Scoping Review on Use of Drugs Targeting Interleukin 1 ... · antagonists of the IL-1 pathway. IL-1 antago-nists may represent therapeutic alternatives. Here, we aim to provide a

REVIEW

Scoping Review on Use of Drugs Targeting Interleukin1 Pathway in DIRA and DITRA

Francisco Gomez-Garcıa . Juan L. Sanz-Cabanillas . Isabel Viguera-Guerra .

Beatriz Isla-Tejera . Antonio Velez-Garcıa Nieto . Juan Ruano

Received: September 26, 2018 / Published online: November 3, 2018� The Author(s) 2018

ABSTRACT

Introduction: Deficiencies in interleukin (IL)-1receptor (IL-R) antagonist (DIRA) and IL-36Rantagonist (DITRA) are rare genetic autoin-flammatory diseases related to alterations in

antagonists of the IL-1 pathway. IL-1 antago-nists may represent therapeutic alternatives.Here, we aim to provide a scoping review ofknowledge on use of IL-1-targeting drugs inDIRA and DITRA.Methods: An a priori protocol was published,and the study was conducted using themethodology described in the Joanna BriggsInstitute Reviewer’s Manual and the recentlypublished PRISMA Extension for ScopingReview statement. A three-step search usingMEDLINE and EMBASE databases until March2018 with additional hand searching was per-formed. Data charting was performed. Thesearch, article selection, and data extractionwere carried out by two researchersindependently.Results: Twenty-four studies on use of anti-IL-1drugs were included [15 studies includingpatients with diagnosis of DIRA (n = 19) and 9studies including patients with diagnosis ofDITRA (n = 9)]. Most studies followed a multi-center observational design. Among all patientswho received treatment with anti-IL-1 drugs,nine and four mutations in IL1RN and IL36RNwere found, respectively. Patients with DIRAwere treated with anakinra (n = 17), canakinu-mab (n = 2), or rinolacept (n = 6). All patientswith DITRA were treated with anakinra, andonly one case was also treated with canakinu-mab. Time-to-response frequencies were evalu-ated as immediate, short, and medium–longterm for DIRA (17/17, 15/17, and 9/10,

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Electronic supplementary material The onlineversion of this article (https://doi.org/10.1007/s13555-018-0269-7) contains supplementary material, which isavailable to authorized users.

F. Gomez-Garcıa � J. L. Sanz-Cabanillas �I. Viguera-Guerra � B. Isla-Tejera � A. V.-G. Nieto �J. Ruano (&)Immune-Mediated Inflammatory Skin DiseaseResearch Group, IMIBIC/Reina Sofıa UniversityHospital/University of Cordoba, Avenida MenendezPidal, Cordoba 14004, Spaine-mail: [email protected]

F. Gomez-Garcıa � J. L. Sanz-Cabanillas �A. V.-G. Nieto � J. RuanoDepartment of Dermatology, Reina Sofıa UniversityHospital, Avenida Menendez Pidal, Cordoba 14004,Spain

I. Viguera-GuerraAgencia de Evaluacion de Tecnologıas Sanitarias deAndalucıa (AETSA), Consejerıa de Salud, Avda. de laInnovacion, Seville 41020, Spain

B. Isla-TejeraDepartment of Pharmacy, Reina Sofıa UniversityHospital, Avenida Menendez Pidal, Cordoba 14004,Spain

Dermatol Ther (Heidelb) (2018) 8:539–556

https://doi.org/10.1007/s13555-018-0269-7

http://orcid.org/0000-0002-0286-4107

http://dx.doi.org/10.6084/m9.figshare.7258685




http://dx.doi.org/10.1007/s13555-018-0269-7

http://dx.doi.org/10.1007/s13555-018-0269-7

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http://dx.doi.org/10.1007/s13555-018-0269-7

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respectively) and DITRA (7/9, 3/9, and 2/9,respectively). Most DITRA patients in whomanti-IL-1 treatment failed experienced goodresponse to anti-tumor necrosis factor alpha oranti-IL-12/23 drugs. The safety profiles of treat-ments were similar in both diseases.Conclusions: Evidence on use of anti-IL-1 drugsin DIRA and DITRA is scarce and based onobservational studies. Larger studies with bettermethodological quality are needed to increaseconfidence in use of these drugs in patients withDIRA and DITRA.

Keywords: Anakinra; Anti-IL-1 drugs;Canakinumab; Deficiency of interleukin(IL)-1receptor(R) antagonist (DIRA); Geneticautoinflammatory diseases; Deficiency of IL-36R antagonist (DITRA); Rilonacept; Scopingreview

INTRODUCTION

Hereditary autoinflammatory diseases are aheterogeneous group of rare genetic disorders inwhich an exaggerated innate immune responseis the pathogenic basis of recurrent episodes ofinflammation. These inflammatory episodesaffect the skin, joints, bones, eyes, gastroin-testinal tract, and central nervous system inassociation with nonspecific signs of systemicinflammation and a lack of high-titer circulat-ing auto-antibodies or antigen-specific T cells[1].

Alterations in the interleukin (IL)-1 pathwayhave been shown to be involved in the patho-genesis of some diseases. IL-1 contributes tocoordination of the early response of the immunesystem to exogenous and endogenous antigens,serving as a prototypic alarm cytokine [2]. Theinterleukin IL-1 family comprises 11 members,including seven proinflammatory agonists (IL-1a,IL-1b, IL-18, IL-33, IL-36a, IL-36b, and IL-36c) andfour defined or putative antagonists [IL-1 receptor(IL-1R) antagonist (IL-1RA), IL-36R antagonist (IL-36RA), IL-37, and IL-38], which exert antiinflam-matory activity [3]. IL-1-related hereditary dis-eases are considered secondary to genetic defectsin both activating and inhibitory pathway mole-cules. Notably, cryopyrin-associated

autoinflammatory syndromes (CAPSs) are pri-mary diseases caused by alterations in IL-1 path-way agonists. Moreover, several new diseasesassociated with alterations in IL-1RA, such asdeficiency of IL-1RA (DIRA) and deficiency of IL-36RA (DITRA), have recently been identified. IL-1RA, encoded by the IL1RN gene, functions as adecoy protein that binds to IL-1R but does notresult in any response signal. IL-36RA, encoded bythe IL36RN gene, has been shown to specificallyinhibit IL-1-induced activation of nuclear factor-jB. Both IL-1RA and IL-36RA are encoded onchromosome 2 and show 44% homology. How-ever, IL-1RA is expressed ubiquitously, whereasIL-36R expression is restricted to epithelial cells,including those in the skin [4]. This fact mayexplain the observation that both DIRA andDITRA share similar skin manifestations but withthe difference that extracutaneous involvement isobserved in DIRA.

DIRA is a rare life-threatening autoinflam-matory disease first described in 2009 [1, 5].DIRA is caused by autosomal recessive muta-tions in the IL1RN gene and presents clinicallyas early onset of generalized cutaneous pustu-losis, multifocal osteomyelitis, and high levelsof acute-phase reactants. DITRA is a morerecently described hereditary autoinflammatorydisease caused by homozygous or compoundheterozygous mutations in the IL36RN gene andcharacterized by repeated flares of generalizedpustular psoriasis associated with high fever,asthenia, and systemic inflammation [6].

Various treatment strategies, such as antiin-flammatories [nonsteroidal antiinflammatorydrugs (NSAIDs) and corticosteroids], antimicro-bial agents (antifungal and antibacterialagents), and immunosuppressants (methotrex-ate, cyclosporine, inhibitors of tumor necrosisfactor-a, and anti-IL-17 monoclonal antibod-ies), have been applied for treatment of DIRAand DITRA, with variable responses. As knowl-edge of the pathogenesis of these diseases hasimproved, increasingly specific treatments havebeen developed. Accordingly, four drugs tar-geting the IL-1 pathway have been developed.These include anakinra, a recombinant IL-1RAthat competes with IL-1R agonists for itsreceptor [7]; rilonacept, which acts as a solubledecoy to prevent activation of IL-1RI [8];

540 Dermatol Ther (Heidelb) (2018) 8:539–556

canakinumab, a human monoclonal antibodytargeting IL-1b [9]; and MABp1, an anti-IL-1amonoclonal antibody [10]. Although the speci-ficities of their mechanisms of action suggestthe feasibility of achieving sufficient efficacy,the molecular differences found in both DIRAand DITRA can yield different levels ofresponse. Moreover, these drugs are associatedwith short- and long-term adverse effects.Therefore, it is necessary to consider treatmentswith the best risk–benefit balance.

However, because DIRA and DITRA are rarediseases that have only been identified withinthe last decade, available evidence on use of IL-1pathway-modulating agents for their treatmentis scarce, and no secondary research has beenpublished to date. Therefore, it is necessary tosynthesize evidence derived from primarystudies on use of anti-IL-1 drugs for treatment ofDIRA and DITRA, map the published articles,and study the epidemiology of genetic charac-teristics and anti-IL-1 drug efficacy/safety resultsbased on available evidence. Such analysis willhelp identify gaps in knowledge and formulatequestions that can be answered through sys-tematic review.

A scoping review is a form of scientific syn-thesis that addresses an exploratory researchquestion, aimed at mapping key concepts andidentifying research gaps related to a definedarea or field by systematically searching, select-ing, and synthesizing existing knowledge [11].Scoping reviews contribute to integrating opti-mal research evidence available with clinicalexperience and patient values to improve care,health, and cost outcomes [12].

Accordingly, in this work, we present theresults of a scoping review on use of anti-IL-1drugs in dermatological diseases whose proto-cols have been previously published [13]. In thisfirst summary, we report and discuss evidenceregarding use of these drugs in patients withDIRA/DITRA.

METHODS

A scoping review protocol was a priori pub-lished [13]. The study was conducted andreported using the methodology described in

the Joanna Briggs Institute Reviewer’s Manual[14] and the PRISMA Extension for ScopingReviews [15]. When necessary, authors of arti-cles were contacted to obtain more data orclarify issues.

Eligibility Criteria

To be included in the review, papers had toshow evidence of use of anti-IL-1 drugs (ana-kinra, canakinumab, rilonacept, or AMB1) inpatients with DIRA or DITRA. Studies wereincluded if they were written in English,involved human participants, and described theconditions formulated in the research question,regardless of publication date or format. Articleswere excluded if they did not fit into the con-ceptual framework of the study (i.e., if a case ofDIRA or DITRA was described as not havingbeen treated with anti-IL-1 drugs). Nonscientificreviews and opinion articles were excluded.

Literature Search

We performed a three-step literature search toidentify and locate all relevant studies on use ofanti-IL-1 drugs in dermatological diseases, andsubsequently selected articles related to use ofthese drugs in patients with DIRA or DITRA. Thefirst step was performed on 9 March 2018 andentailed a limited search strategy [SEARCHQUERY (‘skin disease’ AND ((‘interleukin 1-beta’/exp OR ‘interleukin 1beta’) OR ‘inter-leukin 1’)) AND ‘therapy’] in MEDLINE andEMBASE databases. Next, we extracted keywordsfrom titles, abstracts, and indexing categoriza-tions and used them to perform a new search on10 March 2018 with a more complex strategy(Table S1 in Supplementary Information).Results were ordered by disease based on reviewof the title and abstract. Subsequently, sourcesrelated to DIRA and DITRA were selected. Thethird step involved a new search using the ref-erence lists of all selected reports and articles foridentification of additional relevant studies. Theliterature search and title and abstract filteringwere carried out independently by tworesearchers (F.G.-G. and J.L.S.-C.).

Dermatol Ther (Heidelb) (2018) 8:539–556 541

Data Charting

A datacharting form was jointly developed by tworeviewers to determine which variables to extract.A pilot test was carried out with three studies, andthe chosen variables were included in a .csv file.The two reviewers independently charted thedata, discussed the results, and continuouslyupdated the data charting form in an iterativeprocess. Finally, variables related to patients (dis-ease, drug, treatment response, and safety profile)and to the study design and metadata from pri-mary sources were reported (Tables 1, 2, 3, and 4;Tables S1–S4 in Supplementary Files).

Collating, Summarizing, and ReportingResults

We grouped the articles by disease type. Theresults of the comprehensive search were pre-sented using a PRISMA flow diagram. A narra-tive and qualitative synthesis of DIRA andDITRA mapping studies and epidemiological,genetics, and efficacy and safety findings wereelaborated using tables and figures.

Compliance with Ethics Guidelines

This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

Protocol versus Overview

Our planned search strategy published in Der-matology and Therapy was compared with thefinal reported review methods. Due to time andfunding limitations, we decided to select onlystudies published in English.

RESULTS

Search Results

From 3708 articles regarding use of anti-IL-1-re-lated drugs in dermatological diseases, after

filtering duplicates and selecting studies accord-ing to title, abstract, and keywords, 77 studiesmet the criteria for full-text review. Of these, 21[DIRA (n = 13) and DITRA (n = 8)] fulfilled theinclusion criteria. After reviewing citations ofreferences for these studies, three new articles[DIRA (n = 2) and DITRA (n = 1)] were obtained.Finally, 24 studies, including 15 describing DIRA(n = 15) and 9 describing DITRA (n = 9), wereincluded in the scoping review. A reference list ofall included and excluded articles with reasonsfor exclusion is presented in Fig. S1 in Supple-mentary Information.

Evidence for Mapping the Studies of IL-1-Based Treatment in Patients with DIRA/DITRA

DIRAFifteen studies, published between 2009 and2017 as full papers (n = 11) or congress abstracts(n = 4), followed mainly an observational design(13 case reports, 1 case series), and only one wasan intervention study. Only three studies (20%)had an a priori protocol that was included in apublic registry. Twelve (63.1%) were elaboratedas multicentric studies involving up to nine dif-ferent institutions. The average numbers ofauthors and affiliations per article were 11 (range3–45) and 5 (range 2–14), respectively, and dif-ferent medical specialties were involved [pedi-atrics (n = 11), genetics (n = 11), rheumatology(n = 7), allergy–immunology (n = 6), and der-matology (n = 5)], although authors from aca-demia (n = 4) and the pharmaceutical industry(n = 1) were also included. Most studies wereperformed in the USA [8], with the NationalInstitutes of Health (NIH, Bethesda, MD, USA)and associated centers of institutions participat-ing in more studies (n = 10; Table S1 in Supple-mentary Information). Other countries that alsoparticipated were Brazil (n = 3), Turkey (n = 2),Germany (n = 1), and Puerto Rico (n = 1). Thestudies were published in journals from disci-plines such as rheumatology (n = 5), generalmedicine (n = 4), dermatology (n = 3),immunology (n = 2), and radiology (n = 1).

In seven (46.7%) and ten (66.7%) studies,disclosures related to the source of funding


Table1

Characteristics

ofindividualpatientsfrom

DIRA

studiesincluded

inthereview

DIR

Apatient

Cou

ntry

Age

Gender

Clin

ical

features

Mutations

Ref.

Gestation

(weeks)

Onset

(days)

Diagnosis

(mon

ths)

Pustular

derm

atitis

Stom

atitis

Localized

swellin

gFeverRash

Other

skin

cond

itions

Multiple

bone

lesion

s

Lun

ginvolvem

entLiver/

spleen

Throm

bosis

Other

clinical

#1Canada

35.5

1513

M?

??

-MS

P?

--

-1

Hom

ozygousfor

IL1R

Nc.156_157delCA

deletion

[1]

#2The

Netherlands

380

86F

?-

--

M?

??

?-

-Hom

ozygousfor

IL1R

Nc.229G

[T

(p.Glu77Ter)

mutation

[1]

#3The

Netherlands

3817

2F

??

--

S?

??

?-

-Hom

ozygousfor

IL1R

Nc.229G

[T

(p.Glu77Ter)

mutation

[1]

#4Lebanon

385

20M

??

--

SP

?-

--

2Hom

ozygousfor

IL1R

Nc.160C

[T

(p.Gln54Ter)

mutation

[1]

#5Lebanon

382

4M

-?

--

M?

??

?–

2Hom

ozygousfor

IL1R

Nc.160C

[T

(p.Gln54Ter)

mutation

[1]

#6Pu

erto

Rico

348

114

M-

-?

-M

PG?

-?

--

Hom

ozygousfor

175-kb

deletion

onchromosom

e2q13

a

[1]

#7NA

3310

1.5

M?

--

-MS

??

??

?-

Hom

ozygousfor

175-kb

deletion

onchromosom

e2q13

a

[5]

#8Brazil

NA

030

F?

--

?S

P/A

?-

??

-Hom

ozygousfor

IL1R

Nc.213_227del

AGATGTGGT

ACCCAT

(p.Asp72_Ile76del)

[35]

#9Brazil

NA

027

F-

--

?MS

??

-?

?-

Com

poun

dheterozygous

for

IL1R

Nc.229G

[T

(p.Glu77Ter)and

IL1R

Nc.140delC

(p.T47TfsX4)

[35]


Table1

continued

DIR

Apatient

Cou

ntry

Age

Gender

Clin

ical

features

Mutations

Ref.

Gestation

(weeks)

Onset

(days)

Diagnosis

(mon

ths)

Pustular

derm

atitis

Stom

atitis

Localized

swellin

gFeverRash

Other

skin

cond

itions

Multiple

bone

lesion

s

Lun

ginvolvem

entLiver/

spleen

Throm

bosis

Other

clinical

#10

NA

NA

142

M-

-?

?M

??

-?

?-

Com

poun

dheterozygous

for

IL1R

Nc.229G

[T

(p.Glu77Ter)

mutationand

175-kb

deletion

onchromosom

e2q13

a

[36]

#11

Puerto

Rico

31165

180

M?

--

?S

??

-?

?-

Hom

ozygousfor

175-kb

deletion

onchromosom

e2q13

a

[19]

#12

NA

NA

301.5

M-

-?

?M

??

-?

-?

NA

[34]

#13

Puerto

Rico

3760

5M

?-

-?

S?

??

?-

3Hom

ozygousfor

175-kb

deletion

onchromosom

e2q13

a

[29]

#14

Germany

38NA

24F

--

??

M?

?-

?-

4Hom

ozygousfor

IL1R

Nc.840-6bp

deletion

[18]

#15

Puerto

Rico

NA

73

F?

--

?M

P?

??

-?

Hom

ozygousfor

175-kb

deletion

onchromosom

e2q13

a

[30]

#16

Turkey

NA

365

144

F?

--

-M

??

??

-?

Hom

ozygousfor

IL1R

Nc.78G[

A(p.Thr26X)

mutation

[33]

#17

Turkey

NA

084

M?

--

?S

??

??

-?

Hom

ozygousfor

IL1R

N(c.396delC)

deletion

b

[32]

#18

India

NA

215

F-

-?

?M

??

??

-?

Hom

ozygousfor22.5-

kbdeletion

spanning

firstfour

exons(twocoding)

ofIL1R

Nc

[24]

#19

Brazil

NA

120

84M

?-

-?

S?

??

?-

?Com

poun

dheterozygous

for

IL1R

Np.Ile74_Pro78del

andp.Gln48Thr

[31]

Mmale,Ffemale,Ppathergy,P

Gpyodermagangrenosum,M

mild,M

Smild–severe,Aabscesses

1:centralnervoussystem

vasculitis;2:

conjun

ctivalinjection;

3:nonspecific

inflammationof

thewholeintestinebutwithout

granulom

as;4:

system

icinflammatoryresponse

synd

rome(SIRS)

aAdeletion

ofapproxim

ately175kb

onchromosom

e2q

thatincludessixgenesfrom

aclusterof

interleukin-1-relatedgenes:IL1R

Nandthegenesencoding

interleukin-1family,m

embers9(IL1F

9),6

(IL1F

6),8

(IL1F

8),5

(IL1F

5),

and10

(IL1F

10)

bThisfram

eshiftmutation,

which

makes

thestop

codonat

position

c.534disappear,results

inanonfun

ctioning

protein

cUnreportedintronicvariantupstream

totheexon

9splice-acceptor

site

ofun

know

nclinicalsignificancein

theIL1R

1gene,w

hich

couldpotentially

interferewithtranscript

splicing


Table2

Characteristics


DIRA

studiesincluded

inthereview

(cont.)

DIR

Apatient

Anti-IL-1

drug

Initial

dosage

Maintenance

dosage

Duration

(days)

Adjuvant

corticosteroids

Reduction

/withd

rawal

ofcorticosteroids

Initial

efficacy

Short-term

efficacya

Medium/lon

g-term

efficacyb

Clin

ical

efficacy

Analytical

efficacy

Recurrence

Adverse

events

#1Anakinra

1mg/kg/

24h

(1)

350

Yes

Withdrawal

Yes

Yes

Yes

Yes

Yes

Yes

Aggregate

data

#2Anakinra

1mg/kg/

24h

(1)

1500

Yes

Withdrawal

Yes

Yes

Yes

Yes

Yes

Yes

Aggregate

data

#3Anakinra

1mg/kg/

24h

(1)

40Yes

Withdrawal

Yes

Yes

NA

Yes

Yes

Yes

Aggregate

data

#4Anakinra

1mg/kg/

24h

(1)

14Yes

Withdrawal

Yes

Yes

NA

Yes

Yes

Yes

Aggregate

data

#5Anakinra

1mg/kg/

24h

(1)

30Yes

Withdrawal

Yes

Yes

NA

Yes

Yes

Yes

Aggregate

data

#6Anakinra

1mg/kg/

24h

(1)

100

Yes

Reduction

No

Yes

NA

Yes

No

Yes

Aggregate

data

#7Anakinra

5mg/kg/

24h

2.5mg/kg/24h

180

No

NA

Yes

Yes

Yes

Yes

Yes

Yes

NA

#8Anakinra

1mg/kg/

24h

2.5mg/kg/24h

Months

Yes

Withdrawal

Yes

Yes

NA

Yes

Yes

Yes

NA

#9Anakinra

1mg/kg/

24h

3mg/kg/24h

Months

Yes

Withdrawal

Yes

Yes

Yes

Yes

Yes

Yes

NA

#10

Anakinra

NA

NA

180

Yes

Withdrawal

Yes

Yes

Yes

Yes

Yes

NA

NA

#11

Anakinra

1mg/kg/

24h

1mg/kg/24h

240

NA

NA

Yes

Yes

Yes

Yes

Yes

NA

None

#12

Anakinra

NA

NA

NA

NA

NA

Yes

NA

NA

Yes

Yes

NA

None

#13

Anakinra

3mg/kg/

24h

3mg/kg/24h

60Yes

Withdrawal

Yes

Yes

NA

Yes

Yes

NA

NA

#14

Anakinra

NA

NA

270

NA

NA

Yes

Yes

No

Yes

Yes

NA

NA

#15

Anakinra

NA

6weeks

NA

NA

NA

Yes

Yes

NA

Yes

Yes

NA

NA

#16

Canakinum

ab150mgew

6weeks

150mg

ew9

6weeks

365

NA

NA

Yes

Yes

Yes

Yes

Yes

NA

None

#17

Anakinra

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

#18

Anakinra

1.5mg/kg/

24h

(2)

365

Yes

Reduction

Yes

Yes

Yes

Yes

Yes

NA

#19

Canakinum

ab2mg/kg/

ew 4weeks

4mg/kg/

ew9

4–6weeks

NA

NA

NA

noYes

NA

Yes

Yes

NA

Generalized

urticarial

rash

Vom

itingand

diarrhea

eweveryweek

(1)The

dosage

was

increasedby

0.5mg/kg/day

atfollow-upvisitsto

achieveC-reactiveproteinlessthan

0.5mg/dl

anderythrocytesedimentation

rate

lessthan

15mm/h

(2)Reduced

dosage

becauseof

generalized

urticarialrash

a\

12weeks

b[

24weeks


Table3

Characteristics


DITRA

studiesincluded

inthereview

DIT

RA

patient

Cou

ntry

Age

Gender

Cutaneous

presentation

Cutaneous

clinical

evolution

Fever

Elevated

acute-

phase

reactants

Previou

streatm

ent

Mutations

Ref.

Gestation

(weeks)

Onset

(days)

Diagnosis

(mon

ths)

#1Morocco

4160

17M

Multiplepustules

appeared

inthe

perioralanddiaper

area

Recurrent

episodes

oferythroderma

??

Cyclosporine

Hom

ozygousforIL36RN

c.80T[

C(p.Leu27Pro)

mutation

[1]

#2NA

NA

1080

38F

Generalized

pustular

lesions

Generalized

?NA

Antibiotics

Corticosteroids

Acitretin

Cyclosporine

Com

poun

dheterozygous

forIL36RN

c.227C

[T

(p.Pro76Leu)andc.338C

[T(p.Ser113L

eu)mutations

[1]

#3NA

NA

Infancy

Adolescent

FGeneralized

pustular

psoriasis

Generalized

pustular

psoriasis

NA

?Corticosteroids

Acitretin

Methotrexate

Cyclosporine

Adalim

umab

Infliximab

Hom

ozygousforIL36RN

c.115?

6T[

Cmutation

[1]

#4Tun

isia

NA

14years

3M

Erythem

atousand

scalyeruption

over

thescalpand

perineum

Generalized

exfoliative

derm

atitis

No

?Corticosteroids

Acitretin

Hom

ozygousforIL36RN

c.80T[

C(p.Leu27Pro)

mutation

[1]

#5NA

NA

47years

54years

MNA

NA

NA

NA

Acitretin

Methotrexate

Cyclosporine

Infliximab

HeterozygousforIL36RN

c.338C

[T(p.Ser113L

eu)

mutation

[1]

#6NA

NA

NA

NA

MGeneralized

pustular

lesions

Generalized

erythema

NA

NA

Corticoids

Acitretin

Cyclosporine

HeterozygousmutationforIL36RN

c338C[

T(pSer113Leu)

[1]

#7NA

NA

40years

40years

MScalyerythemaon

elbows

Severe

flare

ofGPP

??

Antibiotics

Corticosteroids

Methotrexate

Cyclosporine

Adalim

umab

Com

poun

dheterozygous

forIL36RN

c.142C

[T

(p.Arg48Trp)andIL36RN

c.338C

[T(p.Ser113L

eu)

mutations

[5]

#8Morocco

3760

8F

Initially

locatedatthe

diaper

area

Generalized

??

Antibiotics

Corticosteroids

Acitretin

Com

poun

dheterozygous

forL36RN

c.T80C

(p.Leu27Pro),

c338C[

T(p.Ser113L

eu)andc.142C

[T(p.Arg48Trp)

mutations,and

NSD

1(5q35.2-q35.3)

microduplication

[35]


(five, public sources; one, public and pharma-ceutical sources; and one without funding) orauthors’ conflicts of interest (CoIs) weredeclared, respectively. AMGEN (five authors),Novartis (two authors), and Lilly (two authors)were the pharmaceutical companies most fre-quently cited in CoIs by the authors.

DITRANine studies related to use of anti-IL-1 drugs inDITRA were found. All were observational casereport studies. No a priori design or registrationwas reported for any of these studies. Five ofnine (55.5%) were multicenter studies (range1–5). No centers participated in more than onestudy. Two were performed in Spain and France,and one each was performed in The Nether-lands, USA, Italy, Denmark, and Germany.Articles were published between 2011 and 2018.Six papers were published in dermatology jour-nals, two in rheumatology journals, and one ina pediatrics journal. Three were full papers,three were letters, and three were abstracts fromconferences. The average numbers of authorsand affiliations per article were 7.2 (range 4–15)and 3.22 (range 1–7), respectively. The mostfrequent specialties were dermatology in eightpapers and genetics and pediatrics in fivepapers. One study [16] declared funds fromStrasbourg High Throughput Next GenerationSequencing facility (GENOMAX) and INSERMUMR_S 1109. Four did not report funding or didnot provide funding information. In two of thestudies, the authors declared CoIs (Novartis andSobi for three and two authors, respectively;these companies were the most frequentlydeclared in CoIs). Three and four papersdeclared no CoIs or did not provide suchinformation, respectively.

Evidence for Analysis of Epidemiologyof IL-1-Based Agents in Treatmentof Patients with DIRA/DITRA

DIRAIndividual data were obtained from 19 patientswho had been treated with anakinra (n = 17)and canakinumab (n = 2). Eight of 19 (42.10%)patients were female. Of these 19 patients, 3

Table3

continued

DIT

RA

patient

Cou

ntry

Age

Gender

Cutaneous

presentation

Cutaneous

clinical

evolution

Fever

Elevated

acute-

phase

reactants

Previou

streatm

ent

Mutations

Ref.

Gestation

(weeks)

Onset

(days)

Diagnosis

(mon

ths)

#9Denmark

3890

4F

Generalized

pustular

psoriasis

Generalized

pustular

psoriasis

NA

Normal

Antibiotics

Corticosteroids

Methotrexate

Com

poun

dheterozygous

forIL36RN

c.338C

[T

(p.Ser113L

eu)andNLRP3

c.2107C[

A(p.Gln703L

ys)

[35]


Table4

Characteristics


DITRA

studiesincluded

inthereview

(cont.)

DIT

RA

patient

Anti-IL-1

drug

Initial

dosage

Maintenance

dosage

Duration

(days)

Adjuvant

corticosteroids

Reduction

/withd

rawal

Initial

efficacy

Short-

term

efficacya

Lon

g-term

efficacyb

Final

treatm

ent

Adverse

events

#1Anakinra

5mg/kg/

24h

No

6No

NA

Yes

No

NA

Acitretin/

etanercept

NA

#2Anakinra

5mg/kg/

24h

3mg/kg/24h

60Yes

No

Yes

No

NA

Ustekinum

abSystem

icinfection

#3Anakinra

No

3No

NA

No

No

NA

Secukinu

mab

Renaland

hepatic

laboratory

abnorm

alities

Risingwhite

bloodcell

coun

t

Deteriorating

clinicalstatus

with

progressive

pustulation

#4Anakinra

2–4mg/

kg/24h

No

60No

NA

Yes

Yes

NA

Anakinra

Pain

atthe

injectionsite

without

erythema

#5Anakinra

100mg/

24h

NA

365

No

NA

Yes

Yes

Yes

Anakinra

NA

#6Anakinra

NA

NA

NA

No

NA

Yes

No

No

Adalim

umab/

methotrexate

NA

#7Anakinra

100mg/

24h

NA

224

No

NA

Yes

Yes

Yes

Anakinra

NA

#8Anakinra//canakinum

ab5mg/kg/

24h//

3mg/kg

every

8weeks

NA//NA

90//NA

No//no

NA//NA

No//

noNo//no

No//no

–NA

#9Anakinra

4mg/kg/

24h

8mg/kg/24h

8weeks

No

NA

Yes

No

No

Infliximab

NA

a\

12weeks

b[

24weeks


each were from Brazil and Puerto Rico, 2 eachwere from Turkey, Lebanon, and The Nether-lands; and 1 each was from India, Canada, andGermany. Data from three patients could not beobtained. Seven of 11 (63.63%) patients werefull-term infants, and 4 of 11 (36.36%) werepreterm newborns. Data for eight patients weremissing. Pustular dermatitis and localized swel-ling were observed in 12 and 6 patients, repre-senting the most frequent symptom of onset ofthe disease. During disease evolution, patientspresented with pustular skin rash (severe in 6 of19 cases), multiple bone involvement (ribsbeing the most frequent site, in 17 of 19), fever(in 8 of 16), lung involvement (in 7 of 19),venous thrombosis (in 5 of 19), and elevation ofacute-phase reactants (in 19 of 19). With respectto age at disease presentation, data wereobtained from 18 patients. The median age was14 days (range 0–365 days). Median age at diag-nosis was 24 months (range 1.5–180 months).The median delay in diagnosis was 19.5 months(range 0.5–179.5 months). Seventeen of 18(94.4%) patients had received previous treat-ment. Of these, 13 were treated with corticos-teroids, 12 with antibiotics, 4 with NSAIDs, 3with antifungals, 3 with acitretin, and 1 eachwith methotrexate, cyclosporine, intravenousimmunoglobulins, azathioprine, thalidomide,and etanercept.

One study [17] presented aggregate datafrom six patients who had been treated withrinolacept. These patients received pretreat-ment with anakinra and were included amongthe 19 previously exposed patients describedabove.

DITRAIndividual data were obtained from ninepatients. All had been treated with anakinra,and one had also received canakinumab. Threeof eight (37.5%) were female. One patient hadmissing data. Two patients were from Morocco,and one patient each was from Tunisia andDenmark. The origins of the remaining patientswere not reported. Onset disease was localizedin four patients (two for the diaper and scalp,two for the elbow and perineum) and general-ized in four patients. During disease evolution,the disease worsened, presenting with

erythroderma or pustules in all patients forwhom data were available. The process wasaccompanied by fever in four of six (66.6%)patients and elevation of acute inflammationreactants in five of six (83.3%) patients. Theages at onset and disease diagnosis varied fromneonate to adulthood (14 days to 47 years and3 months to 54 years, respectively). The delay indiagnosis ranged from 2 months to 17 years. Allpatients previously received other treatments,including corticosteroids in seven patients, aci-tretin and ciclosporin in six patients each,methotrexate in four patients, cyclosporine inthree patients, and adalimumab and infliximabin two patients each.

Evidence of Different GenotypicVariations in Patients with DIRA/DITRATreated with IL-1 Inhibitors

DIRANine different mutations in IL1RN, showing ahomozygous genotype in all cases, were descri-bed among patients with DIRA treated withanti-IL-1 drugs in the included studies. Agenomic 175-kb deletion on chromosome 2 wasobserved in patients #6, #7, #11, #13, and #15;two nonsense mutations were detected inpatients #2, #3, and #10 (c.229G ? T) andpatients #4 and #5 (c.160C ? T); a 15-bp framedeletion (c. 213_227delAGATGTGGTACCCATresulting in p.Asp72_Ile76del) was observed inpatients #8 and #9; 2-bp (c.156_157delCA) and22-kb1 frameshift deletions were identified inpatients #1 and #18, respectively; and anintronic variant of unknown clinical signifi-cance in the IL1R1 gene (position c.840, 6 bpupstream of the exon 9 splice-acceptor site),which could potentially interfere with tran-script splicing machinery, was found in patient#14. Additionally, the p.R26X IL1RN mutationwas observed in patient #16, c.396delCnucleotide deletion was observed in patient#17, and both p.Ile74_Pro78del and p.Gln48Thr

1 This frameshift spans four exons (two coding) ofIL1RN, Q54X, and an unreported intronic variant ofunknown clinical significance in the IL1R1 gene. Thisvariant resides at position c.840, 6 bp upstream of theexon 9 splice-acceptor site and could potentially inter-fere with transcript splicing.


IL1RN mutations were observed in patient #19.No mutation analysis was performed in patient#12.

DITRAThee different homozygous and heterozygousmutations in IL36RN were described amongpatients with DITRA treated with anti-IL-1drugs in the included studies. IL36RN c.80T[C(p.Leu27Pro) was the most frequent homozy-gous mutation, present in patients #1, #4, and#8. Patient #8 also presented a microduplicationincluding the NSD1 gene (5q35.2-q35.3).Homozygous mutation at c.115 ? 6T[C inpatient #3 was also reported. Patient #6 wasdiagnosed with an homozygous mutation forIL36RN, but the position was not reported.Regarding heterozygous mutations, patients #2,#6, and #8 were identified as carriers of IL36RNc338C[T (pSer113Leu) at exon 5, in patients#2, #6, #8, and #9. Patients #8 and #9 also pre-sented a heterozygous mutation in IL36RNc.142C[T (p.Arg48Trp) and NLRP3c.2107C[A (p.Gln703Lys) at exon 3,respectively.

Evidence for Efficacy and Safety of IL-1-Based Agents in Treatment of DIRA/DITRA

DIRAWe obtained individual data for 17 patientstreated with anakinra and 2 patients treatedwith canakinumab. Length of therapy variedbetween 2 weeks and 4.5 years for anakinra andwas up to 12 months for canakinumab. Theinitial dosage of anakinra ranged from 1 to5 mg/kg/day, with 1 mg/kg/day being thedosage most frequently used, in 9 of 13 patients(69.2%) for whom data were available. Thedosage was increased in eight patients up to2.5–3 mg/kg/day or until achieving clinical andanalytical response. Two patients requireddosage reduction, one due to achieving thera-peutic response and the other due to develop-ment of generalized urticaria. In two otherpatients, the initial dosage was maintained. In11 patients treated with anakinra, concomitantuse of corticosteroids was reported; in nine ofthese cases, the drugs were finally withdrawn,

and in two cases, dosage reduction was per-formed. All patients achieved immediate(day–hours) clinical responses, and all but onepatient also showed an analytical response. Thepatient who did not show complete response toanakinra was homozygous for a deletion ofapproximately 175 kb on chromosome 2q,which harbored six genes from a cluster of IL-1-related genes, i.e., IL1RN and genes encoding IL-1 family members 9 (IL1F9), 6 (IL1F6), 8 (IL1F8),5 (IL1F5), and 10 (IL1F10) [1].

In the short term (\12 weeks), 15 (88.2%)patients showed good clinical response. In twocases, response was not reported. Ninety per-cent of patients for whom data were available inthe medium/long term ([24 weeks) (n = 10)showed good response. The nonresponder inthis group showed a clinical phenotype ofchronic recurrent multifocal osteomyelitis andfinally responded to azathioprine, corticos-teroids, and intravenous immunoglobulins [18].

In the two patients treated with canakinu-mab, one showed good immediate, short-term,and medium/long-term response, and the otherrequired dosage increase to achieve goodresponse in the short term. No medium/long-term data were available for this patient.

With respect to drug safety, anakinra wasassociated with some adverse events, includingtransient injection-site reactions (n = 3) andanaphylactic reactions (n = 2). An episode ofvomiting and diarrhea was reported in a patienttreated with high dosage of canakinumab.Finally, subsequent discontinuation of anakinrain nine patients was reported following a flare-up of their disease.

Aggregated data from six patients with DIRAtreated with rinolacept were reported in anintervention study with follow-up visits at 3, 12,and 24 months. These patients had previouslyreceived anakinra, and their data were amongthose published individually, corresponding topatients #8, #9, #10, #13, and #15. The sixthpatient corresponded to one of those includedin the article by Aksentijevich et al. (Table S1 ofSupplementary Information). All patients weretreated with an initial bolus of 4.4 mg/kg/doserilonacept and were discharged on 2.2 mg/kg/week. All except one patient required rilonaceptdosage escalation to 4.4 mg/kg/week due to


partial clinical response. All patients remainedin clinical and analytical remission. Rilonaceptwas well tolerated, no serious adverse eventswere reported, and none of the patients metprotocol adverse event criteria for rilonaceptdosage reduction or permanent discontinua-tion. The most common events were upperrespiratory infection (100%), otitis media(66.7%), and rash (66.7%). Finally, clinicalresponses to rilonacept were comparable tothose observed with anakinra, although therewas a clear preference by relatives and patientsfor staying on weekly versus daily injections[17].

DITRAEfficacy and safety data were available for ninepatients with DITRA. All patients were treatedwith anakinra at 2–5 mg/kg/day or 100 mg/day,and one patient was also treated with canaki-numab 3 mg/kg every 8 weeks. Duration ofanakinra treatment ranged from 3 days to12 months. With regard to efficacy, 77.8% ofpatients who received anakinra experiencedgood initial (hours–days) clinical response. Ofthese, 33.3% maintained the response in theshort term (\12 weeks). In the medium/longterm ([24 weeks), 22.2% of patients continuedthe treatment. One patient, in whom anakinrahad previously failed, received treatment withcanakinumab, and this treatment did not proveeffective at the initial time or in the short- orlong-term analyses [16].

With respect to the safety of anakinra, onecase of systemic infection was reported, anotherone of renal and hepatic laboratory abnormali-ties, rising white blood cell count, and deterio-rating clinical status with progressivepustulation and, finally, pain at the injectionsite without erythema. No adverse events werereported in the patient who had been treatedwith canakinumab.

In five of eight patients in whom anti-IL-1drugs failed, the final therapeutic regimens wereetanercept and acitretin [19], adalimumab andmethotrexate [20], secukinumab [21], ustek-inumab [22], and infliximab [23].

DISCUSSION

Summary of Findings

This is the first scoping review to map andsummarize use of drugs targeting the IL-1pathway in patients with DIRA and DITRA.DIRA and DITRA were first identified in 2009and 2011, respectively, and clinical experiencewith use of anti-IL-1 drugs is scarce. The bestavailable evidence is based on results fromobservational studies, most of which were notpublished in a public repository with an a prioridesign. Studies of both diseases have beenmulticenter, multidisciplinary studies, and thefindings of these studies have generally beenobtained from public sources, with few authorsdeclaring CoIs.

Anakinra is the most commonly used drugfor both diseases. The use of canakinumab isanecdotal, and rinolacept has only been used inDIRA. Patients with DIRA tended to be youngerat time of onset and start of treatment, and adelay in diagnosis was common for patientswith DITRA. No relationships were observedamong initial features, evolution, or response totreatment or in the type of genetic mutationspresent in patients treated with anti-IL-1 drugs.The effectiveness of these treatments differs inboth diseases, with greater efficacy observed inpatients with DIRA than in patients with DITRAat all time points. Patients with DITRA typicallyshowed good immediate response, butdecreased short- and medium/long-termresponses. No relevant differences in safety havebeen found.

Strengths and Limitations

Methodologically, this study was conductedbased on an a priori protocol, previously pub-lished in a scientific journal and using the lateststandards in scoping review methodology. Ineach of the phases, at least two researchers wereinvolved. Contact with authors of some of thestudies allowed us to clarify important pointsfor analyzing the primary data. This report wasmade according to the recommendations of thePRISMA Extension for Scoping Reviews.


Limitations related to funding and timeprevented us from including some articleswritten in languages other than English. Addi-tionally, it was not possible to contact some ofthe authors of the articles in order to reduce thepercentage of missing data. This was particu-larly limiting for articles published in the formof abstracts, because we did not exclude thesetypes of publication. This work is a substudy,and although we believe that the global searchstrategy was complete and that the develop-ment of the three-phase search minimized lossof relevant articles, it is possible that we havenot included some papers describing studiesrelated to the research topic. The risk of bias inthe studies, the quality of the evidence, andstatistical analysis techniques were not evalu-ated. Finally, this is the first scoping reviewcarried out by this research team; therefore, it ispossible that there may have been some otherunknown limitations.

Research Gaps

The low number of studies, low quality of evi-dence based on study design, and lack of ana priori design included in a public repositoryincrease the uncertainty regarding the validityof the results. The studies reported in thisreview were multicenter, multidisciplinarystudies, and these characteristics were moreevident for DIRA than for DITRA, because DIRAexhibits greater systemic involvement and isfundamentally a disease of the bone system.The included studies were performed in differ-ent countries, mostly developed countries, andthis observation was more evident for DITRAthan DIRA. Surprisingly, no center participatedin more than one study in DITRA articles,whereas in articles on DIRA, the NIH, whichincluded various institutions, was involved in10 of 15 studies. Finally, the absence or publicnature of the funding source and the lownumber of author CoIs were notable. This maybe due to the small market for drugs used totreat rare diseases, which can make drugsextremely expensive. Consequently, manypharmaceutical companies may stop manufac-turing these drugs or may not initiate research

and development into new therapies [25]. Basedon these above findings, primary studies ofhigher methodological quality and with agreater number of patients are necessary, andsecondary scientific investigations should serveas the basis for development of clinical guide-lines. Because DIRA and DITRA are rare diseases,making it difficult to include large numbers ofpatients and find funding, these studies shouldbe multicenter studies, likely with a referencecenter (similar to that observed for DIRA), andimprovement of public and private financialsupport is needed.

With regard to knowledge on the epidemi-ology and genetics of DIRA and DITRA, becausethe reporting of results has not been system-atized, preparation of a summary of the resultsrelated to use of anti-IL-1 drugs is complex.Accordingly, it would be useful for study sum-maries to provide case reports for reportingprotocols, such as CARE guidelines [26]. Despitethis, it was possible to observe the onset of thedisease and the earlier administration of treat-ments in patients with DIRA versus patientswith DITRA. Both of these patient groupsexhibited delays in diagnosis, probably due tothe characteristics of rare diseases and the needfor appropriate technology for genetic diagno-sis, which may be particularly important indeveloping countries. In all of the presentedcases, the existence and/or the type and posi-tion of the mutation found in IL1RN or IL36RNgenes were reported. Thus, of the 43 [27] and 60[28] homozygous or homozygous andheterozygous mutations that have been descri-bed in DIRA and DITRA, respectively, we foundnine and four differences in patients who hadreceived treatment with anti-IL-1 drugs. Giventhe small number of cases published, it is diffi-cult to find associations between the form ofpresentation or the severity of the disease andthe type of mutation in patients treated withanti-IL-1 drugs.

With regard to efficacy, we have not foundvalidated instruments or severity criteria toevaluate the degree of improvement in patientswith DIRA or DITRA following treatment. Thismakes it difficult to quantify the response. Todate, treatment efficacy in studies of patientswith DIRA has been measured by assessing


clinical and analytical improvement. In patientswith DITRA, the reported response is funda-mentally clinical. Based on this limited evi-dence, patients with DIRA showed higherresponses at all measured times and did notexhibit disease recurrence; thus, the dosage ofcorticosteroids can be reduced while receivingtreatment with anti-IL-1 drugs. Only onepatient with DIRA, who also presented withchronic recurrent multifocal osteomyelitis,showed disease recurrence when being admin-istered anakinra [18]. However, patients withDITRA who responded well immediatelyshowed only weak short- and medium/long-term response. Thus, these patients should begiven alternative treatments. In relation to thebest available evidence on use of other biologi-cal drugs in DITRA that we have been able tofind, Boehner et al. recently published a sys-tematic review on generalized pustular psoria-sis, including DITRA patients [38]. Thoseauthors found that anti-TNF (7/8) and anti-IL-12/IL-23(p40) (1/1) drugs also seemed to beeffective in DITRA patients. In our study, in fiveof eight patients in whom anti-IL-1 drugs failed,the final therapeutic regimens were etanerceptand acitretin, adalimumab and methotrexate,secukinumab, ustekinumab, and infliximab.Only one patient with DITRA who had poorresponse to etanercept and experienced relapseafter adalimumab was treated successfully withanakinra [37].

With respect to safety, data from observa-tional studies are unreliable, and cases of para-doxical generalized pustular psoriasis, andworsening of the disease or severe infectionsafter anti-TNF and anti-interleukin 1 treatmentshave been described in literature. Thus, ourobservations suggest that DITRA patients mayexperience a better response with a similarsafety spectrum with anti-TNF, anti-IL-12/IL-23(p40) or anti-IL-17 drugs as compared withother molecules blocking the IL-1 pathway[39, 40]. With regard to concomitant use ofcorticosteroids, only one case was reported, andworsening of the disease was observed [22].

The response to canakinumab and rinolaceptwas generally similar to that to anakinra forboth diseases in the reported cases. No differ-ences were observed in the safety of these

treatments in both diseases. Finally, no rela-tionships between the location of the geneticmutation and the response to treatment wereobserved; For example, genetic alterations werepresent in the one patient [1] with DIRA whodid not respond completely to anakinra treat-ment, but were also present in the other fourpatients (#5, #29, #30, and #31) who didrespond to treatment.

CONCLUSIONS

Available evidence on use of anti-IL-1 drugs inpatients with DIRA and DITRA is scarce andbased on observational studies. Anakinra is themost commonly used drug in patients withDIRA or DITRA, and most experience withcanakinumab has been anecdotal. Rinolacepthas only been used in patients with DIRA. Therewas no apparent relationship between muta-tions found in patients treated with anti-IL-1drugs and the onset symptoms, disease evolu-tion, or treatment response. The observed effi-cacy was high in patients with DIRA at all timepoints and at the initial (immediate) time inpatients with DITRA, but was low at short- andmedium/long-term periods in these patients.No differences in safety were found.

Confidence in these results is limited by thelack of available evidence and the type ofmethodology used in the studies. Systematizingthe collection and reporting of cases, standard-izing scales of severity measurement, and hav-ing greater public/private involvement arenecessary to produce primary studies that canbe used to answer questions regarding the effi-cacy, safety, and association of mutations withresponse to treatments using systematic reviewsand metaanalysis techniques.

ACKNOWLEDGEMENTS

We wish to acknowledge the assistance receivedfrom Dr. Gina Montealegre [TranslationalAutoinflammatory Disease Section (TADS),National Institute of Allergy and InfectiousDiseases, NIH/NIAID/LCIM, Bethesda, US] foranswering our questions about some aspects of


the DIRA patients during the phase of thereview.

Funding. This work was supported, in part,by project ICI1400136 to JR, integrated into theNational Plan of R ? D ? I 2008–2011 and co-financed by the ISCIII-Subdireccion General deEvaluacion and European Regional Develop-ment Fund (ERDF), by project PIN-0316-2017 ofthe Consejerıa de Salud, Junta de Andalucıa(Spain) to JR, and by grant PP13/009 of PlanPropio de movilidad para investigadores delInstituto Maimonides de Investigacion Biome-dica de Cordoba (IMIBIC). No funding wasreceived from any pharmaceutical company. Nofunding was received for publication of thisarticle.

Authorship. All named authors meet theICMJE criteria for authorship for this manu-script, take responsibility for the integrity of thework as a whole, and have given final approvalfor the version to be published. Finally, theauthors would like to thank Editage (www.editage.com) for English language editing.

Disclosures. Francisco Gomez-Garcıa hasreceived honoraria for research from Pfizer, andfor lecturing from Abbvie, Janssen-Cilag andNovartis; Antonio Velez-Garcıa Nieto hasreceived honoraria for lecturing from Pfizer,Novartis, AbbVie, and Janssen-Cilag, and otherfinancial benefits from AbbVie, Novartis, andJanssen-Cilag; Juan Ruano has received hono-raria for lecturing and grants for research fromPfizer, honoraria for lecturing from Janssen-Ci-lag and Novartis, and other financial benefitsfrom Abbvie and Novartis. Juan Ruano is amember of the Cochrane Bias Methods Groupand Skin Group. Francisco Gomez-Garcıa is amember of the Cochrane Bias Methods Groupand Skin Group. Beatriz Isla-Tejera is a memberof the Cochrane Bias Methods Group and SkinGroup. Juan L. Sanz-Cabanillas and Isabel Vig-uera-Guerra have nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with human

participants or animals performed by any of theauthors.

Data Availability. All data generated oranalyzed during this study are included in thispublished article/as supplementary informationfiles.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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Scoping Review on Use of Drugs Targeting Interleukin 1 ... · antagonists of the IL-1 pathway. IL-1 antago-nists may represent therapeutic alternatives. Here, we aim to provide a

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