Incidence of Skin Cancer in Patients With Chronic Inflammatory Cutaneous Diseases on Targeted Therapies: A Systematic Review and Meta-Analysis of Observational Studies

Incidence of Skin Cancer

in Patients With Chronic

Inﬂammatory Cutaneous Diseases

on Targeted Therapies: A Systematic

Review and Meta-Analysis

of Observational Studies

Salvatore Crisafulli

†

, Lucrezia Bertino

†

, Andrea Fontana

, Fabrizio Calapai

Ylenia

Ingrasciotta

, Massimiliano Berretta

, Gianluca Triﬁrò

and Claudio Guarneri

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy,

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy,

Unit of Biostatistics, Fondazione

IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy,

Department of Chemical, Biological, Pharmaceutical

and Environmental Sciences, University of Messina, Messina, Italy,

Department of Clinical and Experimental Medicine,

Section of Infectious Diseases, University of Messina, Messina, Italy,

Department of Diagnostics and Public Health,

University of Verona, Verona, Italy

Cancer is one of the several comorbidities that have been linked with chronic cutaneous

inﬂammatory diseases namely psoriasis/psoriatic arthritis and hidradenitis suppurativa.

Although the chronic inﬂammatory state, typical of the diseases, may induce pro-

tumorigenic effects, the debate whether or not the drugs currently used in clinical

practice do in facts increase a patient’s risk of malignancy remains largely unsolved.

The therapeutic armamentarium has been greatly enhanced at least in the last two

decades with the advent of biologics, a heterogeneous group of laboratory-engineered

agents with more in the pipeline, and other targeted small molecules. Among the organ

systems, skin results as one of the most commonly affected, non-melanoma skin cancers

being the main drug-induced manifestations as side effect in course of these treatments.

The objective of the study is to systematically review the cutaneous malignancy risk of the

newer therapies through an overview of meta-analyses and observational studies on

the topic.

Keywords: skin cancer, non-melanoma skin cancer, melanoma, biologics, psoriasis

INTRODUCTION

Psoriasis, psoriatic arthritis and hidradenitis suppurativa are three common inﬂammatory and

immune-mediated skin diseases characterized by increased levels of pro-inﬂammatory cytokines

and chemokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-17 and IL-23 (1–7).

Chemical inﬂammatory mediators involved in the pathogenesis of these diseases may increase the

Frontiers in Oncology | www.frontiersin.org June 2021 | Volume 11 | Article 6874321

Edited by:

Gabriella Brancaccio,

University of Campania Luigi Vanvitelli,

Italy

Reviewed by:

Anfernee Kai Wing Tse,

Caritas Institute of Higher Education,

China

Robert Laird Judson-Torres,

The University of Utah, United States

*Correspondence:

Claudio Guarneri

[email protected]

†

These authors have contributed

equally to this work

Specialty section:

This article was submitted to

Skin Cancer,

a section of the journal

Frontiers in Oncology

Received: 29 March 2021

Accepted: 12 May 2021

Published: 03 June 2021

Citation:

Crisafulli S, Bertino L, Fontana A,

Calapai F, Ingrasciotta Y, Berretta M,

Triﬁrò G and Guarneri C (2021)

Incidence of Skin Cancer in Patients

With Chronic Inﬂammatory Cutaneous

Diseases on Targeted Therapies: A

Systematic Review and Meta-Analysis

of Observational Studies.

Front. Oncol. 11:687432.

doi: 10.3389/fonc.2021.687432

SYSTEMATIC REVIEW

published: 03 June 2021

doi: 10.3389/fonc.2021.687432

risk of malignancies through the induction of pro-cancerous

mutations, adap tive responses, resistance to apoptosis and

environmental changes such as the stimulation of angiogenesis

(8, 9). A number of observational studies suggested that patients

affected by these diseases are at increased risk of developing

cancer (10–13). In particular, increased rates of cancer, especially

keratinocyte skin cancer and lymphomas were reported in

patients with psoriasis or psoriatic arthritis (14). A signiﬁcantly

increased risk of overall cancer was observed also among patients

affected by hidradeni tis suppurativa in a recently published

population-based cohort study (15).

The recent marketing of systemic biological (i.e. the TNF-a

inhibitors etanercept, inﬂiximab and adalimumab, the anti-IL-

12/23 ustekinumab, the IL-17/IL-17 receptor antagonists

secukinumab, ixekizumab and brodalumab and the anti-IL-23

agents tildrakizumab, guselkumab and risankizumab) and

chemically synthetized drugs (e.g. apremilast and tofacitinib) as

targeted therapies has i mproved the management of these

diseases (16–18). However, since these drugs target molecules

that may be relevant to cancer immunosurveillance mechanisms,

some concerns were raised about their association with an

increased risk of cancer occurrence (19–23). A recent meta-

analysis of randomized clinical trials (RCTs) and open-label

extension (OLE) studies r eported that TNF inhibitors are

associated with an increased risk of non-melanoma skin

cancers (NMSC) in people with psoriasis. However, the

authors of this study found that no real-world evidence was

available and acknowledged the signiﬁcant limitations associated

with the study design of the articles included, that make it

difﬁcult to extrapolate to real-world practice (24). Evidence on

the risk of skin cancer in patients with chronic inﬂammatory

cutaneous diseases on targeted therapies is still sparse

controversial. Therefore, the aim of this systematic review and

meta-analysis was to assess the risk of cutaneous malignancies in

patients with psoriasis, psoriatic arthritis or hidradenitis

suppurativa treated with targeted therapies.

METHODS

Search Strategy and Study

Selection Criteria

This systematic review and meta-analysis was conducted in

accordance with the Preferred Reporting Items for Systematic

Reviews and Meta-Analyses (PRISMA) statement, following an a

priori-established protocol registered on the International

Prospective Register of S ystematic Reviews (PROSPERO:

CRD42020212137). The completed PRISMA c hecklist is

provided in Supplementary Figure 1.Twoauthors(SC,FC)

independently searched the bibliographic databases PubMed and

EMBASE for literature related to the risk of skin cancer in patients

affected by inﬂammatory cutaneous diseases and treated with

targeted therapies. Literature was searched from databases

inception until 15

September 2020. The search strategy

concerned terms related to inﬂammatory cutaneous diseases (i.e.

psoriasis, psoriatic arthritis and hidradenitis suppurativa), skin

cancers (e.g. squamous cell carcinoma, basal cell carcinoma and

melanoma) and targeted therapies (i.e. etanercept, inﬂiximab,

adalimumab, ustekinumab, secukinumab, ixekizumab,

brodalumab, tildrakizumab, guselkumab, risankizumab,

apremilast and tofacitinib). Citations, titles and abstracts were

exported into Endnote X9. The detailed literature search strategy

for different databases is provided in Supplementary Table 1.

Original observational studies were included if they (a) included

patients affected by psoriasis, psoriatic arthritis or hidradenitis

suppurativa; (b) clearly reported a well-deﬁned measure of skin

malignancies incidence; (c) included patients treated with

biological drugs and/or the small mo lecules, apremilast and

tofacitinib; (d) were written in English. To reduce the risk of

publication bias, conference abs tracts were also eligible for

inclusion. Narrative or systematic reviews, meta-analyses, book

chapters, editorials and pooled analyses were not included, but the

reference lists in reviews and meta-analyses were screened to

potentially identify further studies to include.

After duplicate studies were removed, two authors (SC and

FC) individually reviewed titles and abstracts to remove clearly

irrelevant articles and, subsequently, full text of the articles that

both reviewers considered potentially eligible. Any

inconsistencies were resolved at this stage through discussion

or the intervention of a third independent assessor (GT or CG).

Data Extraction

For eligible studies, information on the following items was

independently collected by the same two authors and stratiﬁed

by skin ca ncer type: study authors, year of publication,

cat chment area, data source , study po pul ation, study years,

study design and risk estimate. Any disagreements were

resolved by consensus with a third author (GT or CG).

Assessment of Risk of Bias and Overall

Quality of the Evidence

The ri sk of bias of the observational studies included in this

systematic review was independently assessed by two authors

(SC and FC) using the Newcastle-Ottawa quality assessment

scale (25). This instrument consists of eight different domains

for cohort studies (representativeness of the exposed cohort,

selection of the non-exposed cohort, ascertainment of

exposure, demonstration that outcome of interest was not

present at start of study, comparability of cohorts on the

basis of the design or analysis, assessment o f outcome,

follow-up long enough for outcomes to occur, adequacy of

follow up) and case-control studies (adequate case deﬁnition,

representativeness of the c ases, selection of controls, deﬁnition

of co ntrol s, comparabil ity of cases and con trols on the basis of

the design or analysis, ascertainment of exposure, same method

of ascertainment for cases and controls, non-response rate).

The included studies were categorized as “low r isk of bias” if at

least six of the eight domains were judged to be at low risk

of bias.

Statistical Analysis

Foreachincludedstudy,skincancerincidencerates(IR)per

10,000 person-years (PY) were considered as the primary

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outcome f or the meta-analysis . Meta- analysis of IRs was

performed assuming that the logarithm of each study-speciﬁc

rate was normally distributed and the corresponding standard

error, used to p erform the inverse-variance weighting, was

computed from the 95% CI (or p-value) reported in the

original IRs. Between-study heteroge neity of the estimates

was assessed using the Cochran’sQ-test(26)alongwithits

derived measure of inconsistency (I

), and was considered to be

present when Cochran’s Q-test p-value was < 0.10 or I

> 40%

(27). Estimates were summarized by ﬁxed-effects or rando m-

effects models, according to the absence or the presence of

heterogeneity, respectively. It is generally accepted that when

there are fewer than ten studies in a meta-analysis, both meta-

regression (27) and test for publicati on bias (28) should not be

considered. Both the study speciﬁcaswellasthepooled

epidemiological estimates, were graphically depicted, with

their 95% CI, on a forest plot. Analyses were stratiﬁed for

speciﬁc skin cancer types, i.e. NMSCs and melanoma. If a study

presented more than one estimate, the most recent one was

used. Two-sided p-values<0.05 were conside red for statistic al

signiﬁcan ce. All calculations were carried out using R

Foundation for Statistical Computing (version 4.0,

package: metafor).

RESULTS

Characteristics of the Studies Included

The original electronic search yielded 1762 (1549 after removing

duplicates) papers potentially relevant for this review (Figure 1).

After removing duplicates, 1549 were initially screened. Of these,

1467 were excluded after the screening of study titles and

abstracts. The remaining 82 studies were retrieved for more

detailed evaluation and 10 of them met the review inclusion

criteria. The main characteristics of the included studies are

reported in Table 1. Most of the included studies were

prospective cohort studies (N= 5; 50.0%) (33–36, 38 ), three

(30.0%) (29, 31, 32) were retrospective cohort studies, one was

FIGURE 1 | PRISMA ﬂow-chart showing the process of literature search and study selection.

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TABLE 1 | Characteristics of the studies included in the systematic review.

Reference Catchment area Data source Study population Study drugs Study

years

Study design IR per 10,000

PYs [95%CI]

Non-melanoma skin cancer

29 California (USA) Kaiser Permanente Northern

California (KPNC)

All KPNC members aged ≥ 18 years, diagnosed

with psoriasis between 1998 and 2011 and

treated with a systemic antipsoriatic agent

Adalimumab,

etanercept, inﬂiximab,

ustekinumab

1998-2011 Retrospective cohort

study

120

[98-143]

30 USA US Truven MarketScan

database

Patients with moderate to severe PsA, deﬁned

by ≥1 inpatient or ≥2 outpatient 696.0 diagnosis

codes on 2 unique calendar days

Adalimumab,

etanercept, inﬂiximab,

apremilast

2010-2015 Clinical trial and real-

world data comparison

149.3

[116.5-182.0]

31 United Kingdom British Society for

Rheumatology Biologics

death registers

All patients diagnosed with PsA starting a TNF-

inhibitor and registered in the British Society for

Rheumatology Biologics Register

Etanercept,

adalimumab, inﬂiximab

2002-2012 Retrospective cohort

study

N.A.

32 USA Market-Scan

database and

Medicare

Patients with a diagnosis of psoriasis, with the

ﬁrst outpatient qualifying ICD-9 CM code

Etanercept

Adalimumab

Inﬁximab

2005-2009 Retrospective cohort

study

185.8

[160.2-211.42]

33 USA, Canada, Germany, France,

Czech Republic, Greece,

Netherlands, Spain, UK, Austria,

Denmark, Ireland, Sweden

ESPRIT Registry Patients aged ≥ 18 years of age with chronic

plaque psoriasis who had been prescribed

adalimumab

Adalimumab 2008-2015 Prospective cohort

study

[52-72]

34 Canada OBSERVE-5 surveillance

registry

Adult patients with moderate to severe psoriasis

initiating etanercept

Etanercept 2006-2012 Prospective cohort

study

125

[60-240]

34 USA OBSERVE-5

surveillance registry

Adult patients with moderate to severe psoriasis

initiating etanercept

Etanercept 2006-2012 Prospective cohort

study

262

[220-310]

35 Germany The German Psoriasis Registry

PsoBest

Adult patients with moderate-to-severe psoriasis

at the time point of a new drug to be started

TNF-a inhibitors 2008-2012 Prospective cohort

study

[12-90]

35 Germany The German Psoriasis Registry

PsoBest

Adult patients with moderate-to-severe psoriasis

at the time point of a new drug to be started

Ustekinumab 2008-2012 Prospective cohort

study

[10-136]

36 The Netherlands Radboud University

Nijmegen Medical Centre

pharmacovigilance registry

Patients starting biological treatment for

psoriasis in the Dermatology outpatient clinic of

the Radboud University Nijmegen Medical

Centre

Etanercept,

adalimumab, inﬂiximab,

ustekinumab

2005-2010 Prospective cohort

study

N.A.

Melanoma

29 California (USA) Kaiser Permanente Northern

California (KPNC)

All KPNC members aged ≥ 18 years old,

diagnosed with psoriasis between 1998 and

2011 and treated with a systemic antipsoriatic

agent

Adalimumab,

etanercept, inﬂiximab,

ustekinumab

1998-2011 Retrospective cohort

study

[3-14]

31 United Kingdom British Society for

Rheumatology Biologics

death registers

All patients diagnosed with PsA starting a TNF-

inhibitor and registered in the British Society for

Rheumatology Biologics Register

Etanercept,

adalimumab, inﬂiximab

2002-2012 Retrospective cohort

study

37 America and Europe Psoriasis Longitudinal

Assessment and Registry

(PSOLAR)

Patients aged ≥ 18 years with moderate-to-

severe psoriasis who were receiving, or were

candidates to receive, systemic therapy

TNF-a inhibitors 2007-2015 Nested case-control

study

37 America and Europe Psoriasis Longitudinal

Assessment and Registry

(PSOLAR)

Patients aged ≥ 18 years with moderate-to-

severe psoriasis who were receiving, or were

candidates to receive, systemic therapy

Ustekinumab 2007-2015 Nested case-control

study

(Continued)

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a nested case-control study (10.0%) (37) and one was a study

comparing clinical trials data and real-world data (10.0%) (30).

All included studies focused on the incidence of skin

malignancies in patients treated with TNF-a inhibitors, three

of them included also patients treated with ustekinumab (29, 35,

36) and only one study reported NMSC IRs also for apremilast

and tofacitinib (30). No observational studies assessing the

incidence of skin cancer in patients with inﬂammatory

cutaneous diseases and treated with secukinumab, ixekizumab,

brodalumab, tildrakizumab or risankizumab were found. All the

included studies used real-world data sources, such as drug or

disease registries and claims databases.

Of the 10 studies included in this systematic review, 7

provided data suitable for meta-analysis.

Risk of Bias in Individual Studies

Figure 2 summarizes the risk of bias assessment of individual

studies. The overall risk of bias was rated as low for 7 (29, 30, 32–

34, 35, 38) of the 10 included studies, while 3 ( 31, 36, 37) studies

TABLE 1 | Continued

Reference Catchment area Data source Study population Study drugs Study

years

Study design IR per 10,000

PYs [95%CI]

38 USA, Canada, Germany, France,

Czech Republic, Greece,

Netherlands, Spain, UK, Austria,

Denmark, Ireland, Sweden

ESPRIT Registry Patients aged ≥ 18 years of age with chronic

plaque psoriasis who had been prescribed

adalimumab

Adalimumab 2008-2013 Prospective cohort

study

[3-10]

35 Germany PsoBest Registry Adult patients with moderate-to-severe psoriasis

at the time point of a new drug to be started

Adalimumab,

etanercept, inﬂiximab

2008-2012 Prospective cohort

study

[0-43]

ICD-9 CM: international classiﬁcation of diseases, 9

revision, clinical modiﬁcation; IR, incidence rate; NA, not available; PsA, psoriatic arthritis; PYs, person-years; SIR, standardized incidence ratio; TNF, tumor necrosis factor; UK, United

Kingdom; USA, United States of America.

FIGURE 2 | Risk of bias assessment through the Newcastle-Ottawa Scale

presented as percentages across all included cohort studies (A) and case–

control studies (B).

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proved to have an unclear risk of bias. Limitations mainly

concerned the assessment of the presence or absence of

prognostic factors and the adequacy of follow-up.

Targeted Therapies and Skin Cancer

Incidence Rates

IRs of NMSC and melanoma reported in the articles included in

this systematic review are summarized in Figure 3.

Overall, the IR of NMSC in the included studies ranged from

38 (95% CI: 12-90) (35) to 262 (95% CI: 220-310) (34) cases per

10,000 PYs. The pooled IR for the overall risk of NMSC was

124.5 (95% CI 83.4 – 185.8) per 10,000 PYs. A considerable

heterogeneity was found among these studies (Cochrane’sQ=

173.0; I

96.5%).

A comparison of the incidence ratio for the overall risk of

NMSC in patients exposed to biologics and small molecules

versus non-biologic drugs users could be obtained only in two

studies (29, 36). In one case (36), the hazard ratio (HR) was 1.42

(95% CI:1.12-1.80), while in the other one the Incidence Rate

Ratio (IRR) was 0.74 (95% CI:0.60-0.91) (29).

The IR of melanoma in the included studies ranged from 5 (95%

CI: 3-10) (38)to8(95%CI:0-43)(35) cases per 10,000 PYs. The

pooled IR for the overall risk of melanoma was 6.1 (95% CI 3.9 –

9.6) per 10,000 PYs. No heterogeneity among studies reporting

melanoma IRs was found (Cochrane’sQ=1.0;I

0.0%). The only

study reporting an HR for melanoma between users of biologic

drugs and small molecules versus non- biologic users (36)showed

no statistically signiﬁca nt difference (HR:1.57, 95% CI: 0.61-4.09).

It was not possible to investigate both the source of

heterogeneity and the presence of publication bias, as fewer

than ten studies were included in the meta-analysis (28).

DISCUSSION

In recent years, we have witnessed a revolution in the treatment

of many skin diseases, ranging from bullous diseases, urticaria,

atopic dermatitis, to hidradenitis suppurativa and psoriasis (39).

In particular, psoriasis is a chronic cutaneous inﬂammatory

disease affecting an estimated 125 million people worldwide,

that is often associated with systemic manifestations such as

major adverse cardiovascular event, obesity, inﬂammatory bowel

disease and arthropathic psoriasis (40, 41). The decision to use

one therapy over another is signiﬁcantly inﬂuenced by these

comorbidities and the severity of the disease. Moreover, a better

understanding of the pathogenesis of this systemic disease had

led to identiﬁcation of new therapeutic targets (42). Whereas the

older treatment options, such as phototherapy, methotrexate and

cyclosporine A, are still effective, biotechnological drugs are

substantially improving the therapeutic arsenal. The success of

these new therapies lies in their great selectivity of action which

allows to obtain, in most cases, a signiﬁcant therapeutic efﬁcacy

in a short time with a reduction in side effects compared to

traditional therapies. Through these therapies, even the severest

symptoms of psoriasis and psoriatic arthritis can be excellently

treated (43, 44). The biological drugs produced so far are

FIGURE 3 | Forest plot of the estimated skin cancer incidence per 10,000 person-years along with 95% conﬁdence intervals, stratiﬁed by skin cancer type.

RE, Random-Effects model; FE, Fixed Effect model.

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monoclonal antibodies and fusion proteins. These products have

the enormous advantage of being able to selectively interfere, at

various levels and with different modes of action, in the

immunological processes that trigger and sustain psoriasis (45).

To date they are divided into ﬁve classes: TNF-a inhibitors, IL-

12/23 inhibitors, IL-17 inhibitors, IL-23 inhibitors and

phosphodiesterase type 4 (PDE4) inhibitors (40).

According with the above-mentioned results, our review found

no observational studies assessing the incidence of skin cancer in

patients with inﬂammatory cutaneous diseases and treated with

biologics targeting selectively IL-17 or IL-23, thus obtaining mainly

data on patients under anti-TNF-a therapy and, to a more limited

degree, under ustekinumab, apremilast and tofacitinib.

TNF-a inhibitors inﬂixim ab, etanercept, adalimumab and

certolizumab pegol are the oldest class of currently approved

biotechnological drugs for the treatment of both psoriasis and

psoriatic arthritis and, limited to adalimumab, of hidradenitis

suppurativa. TNF-a exerts several effects. It could promote the

progression of cancer (46), but also blocking TNF-a could result

in arresting antitumor immune response and in promoting the

growth of immunogenic tumors (47–49).

Some of the studies analyzed in this systematic review also

included patients receiving ustekinumab, apremilast and

tofacitinib (29, 30, 35, 36). Ustekinumab belongs to the class of

biologics targeting the IL-12/23 pathway, whereas apremilast is

an anti-PDE4 small molecule and tofacitinib a janus kinase

inhibitor. The inhibition of these pathways causes a

downregulation of the in ﬂammatory response by modulating

the expression of TNF-a, IL-23, IL-17 and other inﬂammatory

cytokines, all involved at least in part in the tumorigenesis.

Consequently, whereas these drugs have shown dramatically

excellent efﬁcacy, concerns have been raised about the risks

related to this class of agents.

Undoubtedly, patients with psoriasis are at an increased risk

of cancer. Assessing the baseline risk of cutaneous malignancies

in psoriasis patients is challenging due to most studies including

both treated and untreated patients, and due to confounding

factors like phototherapy and immunosuppressive therapy (50).

Moreover NMSC and melanoma are known to arise with

increased incidence among p atients that have u ndergone

medical radiation procedures or immunosuppressive therapy

(51–53), such as those immunosuppressed in an iatrogenic way

after a solid organ transplantation (54–56). According to the

World Health Organization, age standardized world incidence of

melanoma and NMSC are respectively 3,4 and 11 per 100.000

PYs. On the other hand, recent data emerging from literature

show that skin cancers have a higher incidence in psoriasis

patients than general population with a standardized incidence

ratio of 3.37 (95% CI 1.84-5.66) ( 57). More in detail, Pouplard

et al. in a meta-analysis reported a standardized incidence ratio

of 5.3 for squamous cell carcinoma (SCC) (95% CI 2.63–10.71)

and of 2.00 for basal cell carcinoma (BCC) (95% CI 1.83–2.20),

whereas the authors reported a similar risk of melanoma in

psoriatic patients compared to the general populations.

When considering the risk of skin cancer in psoriatic patients

under treatment, many aspects should be analyzed: predisposing

factors, duration and timing of exposure, the cumulative dose,

the interaction with other carcinogens and, also, the latency.

Despite all these data to be considered, enough evidence

conﬁrmed the relation between skin cancer and speciﬁc

treatment for psoriasis and it has emerged that the risk

increases even more respect untreated patients (58).

In particular, oral psoralen and ultraviolet A (PUVA) is

associated with an increased risk for skin cancer in a dose

dependent fashion: risk of NMSC is greatest with > 350

treatments, while melanoma ri sk is increased with >250

treatments (59, 60). However, the carcinogenic mechanism of

PUVA has not been elucidated: it maybe acts in a mutagenic and

immunologic way (61). Instead, even if UVB phototherapy may

increase photoaging acting with multiple mechanisms

(inhibition of DNA synthesis, epidermal keratinocyte

hyperproliferation, induction of T-cell apoptosis and of anti-

inﬂammatory cytokines), no increase in skin cancer has been

observed, especially with <100 treatments. Only when patients

have been treated previously with PUVA and, in a second time,

with broadband UVB (>300 treatments), it has been noted a

modest increase in SCC (incidence rate ratio 1.37, 95% CI 1.03–

1.83) and BCC (incidence rate ratio 1.45, 95% CI 1.07– 1.96) (62).

Also systemic non biologic therapies are associated with an

increased risk of skin cancers (63), acting primarily as

immunosuppressants. Treatment with methotrexate results in

higher risk for NMSC, but no association with risk for melanoma

was observed (64). In detail, it has been shown that patients in

treatment with methotrexate seem to have a doubled risk of SCC

compared with people who receive PUVA therapy (65). Cyclosporine

is associated with an elevated risk of SCC, which could increase even

more in relation to treatment duration (>2 years) and previous

therapy (PUVA) (66, 67), as already seen in transplant patients

treated with high doses of cyclosporine and for long periods (68–70).

In our systematic review, we also considered studies evaluating

the risk of skin cancers in patients with hidradenitis suppurativa

in treatment with adalimumab, the only approved biologic agent

for moderate-to-severe hidradenitis (71, 72). No articles were

found that met the inclusion criteria. Nevertheless, data from

literature point to a higher risk of developing NMSC in patients

with hidradenitis than general population (15). Compared with

psoriatic patients who underwent biologic treatment, patients

with hidradenitis start treatment with TNF-a inhibitors after

fewer months/years from the diagnosis of the disease and the

guidelines do not provide obligatory treatment with ﬁrst line

systemic immunosuppressive drug, such as cyclosporine or

methotrexate, before approaching the biologic therapy.

Considering all together the studies included in the

metanalysis, the IR emerging from our systematic review

shows an incidence of skin cancer in biologic treated patients,

124.5 per 10000 PYs for NMSC and 6.1 per 10000 PYs for

melanoma. With regard to NMSC, IRs in literature presented

large variability, from 24 in a psoriatic cohort of a German

registry to 262 coming from a USA surveillance registry on

patients treated with etanercept. The IR has been established on 8

out of 10 studies (Table 1). Concerning melanoma, 3 out of 6

studies reported an IR, ranging from 5 to 8 (Table 1). As a

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comparison, these IRs are signiﬁcantly lower than post-

transplant skin cancer IR, that is 1355 per 100.000 PYs for

SCC and 125 per 100.000 PYs for melanoma (73).

Our ﬁgures substantially agree with those reported in a recent

systematic review and metanalysis by Vaengebjerg et al. (14)who

reviewed 112 observational studies and more than 2 million

persons, thus assessing them for prevalence, incidence and

overall risk of cancer in patients with psoriasis and psoriatic

arthritis. The reported IR per 1000 PY for overall cancer was 11.75

(95% CI, 8.66-15.31) and 4.35 (95% CI, 3.18-5.70) for keratinocyte

cancer, whereas the IR for melanoma was 0.37 per 1000 PYs.

A study by Esse and collaborators was focused on melanoma risk

in patients treated with biologics for common inﬂammatory

diseases, such as inﬂammatory bowel diseases, rheumatoid arthritis

and psoriasis (68). In detail, they considered a total of 7 studies,

consisting of patients treated with TNF-a inhibitors, one of which

regarding patients with psoriasis and, moreover, included in our

review (74). According with their ﬁndings, the risk of melanoma in

biologic-treated patients with IBD and psoriasis compared with their

biologic-naïve counterparts receiving conventional systemic therapy

showed no statistically signiﬁcant increases. Esse et al. included in

their paper only one study (36) concerning psoriatic patients; this

study is currently the only one reporting an HR for melanoma in

patients treated with TNF-a inhibitors compared with non-biologic

usersandshowsnosigniﬁcant difference between the two groups.

With regard to NMSC, the paper by Asgari (36) explicitly

reported an HR for the same comparison. Our review considered

an additional study in which we were able to calculate IRR from

the reported data (29). While Asgari et al. (36) reported an

increased HR for NMSC in patients treated with TNF-a

inhibitors compared with non-biologic users, data coming from

the other study (29) showed no statistically signiﬁcant differences.

The main strengths of our analysis included the use of a well-

deﬁned protocol with strict inclusion and exclusion criteria.

Complying with the protocol, our search addressed a clearly

focused question with standardized data extraction and quality

assessment to minimize errors. In addition, the real-world setting

of the studies, the inclusion of biologic agents and of patients

treated exclusively for common cutaneous inﬂammatory diseases

represent distinctive features of our review and metanalysis.

The main limitation was the small number of eligible studies. The

studies were also heterogeneous, which makes comparison difﬁcult.

Inaddition,amajorweaknessoftheanalysiswastheabsenceof

adjustment for established risk factors for NMSC and melanoma.

Furthermore, in previous studies performed only on patients

with PSO it was found that there were no univocal data on the

higher or lower incidence of tumors in patients with PSO. In

particular, they were studies that analyzed both patients treated

with systemic drugs and patients treated with biological drugs

( 50 , 75). In our systematic review and meta-analysis, we

considered only patients treated with target therapies suffering

from psoriasis, PSA and/or HS.

Incommonwithpreviousstudies,ontheotherhand,thereisthe

fact that the risk of skin tumors itself cannot be excluded because

patients had to undergo immunosuppressive therapy (systemic or

not) before being able to carry out treatment with a target therapy.

Another limit that emerges from our systematic review, in

common with other articles already present in the literature, is the

follow-up time. As demonstrated by many studies, the

development and growth times of skin tumors are long and may

exceed the observation periods of the clinical trials in the literature.

SUMMARY AND PERSPECTIVES

Although with some limitations, the metanalysis of currently

available real-world data seems to suggest that treatment of

psoriasis, psoriatic arthritis and/or hidradenitis suppurativa with

TNF-a inhibitors, ustekinumab, apremilast or tofacitinib does not

increase the risk of NMSC or melanoma compared to “non-

biologic” systemic treatments. The cumulative sample size of the

studies in literature is certainly conspicuous, but, in the light of

the worldwide diffusion and frequency of the aforementioned

diseases as well as their multifactorial nature and response to

treatment, including undesired effects, further data are desirable.

Additionally, the ending yearsoftheperiodsanalyzedinthe

available studies range from 2009 to 2015. Similar evaluations of

real-world evidence concerning molecules marketed in the last 10-15

years, such as secukinumab, ixekizumab, brodalumab, tildrakizumab

or risankizumab, would be of great interest, particularly when

considering that these molecules are widely used in current clinical

practice. Consequently, to conduct future trials it is necessary to

consider the above data and the fact that the number of studies

comparing newer molecules and conventional drugs are small. A

greater number of new trials will have to be conducted, considering

longer follow-up times and, above all, common methods will have to

be applied to allow a comparison between the various studies.

In summary, this updated systematic review and meta-

analysis seems to suggest that no differences exist betwe en

treatment of chronic cutaneous diseases with biotechnological

drugs/small molecules and conventional DMARDs in terms of

HR/IRR for melanoma, while d ata on NMSC are more

controversial. Nevertheless, periodic d ermatologic screening

should be ensured for all patients undergoing these therapies.

DATA AVAILABILITY STATEMENT

The original contributions presented in the study are included in

the article/Supplementary Material. Further inquiries can be

directed to the corresponding author.

AUTHOR CONTRIBUTIONS

Conceptualization: CG and SC. Methodology: SC, FC, GT, LB,

and CG. Validation: SC, LB, and CG. Resources: SC, AF, FC, GT,

YI, LB, MB, and CG. Data curation: SC, AF, FC, YI, GT, MB, and

CG. Writing-original draf t preparation: SC, LB, and CG.

Writing-review and editing: SC, LB, and CG. Supervision: SC,

LB, and CG. All authors contributed to the article and approved

the submitted version.

Crisafulli et al. Skin-Cancer and Biologics for Psoriasis

Frontiers in Oncology | www.frontiersin.org June 2021 | Volume 11 | Article 6874328

ACKNOWLEDGMENTS

We are grateful to Prof. Matthias Augustin, Dr. Christina Sorbe

and all the PsoBest Registry team for providing the data of their

study (35).

SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found online

at: https://www.frontiersin.org/articles/10.3389/fonc.2021.

687432/full#supplementary-material

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Conﬂict of Interest: The authors declare that the research was conducted in the

absence of any commercial or ﬁnancial relationships that could be construed as a

potential conﬂict of interest.

and Guarneri. This is an open-access article distributed under the terms of the

Creative Commons Attribution License (CC BY). The use, distribution or

reproduction in other forums is permitted, provided the original author(s) and the

cited, in accordance with accepted academic practice. No use, distribution or

reproduction is permitted which does not comply with these terms.

Crisafulli et al. Skin-Cancer and Biologics for Psoriasis

Frontiers in Oncology | www.frontiersin.org June 2021 | Volume 11 | Article 68743211