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.
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 expenditure [ 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 contraindicated in patients with active infections or serious liver impairment, nor is routine lab monitoring necessary. Similarly, it can be administered to patients with past or current malignancy [ 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 patients 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 ] .
The purpose of this study is to present our five-year experience 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 systematic literature search.
The March 2016 (apremilast approval in Greece) to June 30 th , 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 having 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) disease, 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 comorbidity diagnosis, apremilast dose, baseline Psoriasis Area and Severity Index (PASI), treatment outcome in terms of efficacy, duration of apremilast treatment (weeks) and adverse 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 approved by the Ethics Committee of the Hospital of Venereal and Cutaneous Diseases, Thessaloniki, Greece.
We conducted this systematic review as stated by Meta-analyses Of Observational Studies in Epidemiology (MOOSE) statement. Published and unpublished prospective 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 presenting real-life data, as well as studies reporting on combination therapy of apremilast and other systemic agents aside from phototherapy, systemic corticosteroids or other medication 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.
Three electronic databases were searched (MEDLINE, ScienceDirect, and the Cochrane Library electronic databases). Google scholar () was also browsed. Abstract compendia of the World Congresses of Dermatology, World Psoriasis and Psoriatic Arthritis 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 4 th , 2021. Amgen ® was 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.
The following search strategy was used for MEDLINE database and modified accordingly for the rest of searched platforms: (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).
The primary endpoint of this study was the documentation of any safety-related outcomes in patients with serious comorbidities having received apremilast (for example comorbidity 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 reviewers (AT and NS) independently screened titles and abstracts for relevance to the study objective. The full text of remaining 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), apremilast dose, baseline PASI, AEs including comorbidity-related events. Any disagreements were resolved in consultation with a third author (ES).
Two authors (AT and ES) independently assessed included reports 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.
The psoriasis-archives search returned 16 eligible cases, one of which was not included in the analysis due to incompletely documented patient data ( Table 1 ). No progression of malignancy, reactivation of chronic / latent infection or deterioration 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 discontinuation, < 14 days, due to Covid-19-related restrictions and consequent difficulties in drug prescription). Desired response (PASI50) was not achieved in 1 case and apremilast was therefore discontinued (primary drug failure).
Cases of psoriasis patients with serious baseline comorbidities treated with apremilast.
The systematic literature search yielded 52 studies eligible for inclusion ( Figure 1 ). One additional study was identified after the last search date (published July 8 th 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 infections – 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 serious 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 response of psoriasis to apremilast was recorded in most cases. Overall, the quality of included studies was good ( Table 3 ).
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.
Literature cases of apremilast administered to psoriasis patients with serious baseline comorbidities.
Methodological quality assessment of included reports.
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 challenging. 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 underlying 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 opposed to other systemic agents, seem to have a lower infection 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 with nine systemic agents in Spain, apremilast had a lower infection (incidence rate 0.3 [95% CI 0.1–0.9]) and malignant 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 acitretin are considered first-line choices ]. Furthermore, many biologics (adalimumab, certolizumab pegol, etanercept, infliximab, ustekinumab, guselkumab, risankizumab, brodalumab, secukinumab, ixekizumab) can be used in patients receiving highly active antiretroviral therapy (HAART) and having undetectable viral load [ 19 ] . In case of detectable 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 preferred 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. According to the World Health Organization, psoriasis patients on small molecules like apremilast are thought to be immunosuppressed [ 6 ] . There have been reports of asymptomatic, as well as of fast and uneventful resolution of COVID-19 infections 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 gastrointestinal symptoms can mimic COVID-19 manifestations [ 6 ] .
A relatively new, special population of psoriatic patients are those receiving therapy with immune checkpoint inhibitors (ICPIs) for various types of cancer. ICPIs have revolutionized 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 clinical 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 exanthems, 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 interrupted, although severity may vary, up to life-threatening Stevens-Johnson syndrome/toxic epidermal necrolysis [ 27 , 28 ] . Similarly, psoriasis is usually managed with topical 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 patients, 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 patient does not respond to phototherapy and/or acitretin [ 30 ] .
Our study is not without its limitations. A few large studies like Armstrong and Levi were excluded from this review and potentially significant data was missed, because results were not reported separately for patients receiving apremilast 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.
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