamous cell carcinoma; Tx = treatment;y
                                                       = years old; URTIs = upper respiratory tract infections; W = week.




9
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                                                                                                                  Table 3. Methodological quality assessment of included reports.
                                                                     Mugheddu 2020            Manfreda           Zarbafian        Reddy 2017          Shah 2019           Sacchelli        Apalla 2019        Reddy 2019           Fotiadou          Jeon 2017
                                                         Report          [22]                 2019 [15]           2019 [5]            [4]                [18]             2018 [32]           [11]               [17]              2018 [33]            [34]
                                                        Quality     Fair                   Fair               Fair               Fair               Fair               Fair               Fair               Fair               Fair               Fair
                                                        Report      Gonzalez-Cantero       Gottlieb 2021      Kahn 2019          Nagata 2019        Uvais 2020         Vico-Alonso        Melis 2020         Perrone 2017       Carpentieri        Peitsch 2019
                                                                    2018 [35]              [36]               [37]               [38]               [39]               2020 [40]          [41]               [42]               2020 [43]          [44]
                                                        Quality     Good                   Good               Good               Good               Good               Fair               Good               Fair               Good               Fair
                                                        Report      Takama 2020 [45]       Foti 2021 [46]     Di Lernia          Aragon-            Tampouratzi        Papadavid          Sahuquillo-        Siciliano 2020     Lanna 2020         Lanna 2019
                                                                                                              2021 [47]          Miguel 2019        2019 [49]          2018 [50]          Torralba 2020      [52]               [53]               [54]
                                                                                                                                 [48]                                                     [51]
                                                        Quality     Fair                   Fair               Good               Good               Good               Good               Good               Good               Good               Good
                                                        Report      Balato 2020 [55]       Queiro Silva       Ighani 2018        Ighani 2018        Ighani 2018        Phan 2020          Ighani 2018        Megna 2020         Del Alcazar        Fremlin 2017
                                                                                           2020 [21]          (1) [56]           (2) [57]           (3) [58]           [59]               (4) [60]           [61]               2020 [62]          [63]
                                                        Quality     Good                   Good               Good               Good               Good               Good               Good               Good               Good               Good
                                                        Report      Foulkes 2017 [64]      Malara 2018        Daudén 2020        Kungurov           Aragon-            Bulic 2019         Fattore 2019       Magdaleno          Magdaleno-         Gioe 2021
                                                                                           [65]               [14]               2019 [66]          Miguel 2019        [68]               [69]               2019 [70]          Tapial 2019        [72]
                                                                                                                                                    [67]                                                                        [71]
                                                        Quality     Good                   Good               Good               Good               Good               Good               Good               Good               Good               Good
                                                        Report      Ibarguren 2021         Kurata 2021        Cohen-Sors
                                                                    [73]                   [74]               2021 [13]
                                                        Quality     Good                   Good               Good

                                                       Case reports have been assessed through the JBI critical appraisal checklist for case reports. Cross-sectional studies have been assessed through the NIH quality assessment tool for observational cohort and
                                                       cross-sectional studies. Each report has been assigned an overall quality marking of poor, good or fair.




Review | Dermatol Pract Concept. 2022;12(4):e2022179
small molecules like apremilast are thought to be immuno-           comorbidity status, therefore the relevant fields of Table 2
suppressed [6]. There have been reports of asymptomatic, as         could not be filled in. Last but not least, baseline comorbidity
well as of fast and uneventful resolution of COVID-19 infec-        cases such as chronic infections were sometimes presented as
tions in psoriasis patients under apremilast, even in the case      a total number, without distinguishing among different types
of serious comorbidities [21-23 ]. What is more, it seems that      of eg infections.
apremilast use does not hinder the formation of antibodies                All in all, according to this case series and systematic
against SARS-CoV-2 [6]. It is important to remember that            review, real-life use of apremilast so far suggests that the
common apremilast AEs like taste alteration and gastroin-           latter is indeed a safe and adequately efficacious option
testinal symptoms can mimic COVID-19 manifestations [6].            for moderate-to-severe psoriasis that cannot be treated/
   A relatively new, special population of psoriatic patients       is challenging to treat with classic systemic agents and/or
are those receiving therapy with immune checkpoint inhib-           ­biologics. What is more, there seems to be no increased risk
itors (ICPIs) for various types of cancer. ICPIs have revolu-       of COVID-19 infection in patients receiving apremilast, with
tionized cancer treatment and their use expands constantly.         evidence suggesting a smoother course of the disease.
They include monoclonal antibodies that target cytotoxic
T lymphocyte–associated antigen-4 (CTLA-4), programmed
                                                                    References
cell death protein 1 (PD-1), or programmed death ligand
1 (PD-L1) [24]. Due to the unique nature of ICPIs, a new             1. Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm
category of AEs emerged concurrently with their clini-                  pilot study in patients with severe plaque-type psoriasis treated
                                                                        with an oral anti-inflammatory agent, apremilast. Curr Med Res
cal use [24]. They are known as ‘‘immune-related adverse
                                                                        Opin. 2008;24(5):1529–1538. DOI:10.1185/030079908X301866.
events’’ (irAEs) and although they can affect any organ, skin
                                                                        PMID: 18419879.
is the one most frequently involved [24]. Morbilliform ex-           2. Shutty B, West C, Pellerin M, Feldman S. Apremilast as a treat-
anthems, pruritus, vitiligo and lichenoid eruptions are by                 ment for psoriasis. Expert Opin Pharmacother. 2012;3(12):
far the most common cutaneous irAEs [25,26]. Numerous                      1761-1770. DOI: 10.1517/14656566.2012.699959. PMID:
others have been reported, among which newly occurring or                  22712800.
                                                                     3.    Palfreeman AC, McNamee KE, McCann FE. New developments
exacerbating previous psoriasis.
                                                                           in the management of psoriasis and psoriatic arthritis: a focus on
   In the majority of cases, cutaneous irAEs are mild-to-­
                                                                           apremilast. Drug Des Devel Ther. 2013;7:201-210. DOI: 10.2147/
moderate (grade 1-2) and anti-cancer treatment is not in-                  DDDT.S32713. PMID: 23569359. PMCID: PMC3615921.
terrupted, although severity may vary, up to life-threatening        4.    Reddy SP, Shah V V., Wu JJ. Apremilast for a psoriasis pa-
Stevens-Johnson     syndrome/toxic     epidermal       necrolysis          tient with HIV and hepatitis C. J Eur Acad Dermatol Vene-
[27,28]. Similarly, psoriasis is usually managed with topi-                reol. 2017;31(11):e481–e482. DOI:10.1111/jdv.14301. PMID:
                                                                           28449227.
cal treatment [24,29]. In moderate/severe cases, treatment is
                                                                     5.    Zarbafian M, Cote B, Richer V. Treatment of moderate to severe
more complicated since immunosuppression by anti-psoriatic
                                                                           psoriasis with apremilast over 2 years in the context of long-term
drugs can theoretically lead to tumor escape. In those pa-                 treated HIV infection: A case report. SAGE Open Med Case Rep.
tients, apremilast seems to be a relatively safe and effective             2019;7:2050313X1984519. DOI:10.1177/2050313x19845193.
choice, however its use is supported only by case reports/                 PMID: 31105941. PMCID: PMC6503584.
small case series. Finally, an algorithm published recently by       6.    Pacifico A, D’Arino A, Pigatto PDM, Malagoli P, Young D,
                                                                           ­Damiani G. COVID-19 vaccines do not trigger psoriasis flares
the ENCADO (European Network for Cutaneous Adverse
                                                                            in patients with psoriasis treated with apremilast. Clin Exp
Event to Oncologic Drugs) also suggests apremilast if the pa-
                                                                          ­Dermatol. 2021;46(7):1344–1346. DOI:10.1111/ced.14723.
tient does not respond to phototherapy and/or acitretin [30].               PMID: 33969530. PMCID: PMC8239919.
   Our study is not without its limitations. A few large stud-       7.     Piaserico S, Messina F, Russo FP. Managing Psoriasis in Patients
ies like Armstrong and Levi were excluded from this review                  with HBV or HCV Infection: Practical Considerations. Am J Clin
and potentially significant data was missed, because results                Dermatol. 2019;20(6):829–845. DOI:10.1007/s40257-019-
                                                                            00457-3. PMID: 31222626.
were not reported separately for patients receiving apremi-
                                                                     8.     Paul C, Cather J, Gooderham M, et al. Efficacy and safety of
last monotherapy and those receiving combination treatment
                                                                            apremilast, an oral phosphodiesterase 4 inhibitor, in patients with
or other systemic agents [31]. On the other hand, it is fairly              moderate-to-severe plaque psoriasis over 52 weeks: a phase III, ran-
possible that some patients included in this review have been               domized controlled trial (ESTEEM 2). Br J D
                                                                                                                      ­ ermatol. 2015;173(6):
counted more than once, as they might have been sourced                     1387–1399. DOI:10.1111/bjd.14164. PMID: 26357944.
from the same databases or research centers (eg multiple             9.     Liu Y, Zhou S, Assaf M, Nissel J, Palmisano M. Impact of Renal
                                                                            Impairment on the Pharmacokinetics of Apremilast and Metabolite
publications by the same authors, Table 2). What is more,
                                                                            M12. Clin Pharmacol Drug Dev. 2016;5(6):469–479. DOI:10.1002/
in studies reporting on multiple patients, efficacy and safety
                                                                            cpdd.256. PMID: 27870479. PMCID: PMC5132082.
outcome measures were usually presented indistinguishably           10.     Grekin SK, Robinson DM, Berk DR, Plc A, Ahluwalia G. Low
for all included patients and not individually, based on the                serious infection rates in patients with psoriasis and psoriatic



Review | Dermatol Pract Concept. 2022;12(4):e2022179                                                                                       11
        arthritis treated with apremilast for 156 weeks and beyond:                  Dermatol Venereol. 2020;34(8):e376-e378. DOI: 10.1111/jdv.​
        Pooled analysis of the phase 3 ESTEEM 1 and 2 and PALACE 1-3                 16625. PMID: 32385859. PMCID: PMC7272987.
        trials. J Am Acad Dermatol. 2017;76(2):AB162. DOI:10.1016/j.           23.   Olisova OY, Anpilogova EM, Svistunova DA. Apremilast as a po-
        jaad.2017.04.630.                                                            tential treatment option for COVID-19: No symptoms of infection
11.     Apalla Z, Psarakis E, Lallas A, Koukouthaki A, Fassas A,                     in a psoriatic patient. Dermatol Ther. 2020;33(4):e13668. DOI:
        ­Smaragdi M. Psoriasis In Patients With Active Lung Cancer: Is               10.1111/dth.13668. PMID: 32449265. PMCID: PMC7267080.
         Apremilast a Safe Option? Dermatol Pract Concept. 2019;9(4):          24.   Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhib-
      300–301. DOI:10.5826/dpc.0904a11. PMID: 31723466. PMCID:                       itors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol.
      PMC68​30556.                                                                   2018;19(3):345-361. DOI: 10.1007/s40257-017-0336-3. PMID:
12.   Kelley AS. Defining “serious illness.”. J Palliat Med. 2014;17(9):985.         29256113.
      DOI: 10.1089/jpm.2014.0164. PMID: 25115302.                              25.   Tattersall IW, Leventhal JS. Cutaneous toxicities of immune
13.   Cohen-Sors R, Fougerousse A-C, Reguiai Z, et al. Biological Ther-              checkpoint inhibitors: The role of the dermatologist. Yale J
      apies or Apremilast in the Treatment of Psoriasis in Patients with a           Biol Med. 2020;93(1):123-132. PMID: 32226342. PMCID:
      History of Hematologic Malignancy: Results from a Retrospective                PMC7087048.
      Study in 21 Patients. Clin Cosmet Investig ­Dermatol. 2021;14:           26.   Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint in-
      845-854. DOI: 10.2147/CCID.S320098. PMID: 34267533.                            hibitor–related dermatologic adverse events. J Am Acad Derma-
      ­PMCID: PMC8275167.                                                            tol. 2020;83(5):1255-1268. DOI: 10.1016/j.jaad.2020.03.132.
14.    Daudén E, Carretero G, Rivera R, et al. Long-term safety of                   PMID: 32454097. PMCID: PMC7572894.
       nine systemic medications for psoriasis: A cohort study using           27.   Ellis SR, Vierra AT, Millsop JW, Lacouture ME, Kiuru M.
       the Spanish Registry of Adverse Events for Biological Ther-                   ­Dermatologic toxicities to immune checkpoint inhibitor ­therapy:
       apy in Dermatological Diseases (BIOBADADERM) Registry.                         A review of histopathologic features. J Am Acad Dermatol.
       J Am Acad Dermatol. 2020;83(1):139–150. DOI:10.1016/j.                         2020;83(4):1130–1143. DOI:10.1016/j.jaad.2020.04.105. PMID:
       jaad.2020.03.033. PMID: 32213306.                                              32360716. PMCID: PMC7492441.
15.    Manfreda V, Esposito M, Campione E, Bianchi L, Giunta A.                28.    Rovers J, Bovenschen H. Dermatological side effects rarely in-
       Apremilast efficacy and safety in a psoriatic arthritis patient               terfere with the continuation of checkpoint inhibitor immuno-
       affected by HIV and HBV virus infections. Postgrad Med.                       therapy for cancer. Int J Dermatol. 2020;59(12):1485–1490.
       2019;131(3):239–240. DOI:10.1080/00325481.2019.1575613.                       DOI:10.1111/IJD.15163. PMID: 32895923.
       PMID: 30700196.                                                         29.   Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, ­Delord JP.
16.    Jick S, Wilcox K, Persson R, et al. The rates of herpes zoster,               Dermatologic complications of anti-PD-1/PD-L1 immune check-
       hepatitis c, and tuberculosis among patients with psoriasis
       ­                                                                             point antibodies. Current Opinion in Oncology 2016;28(4):
       treated with apremilast, biologics, conventional systemics, and               254–263. DOI:10.1097/CCO.0000000000000290. PMID: 2713​
       corticosteroids in the U.S. MarketScan database. J Am Acad                    6138.
       ­Dermatol. 2018;79:AB292. DOI:10.1016/j.jaad.2018.05.1152.              30.   Nikolaou V, Sibaud V, Fattore D, et al. Immune checkpoint-­
17.     Reddy SP, Lee E, Wu JJ. Apremilast and phototherapy for treat-               mediated psoriasis: A multicenter European study of 115 p ­ atients
      ment of psoriasis in a patient with human immunodeficiency                     from the European Network for Cutaneous Adverse Event to
      ­virus. Cutis. 2019;103(5):E6-E7. PMID: 31233584.                              Oncologic Drugs (ENCADO) group. J Am Acad ­            Dermatol.
18.    Shah B, Mistry D, Chaudhary N. Apremilast in people living with               2021;84(5):1310–1320. DOI:10.1016/j.jaad.2020.08.137. PMID:
       HIV with psoriasis vulgaris: A case report. Indian J Dermatol.                33279646.
       2019;64(3):242–244. DOI:10.4103/ijd.IJD_633_18. PMID: 3114​             31.   Armstrong A, Levi E. Real-World Clinical Experience With
       8866. PMCID: PMC6537689.                                                      Apremilast in a Large US Retrospective Cohort Study of Patients
19.    Lambert JLW, Segaert S, Ghislain PD, et al. Practical recom-                  With Moderate to Severe Plaque Psoriasis. J Drugs Dermatol.
       mendations for systemic treatment in psoriasis in case of co-                 2017;16(12):1240-1245. PMID: 29240859.
       existing inflammatory, neurologic, infectious or malignant              32.   Sacchelli L, Patrizi A, Ferrara F, Bardazzi F. Apremilast as ther-
       disorders (BETA-PSO: Belgian Evidence-based Treatment Advice                  apeutic option in a HIV positive patient with severe psoriasis.
       in Psoriasis; part 2). J Eur Acad Dermatol Venereol. 2020;34(9):              Dermatol Ther. 2018;31(6):e12719. DOI: 10.1111/dth.12719.
       1914–1923 DOI:10.1111/JDV.16683. PMID: 32791572. P       ­ MCID:              PMID: 30358044.
       PMC7496856.                                                             33.   Fotiadou C, Trakatelli M, Papathemeli D, Lazaridou E. Safety
20.    Pullamsetti SS, Banat GA, Schmall A, et al. Phosphodiesterase-4               of Apremilast in the treatment of psoriasis patient with chronic
       promotes proliferation and angiogenesis of lung cancer by cross-              hepatitis B. Acta Derm Venereol. 2018;98 Suppl 219:40–41.
       talk with HIF. Oncogene. 2013;32(9):1121–1134. DOI:10.1038/             34.   Jeon C, Nakamura M, Sekhon S, et al. Generalized pustular
       onc.2012.136. PMID: 22525277.                                                 psoriasis treated with apremilast in a patient with multiple
21.    Queiro Silva R, Armesto S, González Vela C, Naharro Fernández                 medical comorbidities. JAAD Case Rep. 2017;3(6):495-497.
       C, González-Gay MA. COVID-19 patients with psoriasis and pso-                 DOI: 10.1016/j.jdcr.2017.07.007. PMID: 29034298. PMCID:
       riatic arthritis on biologic immunosuppressant therapy vs apremi-             PMC5635247.
       last in North Spain. Dermatol Ther. 2020;33(6). DOI:10.1111/            35.   González-Cantero Á, Sánchez-Moya AI, Arias-Santiago S,
       dth.13961. PMID: 32618402. PMCID: PMC7361149.                                 Schoendorff-Ortega C. Apremilast en el tratamiento de la
22.    Mugheddu C, Pizzatti L, Sanna S, Atzori L, Rongioletti F.                     ­psoriasis, experiencia clínica real. Piel Form Contin en derma-
       COVID-19 pulmonary infection in erythrodermic psoriatic                        tología. 2018;33:144–145. DOI:10.1016/J.PIEL.2017.05.009.
       patient with oligodendroglioma: safety and compatibility of             36.    Gottlieb AB, Merola JF, Cirulli J, et al. Characteristics
       apremilast with critical intensive care management. J Eur Acad                 of ­Patients with Psoriasis Treated with Apremilast in the




12                                                                                           Review | Dermatol Pract Concept. 2022;12(4):e2022179
        Corrona Psoriasis Registry. Dermatol Ther (Heidelb) 2021;11(1):             J Eur Acad Dermatol Venereol. 2018;32(7):1173-1179. DOI:
      253–263. DOI:10.1007/s13555-020-00479-4. PMID: 33475970.                      10.1111/jdv.14832. PMID: 29388335.
      PMCID: PMC7858993.                                                      51.   Sahuquillo-Torralba A, de Unamuno Bustos B, Rodríguez Serna M,
37.   Kahn JS, Casseres RG, Her MJ, Dumont N, Gottlieb AB,                          Monte Boquet E, Botella Estrada R. Treatment Persistence and
      ­Rosmarin D. Treatment of Psoriasis With Biologics and Apremilast             Safety of Apremilast in Psoriasis: Experience With 30 ­Patients
       in Patients With a History of Malignancy: A Retrospective Chart              in Routine Clinical Practice. Actas Dermosifiliogr (Engl Ed).
       Review. J Drugs Dermatol. 2019;18(4):S1545961619P0387X.                      2020;111(5):415-418. English, Spanish. DOI: 10.1016/j.ad.​
       PMID: 31013012.                                                              2018.10.031. PMID: 32423533.
38.    Nagata M, Kamata M, Ohtsuki M, Sato S, Tada Y. Scalp psoriasis         52.   Siciliano MA, Dastoli S, d’Apolito M, et al. Pembrolizumab-In-
       in a haemodialysis patient successfully treated with a half-dose of          duced Psoriasis in Metastatic Melanoma: Activity and Safety
       apremilast. Eur J Dermatol. 2019;29(3):341-342. DOI: 10.1684/                of Apremilast, a Case Report. Front Oncol. 2020;10:579445.
       ejd.2019.3588. PMID: 31389793.                                               DOI: 10.3389/fonc.2020.579445. PMID: 33163407. PMCID:
39.    Uvais NA, Rakhesh S V., Afra TP, Hafi NAB, Razmi T M.                        PMC7591674.
       Comorbid psoriasis-bipolar disorder successfully treated with
       ­                                                                      53.   Lanna C, Cesaroni GM, Mazzilli S, et al. Apremilast as a target
       apremilast: Much more than a mere coincidence? Gen ­Psychiatr.               therapy for nail psoriasis: a real-life observational study prov-
       2020;33(3):e100181. DOI: 10.1136/gpsych-2019-100181. PMID:                   ing its efficacy in restoring the nail unit. J Dermatolog Treat.
       32524074. PMCID: PMC7245448.                                                 2022;33(2):1097-1101. DOI: 10.1080/09546634.2020.1801976.
40.    Vico-Alonso C, Sánchez-Velázquez A, Pinilla-Martin B, et al.                 PMID: 32715817.
       ­Psoriasis and chronic myeloid leukemia: treatment with Apremi-        54.   Lanna C, Cesaroni GM, Mazzilli S, Bianchi L, Campione E. Small
       last. Int J Dermatol. 2020;59(4):e102-e103. DOI: 10.1111/                    Molecules, Big Promises: Improvement of Psoriasis Severity and
       ijd.14598. PMID: 31347142.                                                   Glucidic Markers with Apremilast: A Case Report. ­          Diabetes
41.    Melis D, Mugheddu C, Sanna S, Atzori L, Rongioletti F. C   ­ linical         Metab Syndr Obes. 2019;12:2685-2688. DOI: 10.2147/DMSO.
       efficacy, speed of improvement and safety of apremilast for                  S229549. PMID: 31908509. PMCID: PMC6925552.
       the treatment of adult Psoriasis during COVID-19 pandemic.             55.   Balato A, Campione E, Cirillo T, et al. Long-term efficacy and safety
       Dermatol Ther. 2020;33(4):e13722. DOI: 10.1111/dth.13722.                    of apremilast in psoriatic arthritis: Focus on skin manifestations
       PMID: 32475036. PMCID: PMC7300475.                                           and special populations. Dermatol Ther. 2020;33(3):e13440.
42.    Perrone D, Afridi F, King-Morris K, Komarla A, Kar P. Proximal               DOI: 10.1111/dth.13440. PMID: 32306448.
       Renal Tubular Acidosis (Fanconi Syndrome) Induced by Apremi-           56.   Ighani A, Georgakopoulos JR, Walsh S, Shear NH, Yeung J. A
      last: A Case Report. Am J Kidney Dis. 2017;70(5):729–731.                     comparison of apremilast monotherapy and combination therapy
      DOI:10.1053/j.ajkd.2017.06.021. PMID: 28823583.                               for plaque psoriasis in clinical practice: A Canadian multicenter
43.   Carpentieri A, Frisario R, Loconsole F. 18264 Malignancy and                  retrospective study. J Am Acad Dermatol. 2018;78(3):623-626.
      psoriasis treatment with apremilast: Retrospective chart review. J            DOI: 10.1016/j.jaad.2017.09.060. PMID: 28989112.
      Am Acad Dermatol. 2020;83:AB96.                                         57.   Ighani A, Georgakopoulos JR, Shear NH, Walsh S, Yeung J.
44.   Peitsch WK. Apremilast in a patient with psoriasis and mantle                 Short-term reasons for withdrawal and adverse events associated
      cell lymphoma under maintenance treatment with rituximab.                     with apremilast therapy for psoriasis in real-world practice com-
      J Dtsch Dermatol Ges. 2019;17(3):330-332. DOI: 10.1111/                       pared with in clinical trials: A multicenter retrospective study.
      ddg.13771. PMID: 30775841.                                                    J Am Acad Dermatol. 2018;78(4):801-803. DOI: 10.1016/j.
45.   Takama H, Shibata T, Ando Y, et al. Pembrolizumab-induced                     jaad.2017.09.067. PMID: 29017843.
      psoriasis vulgaris successfully treated with apremilast. Eur J          58.   Ighani A, Georgakopoulos JR, Shear NH, Walsh S, Yeung J.
      Dermatol. 2020;30(2):188-190. DOI: 10.1684/ejd.2020.3723.                     Maintenance of therapeutic response after 1 year of apremi-
      PMID: 32538362.                                                               last combination therapy compared with monotherapy for the
46.   Foti C, Tucci M, Stingeni L, et al. Successful treatment with apremi-         treatment of plaque psoriasis: A multicenter, retrospective study.
      last of severe psoriasis exacerbation during nivolumab therapy                J Am Acad Dermatol. 2018;79(5):953-956. DOI: 10.1016/j.
      for metastatic melanoma. Dermatol Ther. 2021;34(1):e14653.                    jaad.2018.04.043. PMID: 29730366.
      DOI: 10.1111/dth.14653. PMID: 33301205.                                 59.   Phan C, Beneton N, Delaunay J, et al. Real-World Effective-
47.   Di Lernia V, Casanova DM, Ricci C. Apremilast in patients with                ness and Safety of Apremilast in Older Patients with Psoriasis.
      history of malignancy: a real-life, single-center experience. Int J           Drugs Aging. 2020;37(9):657-663. DOI: 10.1007/s40266-020-
      Dermatol. 2021;60(1):e22-e24. DOI: 10.1111/ijd.15093. PMID:                   00781-y. PMID: 32696432.
      32857434.                                                               60.   Ighani A, Georgakopoulos JR, Zhou LL, Walsh S, Shear N,
48.   Aragon-Miguel R, Calleja-Algarra A, Calleja-Algarra B, et al.                 Yeung J. Efficacy and Safety of Apremilast Monotherapy for
      Apremilast in plaque psoriasis: A retrospective, real-life study up           Moderate to Severe Psoriasis: Retrospective Study. J Cutan Med
      to 12-month observation. J Am Acad Dermatol. 2019; Volume                     Surg. 2018;22(3):290-296. DOI: 10.1177/1203475418755982.
      81, Issue 4, AB21. DOI: 10.1016/j.jaad.2019.06.115                            PMID: 29373924.
49.   Tampouratzi E, Vrakas S, Koutoufaris G, Xourgias V,                     61.   Megna M, Fabbrocini G, Camela E, Cinelli E. Apremilast ­efficacy
      Katsantonis J. Successful treatment with apremilast psoriatic
      ­                                                                             and safety in elderly psoriasis patients over a 48-week period.
      patient with underlying chronic hepatitis B. In: 24th World Con-              J Eur Acad Dermatol Venereol. 2020;34(11):e705-e707. DOI:
               ­ ermatology Milan, Abstracts Book. 2019.
      gress of D                                                                    10.1111/jdv.16443. PMID: 32277507.
50.   Papadavid E, Rompoti N, Theodoropoulos K, Kokkalis G,                   62.   del Alcázar E, Suárez-Pérez JA, Armesto S, et al. Real-world effec-
      Rigopoulos D. Real-world data on the efficacy and safety of                   tiveness and safety of apremilast in psoriasis at 52 weeks: a retro-
      apremilast in patients with moderate-to-severe plaque psoriasis.              spective, observational, multicentre study by the Spanish Psoriasis




Review | Dermatol Pract Concept. 2022;12(4):e2022179                                                                                                13
      Group. J Eur Acad Dermatol Venereol. 2020;34(12):2821-2829.                   immune checkpoint inhibitors with apremilast. Eur J Cancer.
      DOI: 10.1111/jdv.16439. PMID: 32271966.                                       2019;110:107-109. DOI: 10.1016/j.ejca.2019.01.010. PMID:
63.   Fremlin G, Bedlow A. Real-world experience of apremilast.                     30785013.
      (2017), Bristol Cup Posters. Br J Dermatol, 177: 25-77. DOI:            70.   Magdaleno J, Valenzuela C, Ortiz-Salvado J, et al. Experience
      10.1111/bjd.15426                                                             with Apremilast for the treatment of psoriasis in real-world clin-
64.   Foulkes A, Nemazee L, Griffiths C, Warren R. Apremilast, an                   ical practice. In: 28th EADV Congress. 2019.P1814.
      oral phosphodiesterase 4 inhibitor, in a tertiary-referral psoriasis    71.   Magdaleno-Tapial J, Valenzuela-Oñate C, Hernández-Bel P.
      service. (2017), Bristol Cup Posters. Br J Dermatol, 177: 25-77.              Tratamiento efectivo de la psoriasis ungueal con apremilast. Piel
      DOI: 10.1111/bjd.15426                                                        Form Contin en dermatología. 2019;34:74–76. DOI:10.1016/J.
65.   Malara G, Micelli GF, Arceri F. Is apremilast a promising treat-              PIEL.2018.05.006.
      ment for psoriasis and psoriatic arthritis? J Am Acad Dermatol.         72.   Gioe OA, Savoie C, Grieshaber EB, Hilton DC. Treatment of erythro-
      2018;79:AB171. DOI:10.1016/J.JAAD.2018.05.699.                                dermic psoriasis with apremilast. JAAD Case Rep. 2021;11:36-37.
66.   Kungurov NV, Zilberberg NV, Kokhan MM, Keniksfest JV,                         DOI: 10.1016/j.jdcr.2021.03.011. PMID: 33898682. PMCID:
      Grishaeva EV. Experience in the treatment of psoriasis patients               PMC8054184.
      using Apremilast, a selective signalling pathway inhibitor. Vestn       73.   Mayor Ibarguren A, Enrique EA, Diana PL, Ana C, Pedro HP.
      Dermatol Venerol. 2019;94:67–76.                                              Apremilast for immune checkpoint inhibitor-induced psoria-
67.   Aragon-Miguel R, Calleja‐Algarra A, Andres-Lencina J, et al.                  sis: A case series. JAAD Case Rep. 2021;11:84-89. DOI: 10.10​
      Generalized and palmoplantar pustular psoriasis and acroder-                  16/j.​jdcr.2021.03.015. PMID: 33948464. PMCID: PMC807​
      matitis continua of Hallopeau: a case series of 8 patients treated            9825.
      with apremilast. In: 28th EADV Congress. 2019.P1758.                    74.   Kurata M, Ohyama M. Long-term remission of severe nail pso-
68.   Bulic S, Dediol I. Apremilast in psoriasis patients with a history of         riasis after discontinuation of apremilast in a colorectal cancer
      malignancy - case series. In: 28th EADV Congress. 2019.P1682.                 survivor. J Dermatol. 2021;48(6):e248-e249. DOI: 10.1111/1346-
69.   Fattore D, Annunziata MC, Panariello L, Marasca C,                            8138.15831. PMID: 33739479.
      Fabbrocini G. Successful treatment of psoriasis induced by
      ­




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