887
Kuipe JJW, e al. Ann Rheum Dis 2023;82:887–896. doi:10.1136/ann heumdis-2022-222852
Re iew
EULAR s udy g oup on ‘MHC- I- opa hy’: iden i ying
disease- o e a ching mechanisms ac oss disciplines
andbo de s
Jonas JW Kuipe ,1 Jö g C P inz,2 E s a ios S a ikos,3 Pio Kuśnie czyk,4
Akiko A akawa,2 Sebas ian Sp inge ,5 Dillon Min o ,6,7 I an Padjen,8,9
Russka Shumnalie a,10 Seçil Vu al,11 Ina Kö e ,12,13 Ma leen G an de Sande,14,15
Ayşe Boy a ,16 Joke H de Boe ,1 Geo ge Be sias,17,18 Niek de V ies,14,15
Cha lo e LM K ieckae ,19,20 Inês Leal,21,22 Na aša Vido ič Valen inčič,23,24
Ilknu Tugal- Tu kun,25 Hanane el Khaldi Ahanach,26,27 Félicie Cos an ino,28,29
Simon Gla igny,30,31 Danijela M azo ac Zimak,32 Fabian Lö sche ,33
Floo G Ke s ens,19,20 Ma ija Bakula,8 Elsa Vie a Sousa ,34,35 Pe e Böhm,36
Kees Bosman,37 Tony J Kenna,38 Simon J Powis,39 Maxime B eban ,28,29
Ahme Gul,40 John Bowes ,41,42 Rik JU Lo ies ,43,44 Johannes Nowa zky,45,46
Ge i Jan Wolbink,19,47 Dennis G McGonagle,48,49 F ank ien Tu ks a ,19,20 EULAR
s udyg oup MHC- I- opa hies
To ci e: Kuipe JJW,
P inzJC, S a ikosE,
e al. Ann Rheum Dis
2023;82:887–896.
Handling edi o Jose S
Smolen
►Addi ional supplemen al
ma e ial is published online
only. To iew, please isi
he jou nal online (h p:// dx.
doi. o g/ 10. 1136/ a d- 2022-
222852).
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o
D F ank ien Tu ks a,
Rheuma ology, Ams e dam
Rheuma ology and Immunology
Cen e , Ams e dam 1105, The
Ne he lands; . u ks a@ eade. nl
Recei ed 21 July 2022
Accep ed 25 Janua y 2023
Published Online Fi s
27Ma ch2023
© Au ho (s) (o hei
employe (s)) 2023. Re- use
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and pe missions. Published
by BMJ.
ABSTRACT
The ’MHC- I (majo his ocompa ibili y complex class I)- opa hy’
concep desc ibes a amily o in lamma o y condi ions wi h
o e lapping clinical mani es a ions and a s ong gene ic link
o he MHC- I an igen p esen a ion pa hway. Classical MHC- I-
opa hies such as spondyloa h i is, Behçe ’s disease, pso iasis
and bi dsho u ei is a e widely ecognised o hei s ong
associa ion wi h ce ain MHC- I alleles and gene a ian s
o he an igen p ocessing aminopep idases ERAP1 and
ERAP2 ha implica es al e ed MHC- I pep ide p esen a ion o
CD8+T cells in he pa hogenesis. P og ess in unde s anding
he cause and ea men o hese diso de s is hampe ed
by pa ien pheno ypic he e ogenei y and lack o sys ema ic
in es iga ion o he MHC- I pa hway.
He e, we discuss new insigh s in o he biology o MHC- I-
opa hies ha s ongly ad oca e o disease- o e a ching and
in eg a ed molecula and clinical in es iga ion o deciphe
unde lying disease mechanisms. Because his equi es
ans o ma i e mul idisciplina y collabo a ion, we in oduce
he EULAR s udy g oup on MHC- I- opa hies o uni e clinical
expe ise in heuma ology, de ma ology and oph halmology,
wi h undamen al and ansla ional esea che s om mul iple
disciplines such as immunology, genomics and p o eomics,
alongside pa ien pa ne s. We p io i ise s anda disa ion
o disease pheno ypes and scien i ic nomencla u e and
p opose in e disciplina y gene ic and ansla ional s udies
o exploi eme ging he apeu ic s a egies o unde s and
MHC- I- media ed disease mechanisms. These collabo a i e
e o s a e equi ed o add ess ou s anding ques ions in he
e iopa hogenesis o MHC- I- opa hies owa ds imp o ing
pa ien ea men and p ognos ica ion.
THE INCEPTION OF THE MHC-I-OPATHY FAMILY
In lamma ion agains sel is o ches a ed by a
con inuum o incomple ely unde s ood inna e and
adap i e immune mechanisms. The e m ‘au oin-
lamma o y’ e e s o in lamma ion agains sel ,
caused by abno mal inna e immuni y, whe eas
‘au oimmuni y’ is caused by abe an adap i e
immuni y.1 2 Since his dicho omous de ini ion
o e looked condi ions such as pso iasis (PsO)
and Behçe ’s disease (BD), he concep o ‘mixed-
pa e n’ o ‘in e media e’ diseases was p oposed.3
Genome- wide associa ion s udies (GWAS) o
MHC- I- associa ed diseases, such as BD (associ-
a ed wi h HLA- B*51),4 5 PsO (associa ed wi h
HLA- C*06:02),6–8 HLA- B*27- associa ed spondy-
loa h i is (SpA)9–11 HLA- B*27- associa ed an e io
u ei is (AU)12 and HLA- A*29- associa ed bi dsho
u ei is (BU),13 14 e ealed ha hese ‘in e media e
diseases’ sha e a dis inguishable gene ic backg ound
de ined by MHC- I genes, he an igen p ocessing
genes ERAP1 and ERAP2, and he IL- 17 pa hway
gene IL23R. Such gene ic o e lap implica es
MHC- I pep ide p esen a ion as he key mechanis ic
commonali y. Fu he mo e, i subs an ia es he
idea ha BD, PsO, SpA and BU belong o a dis inc
disease clus e known as ‘MHC- I- opa hies’.15
The e is ongoing deba e and incomple e e idence
ega ding unde lying mechanisms o MHC- I-
opa hies.16–18 MHC- I p o eins (also called HLA- A,
HLA- B and HLA- C) bind sho pep ides om
deg aded o pa hogenic p o eins, which ha e
been p o eolysed inside he cell by he p o ea-
some.19–21 Mos MHC- I pep ides a e de i ed om
p o eins om he hos . ERAP1 and ERAP2 a e
endoplasmic e iculum aminopep idases associa ed
wi h an igen p ocessing ha im a ce ain ac-
ion o hese pep ides i hey a e no sho enough
be o e loading hem on o MHC- I molecules.22 This
p ocess enables MHC- I o p esen ens o hou-
sands o pep ides on he cell su ace, collec i ely
e e ed o as he ‘immunopep idome’.23 CD8+T
cells ead ou he immunopep idome by binding
o he pep ide- MHC- I complexes wi h hei T cell
ecep o s (TCR) ( igu e 1). MHC- I molecules can
P o ec ed by copy igh . on June 27, 2023 a Facul y o Medicine, Uni e si y o Lisbon.h p://a d.bmj.com/Ann Rheum Dis: i s published as 10.1136/a d-2022-222852 on 27 Ma ch 2023. Downloaded om
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888 Kuipe JJW, e al. Ann Rheum Dis 2023;82:887–896. doi:10.1136/ann heumdis-2022-222852
Re iew
also bind o kille - cell immunoglobulin- like ecep o s (KIRs) and
o he ecep o s on na u al kille (NK) cells.24
The e is much conjec u e abou he cause(s) o MHC- I-
opa hies15 25 26 and se e al popula hypo heses ha e been
p oposed which a e no necessa ily mu ually exclusi e. The
p ima y hypo hesis o he cause o MHC- I- opa hies is ha
disease- associa ed MHC- I alleles p esen speci ic immunogenic
pep ides ha igge ‘au oimmune’ eac ions (ie, he a h i o-
genic pep ide heo y).27 The gene ic associa ion wi h ERAP genes
also suppo s his hypo hesis since he ac i i y o hese enzymes
can modi y he immunopep idome.28 P oo o concep has been
shown in PsO and ecen ly in SpA and HLA- B*27+AU.29 The
iden i ica ion o CD8+T cells in PsO eac agains melanocy es
in he con ex o HLA- C06:02 as skin- speci ic a ge cells o he
pso ia ic au oimmune esponse,30–32 while CD8+T cells om
syno ial and eye luid o SpA and AU pa ien s ecognise bo h sel
and mic obial pep ides p esen ed by HLA- B*27.29
The e is s ill no conclusi e e idence ha his mechanism
unde lies o he MHC- I- opa hies since mechanis ic s udies a e
echnically challenging o conduc , owing o mul io gan in ol e-
men ha ing complex issues, which equi es labou - in ensi e
echnology o sc een o many epi opes. Consequen ly, se e al
al e na i e heo ies o MHC- I- opa hies ha e been p oposed,
one o which sugges s ha MHC- I p o ein mis olding di ec ly
leads o in lamma ion. Acco ding o his heo y, p edisposing
MHC- I molecules may exhibi p ope ies which could cause
excessi e mis olding and accumula ion in he ER, p omo ing he
‘un olded p o ein esponse’.33–38 S udies o (HLA- B*27) ans-
genic animals and cellula models suppo his hypo hesis, bu
he e is a pauci y o ansla ional e idence.39–43 A hi d popula
hypo hesis sugges s ha he p edisposing MHC- I alleles a e
ecognised by KIRs o leucocy e immunoglobulin- like ecep o s
(LILRs) on he cell su ace o NK cells.44 45
In ou opinion, he i s hypo hesis applies o he majo i y o
MHC- I- opa hies (wi h he mos obus e idence o PsO and
SpA), bu de ini i e p oo o CD8+T cell- media ed pa hologies
is lacking o se e al o he condi ions. Hypo heses 2 and 3 may
also apply o ce ain condi ions. Fo example, in BD, ERAP1 may
media e HLA- B51 ecogni ion ia NK cells,17 46 47 and pa ho-
gens ha can cause eac i e a h i is induce un olded p o ein
esponses in HLA- B*27- posi i e indi iduals.48 While hese o he
pa hways and mechanisms a e implica ed, including he e y
in e es ing in e ac ions o al e ed mic obiomes in pa ien s,49 we
ocus ou discussion on he MHC- I pa hway as he key de e mi-
nan o his amily o complex condi ions.
THE MANY FACES AND CHALLENGES OF MHC-I-OPATHIES
Se e al condi ions a e conside ed o be ‘classical’ MHC- I-
opa hies (PsO, pso ia ic a h i is (PsA), SpA, B*27- AU, BD and
BU) and sha e s ikingly simila clinical symp oms ( able 1).
BU is a a e and se e e ype o u ei is, leading o e inal damage
and ision loss ha exclusi ely a ec s HLA- A*29- posi i e indi-
iduals.50 51 Al hough i is unclea which o he clinical ea u es
a e sha ed be ween BU and o he MHC- I- opa hies, 1 s udy o
118 cases e ealed ha many pa ien s also su e om a h algia
and PsO.52 We also discuss PsA because i sha es many cha ac e -
is ics wi h PsO, including s ong associa ion wi h MHC- I alleles
and IL23R.7 8 53–55 While some pa ien s wi h in lamma o y bowel
disease may ha e simila symp oms,56 we will only discuss clas-
sical MHC- I- opa hies he e.
MHC- I- opa hies o e lap in hei pa e n o o gan in ol e-
men ( able 1). U ei is, o ins ance, is a disease ea u e epo ed
in e e y classical MHC- I- opa hy, al hough wi h di e en p e -
alence and ana omical loca ion (an e io /pos e io ).57 58 Sac o-
ilii is is p esen in pa ien s wi h SpA, PsA as well as BD.59–61
Cu aneous in ol emen is also a sha ed ea u e o MHC- I-
opa hies ( able 1).
Howe e , no e e y pa ien exhibi s he symp oma ic hall-
ma ks o e e y clinical en i y. Fo example, a e ial, enous and
neu ological complica ions a e common in BD, bu in equen
in o he MHC- I- opa hies.18 62 Fo se e al MHC- I- opa hies,
pa ien s wi h he associa ed isk MHC- I alleles a e mo e likely
o mani es ea ly- onse disease and a wo se p ognosis.63–66
Fu he mo e, subs an ial clinical and geog aphical a ia ion in
disease pheno ypes exis s, o example, he p e alence o gas o-
in es inal in ol emen in BD in Asian e sus Eu opean popula-
ions.67 68
WHAT YOU (DO NOT) SEE IS WHAT YOU (DO NOT) GET!
The clinical managemen o MHC- I- opa hy pa ien s is compli-
ca ed by he e ogenei y in age o onse , symp oms and disease
cou se. Unlike cases wi h commonly ecognised symp oms (e.g.,
Figu e 1 An o e iew o he ole o he MHC- I pa hway in MHC-
I- opa hies. The p o easome p oduces pep ide agmen s ha a e
anspo ed in o he endoplasmic e iculum by he anspo e
associa ed wi h an igen p ocessing (TAP) and immed by ERAP1
and ERAP2 (ERAP) o a leng h o 8- 11 amino acids be o e binding
o MHC- I molecules. A e a icking o he cell su ace he MHC- I-
pep ide complex is “ ead ou ” by su eying immune cells, igge ing
an igen- speci ic CD8+ T cell esponses o na u al kille (NK) cell
ac i a ion. MHC- I- opa hies a e gene ically associa ed wi h unc ionally
dis inc a ian s o MHC- I and ERAP which al e he pep ide epe oi e
p esen ed by MHC- I. Au o eac i e T cells in he pe iphe y ha escape
ole ance mechanisms and p omo e in lamma ion agains sel - pep ide
epi opes. Bio ende so wa e was used o c ea e elemen s om his
igu e unde an academic license.
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889
Kuipe JJW, e al. Ann Rheum Dis 2023;82:887–896. doi:10.1136/ann heumdis-2022-222852
Re iew
u ei is in SpA pa ien s), asymp oma ic o a ypical in ol emen o
he skin, bowel o o he como bidi ies in pa ien s may be o e -
looked ( able 1). Fo example, eexamina ion o SpA pa ien s
e ealed ha up o one- hi d may ha e como bid PsO.69 In he
DUET s udy, o e 40% o pa ien s wi h B*27- AU we e diag-
nosed wi h SpA o PsA on e- e alua ion by a heuma ologis ,70
which was con i med by o he s udies.71 La ge popula ion- le el
da a also co ela e disease mani es a ions o MHC- I- opa hies
such as u ei is, PsO, PsA and BD.58 72 73 Obse a ions om well-
powe ed coho s udies subs an ia e ha o al disease, which is a
hallma k o BD, is also linked o SpA.74–76 Despi e conside able
pheno ypic he e ogenei y, hese s udies suppo ha MHC- I-
opa hies a e in e connec ed condi ions ha canno be unde -
s ood in isola ion and equi e a mul idisciplina y app oach.
The human pheno ype on ology (HPO) p o ides a amewo k
o s anda dised nomencla u e o disease symp oms, which
can acili a e imp o ed classi ica ion o disease pheno ypes.77
Al hough o iginally designed o sys ema ically cap u e he clin-
ical mani es a ions o a e, monogenic condi ions, HPO has
mo e ecen ly been used o success ully in e se e al a e pheno-
ypes o he UK Biobank.78 In i s cu en o m, he HPO may no
be op imal o he anno a ion o he clinical spec um o pa ien s
wi h MHC- I- opa hies. As a esul , he EULAR s udy g oup aims
o e alua e he HPO and adap i o i he symp oms o MHC-
I- opa hies. The spec um o MHC- I- opa hies will bene i om
s anda disa ion o disease mani es a ions, allowing exis ing
coho s o be me ged in o a well- powe ed s udy. The p ecise
delinea ion o clinical pheno ypes will allow us o ela e hem o
molecula endo ypes. We expec ha his p ocess will acili a e
he disco e y (and alida ion) o be e diagnos ic, p ognos ic
and he apeu ic bioma ke s.
A COMMON GENETIC ARCHITECTURE
MHC-I, he ip o he icebe g
S ong gene ic associa ion wi h ce ain MHC- I alleles is he
hallma k o he MHC- I- opa hy clus e : MHC- I associa ion
s udies da e back o 1973 wi h he disco e y o he associa ion
o HLA- B*27 and SpA as well as HLA- B*51 and BD ( o me ly
‘HL- A5’),79–81 ollowed by epo s on HLA- C*06:02 (p e iously
known as ‘HLA- Cw6’) and PsO in 1977,82 83 and he associa ion
be ween HLA- A*29 and BU in 198284 ( able 2). In compa ison
o genes associa ed wi h complex in lamma o y condi ions, he
e ec size o MHC- I alleles accoun s o a disp opo iona e
amoun o gene ic isk. Fo almos 50 yea s, esea che s ha e
s uggled o unde s and he ole hese class I alleles play in hei
disease biology.
In e es ingly, ecen ine- mapping s udies showed ha s a is-
ical adjus men o HLA- B*27 in SpA e ealed independen
associa ions o o he MHC- I alleles, including HLA- A*02:01,
HLA- B*07, HLA- B*57 and HLA- B*4085 86 ( able 2). This
is signi ican because i also implica es he MHC- I pa hway
o cases lacking he p ima y MHC- I isk allele and s ongly
inc imina es pep ide p esen a ion a he han al e na i e
mechanisms.
Associa ion wi h se e al o hese alleles was also ound a e
co ec ing o he p ima y isk MHC- I allele in PsO (HLA-
A*02:01, HLA- B*27 and HLA- B*07), BD (eg, HLA- B*27 and
HLA- B*57), PsA (eg, HLA- B*07 and HLA- A*02) and AU.7 12 87–90
To da e, small GWAS in he a e BU had limi ed powe o de ec
HLA- A*29- independen loci in de ail, bu also epo ed inde-
penden isk MHC- I alleles.13 14 These indings aise he possi-
bili y ha an ensemble o disease- o e a ching MHC- I alleles
con ibu e o MHC- I- opa hy suscep ibili y.
Table 1 Summa y o issue in ol emen pe MHC- I- opa hy, o ganised pe clinical special y ( e e ences unde lying he summa ised da a and
sco es can be ound in online supplemen al able 1
Disease PsO* PsA† SpA B*27 AU BD BU
Medical special y P ima y isk MHC- I- allele(s) C*06 C*06/B*27 B*27 B*27 B*51 A*29
P ognosis wo se when p ima y MHC- I allele p esen 3 0 3 n.a 3 0
Oph halmology U ei is‡ 1 1 3 3 3 3
De ma ology O al ulce a ions 0 1 1 0 3 0
De ma ology Geni al ulce a ions 0 0 0 0 3 0
De ma ology Pso iasi o m de ma i is§ 3 3 2 2 1 1
De ma ology Pus ula lesions¶ 2 2 1 0 3 0
De ma ology E y hema nodosum- like lesions 0 0 0 0 3 0
Rheuma ology Spondyli is 1 3 3 3 1 0
Rheuma ology A h i is 2 3 3 2 3 0
Rheuma ology En hesi is 2 3 3 3 1 0
Rheuma ol/immunol Vasculi is** 1 1 1 0 3 0
Gas oen e ology In lamma o y bowel disease 1 1 2 1 2 0
In e nal medicine Como bid hype ension 1 2 2 0 0 2
Neu ol/In Med/ca diol Como bid ca dio asc disease 2 2 2 0 1 0
Legend: 3 pa o he disease ec um
2 egula ly epo ed
1 in equen ly epo ed
0
3 pa o he disease spec um.
2 egula ly epo .
1 in equen ly epo ed.
0 ei he unknown / no epo s / no p esen .
*Pso iasis: besides plaque pso iasis. This encompasses o he o ms o pso ia ic disease like pso iasis gu a e and (se e al ypes o ) pus ula pso iasis.
†PsA: bo h axial and pe iphe al disease.
‡U ei is an e io is he main sub ype epo ed in PsO, PsA, SpA, whe eas in Behçe ’s mul iple ana omical sub ypes o u ei is a e epo ed. BU mani es s as pos e io u ei is.
§Pso iasi o m lesions: e e s o he se e al ypes o pso iasis; classical plaque pso iasis, gu a e, nail lesions and e y hema ous as well as pus ula lesions.
¶Pus ula lesions: co e s acnei o m, papulopus ula and non- ollicula pus ules.
**Vasculi is in PsO as well as in PsA and SpA asculi is is in he la ge essels (ao i is); in B27- AU and BU no epo ed ou side he eye; in Behçe ’s asculi is is in all ypes o essels, a e ies and eins.
BU, bi dsho u ei is; PsA, pso ia ic a h i is; PsO, pso iasis; SpA, spondyloa h i is.
P o ec ed by copy igh . on June 27, 2023 a Facul y o Medicine, Uni e si y o Lisbon.h p://a d.bmj.com/Ann Rheum Dis: i s published as 10.1136/a d-2022-222852 on 27 Ma ch 2023. Downloaded om
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Re iew
The e o e, unc ional s udies ha conside only one MHC- I
allele may no cap u e he complexi y o he MHC- I pa hway in
pa ien s. This emphasises he need o use p ima y pa ien issues
o in es iga e disease mechanisms. I emains o be de e mined
whe he he ull MHC haplo ype (including ‘seconda y’ isk
MHC- I alleles) imp o es pa ien s a i ica ion. La ge popula ion-
based s udies (ie, UK Biobank) suppo ha MHC- I alleles a e
associa ed wi h a a ie y o heal h bioma ke s.91 A i s s ep
in o his di ec ion could be he conduc ion o a mul iances al
MHC- I- opa hy GWAS analysis by combining se e al a ailable
la ge- scale genome- wide da ase s and in e oga ing he MHC o
di e en pheno ypic s a es.
The de il is in he ERAP1 and ERAP2 de ails
Pe haps one o he majo accomplishmen s o he p og ess in
he unde s anding o MHC- I- opa hies was he disco e y o he
associa ion wi h he ERAP1 and/o ERAP2 genes.4 6 7 9 12–14 92–95
These genes encode wo ER- esiden enzymes specialised in im-
ming pep ides o acili a e o p e en hei binding in he g oo e
o MHC- I.96 97 By gene a ing and des oying pep ide epi opes,
ERAPs can a ec CD8+T cell and NK cell esponses.98–101
Gene ic a ian s in ERAP1 and ERAP2 a ec he enzyma ic
ac i i y and exp ession le els o hese enzymes.93 102 Conse-
quen ly, a change in ERAP ac i i y may expose CD8+T cells
o al e ed pep ide epe oi es (sel o non- sel ) ia MHC- I isk
alleles, which can be ha m ul.28
Gene ic associa ion be ween ERAP1 and MHC- I- opa hies is
ypically obse ed in indi iduals ca ying he p ima y isk MHC-
I.4 6 11 13 85 93 Coding a ian s in ERAP1 o ganise in o se e al
common haplo ypes o en e e ed o as ERAP1 ‘allo ypes’103 104
ha exhibi a wide ange o enzyma ic ac i i ies owa ds pep ide
subs a es and di e en ially shape he immunopep idome o
MHC- I.28 105 Risk polymo phisms in ERAP1 (and ERAP2) a e
also s ongly associa ed wi h mRNA and p o ein exp ession
le els o hese aminopep idases.50 102 106 Haplo ype- based anal-
yses ha e singled ou speci ic ERAP1 allo ypes as isk ac o s
o MHC- I- opa hies. While se e al e ms ha e been p oposed
o ERAP1 allo ypes, s anda dised nomencla u e has ye o be
widely adop ed. One unc ionally dis inc ERAP1 allo ype (o en
e e ed o as Haplo ype 10 (hap10)) is a isk ac o o BD and
BU,93 107 bu p o ec i e o SpA, AU and PsO.28 108 In e es ingly,
in PsO, he p o ec i e hap10 was less e ec i e in gene a ing
he au oan igenic epi ope han he isk haplo ypes o ERAP1,
leading o lowe HLA- C exp ession and immunogenici y o
melanocy es.31
ERAP1 may also in luence NK cell esponses ia inhibi o y
ecep o s NKG2A/CD94 (also exp essed by CD8+T cells109) o
non- classical MHC- I molecule HLA- E.46 The inhibi o y ac i i y
o HLA- E equi es he p esen a ion o a signal sequence om
MHC- I molecules, which a e also p esen in HLA- A29, HLA-
B27 and HLA- B51.110–112 The e o e, ERAPs may also a ec NK
cells and CD8+T cells ia MHC- I- ela ed molecules, as was
p e iously shown in cance models.46 113 Al hough KIR ecep-
o s can ecognise immunopep idome changes caused by ERAP1,
KIR genes do no in luence HLA- B*27 and ERAP1- media ed
ankylosing spondyli is isk.114 115 This sugges s ha he disease
mechanisms media ed by ERAP1 and MHC- I a e less dependen
on KIRs.
In con as o ERAP1, ERAP2 gene ic a ian s a e no associ-
a ed wi h all MHC- I- opa hies (eg, BD). Also, ERAP2 is associ-
a ed wi h SpA ega dless o HLA- B*27 s a us. Because he e is
also epis asis be ween ERAP1 and HLA- B*40 in SpA (indepen-
den o HLA- B*27),85 i is possible ha ERAP2 modi ies disease
in SpA ia al e na i e isk MHC- I alleles. Func ional s udies
suppo ha ERAP2 signi ican ly a ec s he immunopep idome
o many MHC- I alleles, including HLA- B*40115 116
No e ha ERAP2 allo ypes co- occu non- andomly wi h
ERAP1 allo ypes.93 105 Fu he mo e, al hough HLA- A*29 is
common in many egions, HLA- A*29- posi i e indi iduals who
ca y bo h ERAP1 and ERAP2 isk alleles a e only obse ed in
coun ies whe e BU is p e alen .93 The e o e, an indi idual’s
ERAP1 and ERAP2 allo ypes along wi h hei MHC- I p o ile
(and T cell epe oi e) a e mos likely o de e mine hei suscep-
ibili y o MHC- I- opa hies.117
S udies linking ERAP geno ypes wi h clinical end poin s may
ha e po en ial,118 119 bu we would like o emphasise ha hese
s udies should be ca e ully con olled and well powe ed. Bo h
ERAP1 and ERAP2 a e common denomina o s o MHC- I-
opa hies, which place an igenic pep ide p esen a ion a he hea
o hei pa hogenesis.
IL23R and T cells
The e a e many o he genes associa ed wi h condi ions wi hin
he MHC- I- opa hy spec um ha ha e been disco e ed h ough
GWAS. While hey a e impo an o disease biology, we only
b ie ly discuss IL23R, a ecep o o IL- 23 exp essed by T cells (and
Table 2 Repo ed HLA class I associa ions in ou MHC- I- opa hies
MHC- I- opa hy P e alence P ima y HLA class I associa ion % cases nega i e o p ima y HLA class I allele Independen * HLA class I associa ions
Bi dsho u ei is 1- 5/500 000 HLA- A*29:02 0HLA- A*3013 14
HLA- A*3314
Spondyloa h i is† 0.5% HLA- B*27 ~ <30 HLA- B*4085 86
HLA- A*0285
HLA- B*0785
HLA- B*5785
HLA- C*1586
Behçe ’s Disease 0.19- 120/100 0009HLA- B*51 ~30–70 HLA- A*0287
HLA- B*2787
HLA- B*5787
HLA- A*0387
HLA- B*1587
HLA- B*4987
HLA- A*2687 89
HLA- C*0789
Pso iasis 2–4% HLA- C*06:02 ~30–70 HLA- A*02122
HLA- B*27122
HLA- B*07122
HLA- C*07176
*Iden i ied by s a is ical adjus ing o p ima y associa ed HLA class I allele.
†Majo i y o da a a e om gene ic s udies in ankylosing spondyli is. Includes bo h isk and p o ec i e alleles.
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inna e lymphocy es), because i is common o MHC- I- opa hies
and is associa ed wi h disease se e i y and pheno ypes.8 118 120–122
Fascina ingly, despi e IL23R exp ession by CD4+T cells, epigen-
e ic analyses implica e CD8+T cells as majo pe pe a o s o
MHC- I- opa hies.88 In e leukin- 17- p oducing CD8+T cells
( e med ‘Tc17’) in il a ing skin and syno ial lesions in PsO,
BD, SpA and PsA pa ien s exp ess IL23R.123–125 Tc17 cells a e
also mo e abundan in pa ien s wi h BU.126 127 IL23R’s ole in
he pa hophysiology o MHC- I- opa hies is incomple ely unde -
s ood, bu likely o be issue- dependen .128 This may explain
why pa ien s wi h PsO129 and PsA130 exhibi clinical esponse
o he apy ha dis up s T cell IL- 23 signalling, while ini ial
ials we e less success ul in SpA.131 132 A be e unde s anding
o clinical and molecula ea u es will help o e come challenges
posed by pa ien he e ogenei y as well as iden i y he apeu ic
bioma ke s which will guide he selec ion o candida es eligible
o ea men wi h IL- 23 inhibi o s.21 128 131–134
UNMET NEEDS IN MHC-I-OPATHY PATHOPHYSIOLOGY
UNDERSTANDING
E idence o au o eac i e CD8+ T cell in ol emen
A numbe o immunopep idome s udies in cell models ha e
shown ha polymo phisms in ERAP cause change in he
pep ides p esen ed by HLA- B27, HLA- B51, HLA- A29 and
o he MHC- I alleles.28 115 116 Ci cums an ial e idence sugges s
ha hese enzymes in oduce o emo e pep ides ha bind o
isk MHC- I alleles and signal CD8+T cells o a ack heal hy
issues. The ac ha CD8+T cells a e clono ypically expanded
in pa ien s wi h SpA, PsO and PsA suppo s his concep .135–138
In BD, ca ie s o he disease- associa ed ERAP1 allo ype107
show en ichmen o ci cula ing an igen- expe ienced e ec o
CD8+T cells and ERAP1 modula ion in luenced CD8+T cell
esponses.107 The lack o iden i ica ion o causa i e au oan igens
o indeed alloan igens has esul ed in discussion abou whe he
CD8+T cells d i e pa hology in MHC- I- opa hies.17 Rega dless,
au oan igen- de i ed pep ide ecogni ion by CD8+T cells in
pa ien s has p e iously been epo ed, including an HLA- B51-
p esen ed pep ide de i ed om a s ess- inducible au oan igen in
BD,139 HLA- C06:02 p esen ed pep ide om inna e hos de ence
p o ein LL- 37 in PsO,140 and HLA- B27- es ic ed epi ope om
a pep ide ho mone ecep o and ca ilage- de i ed pep ides in
SpA.141 142
To da e, he mos compelling concep ual p oo ha CD8+T
cells media e au oimmune in lamma ion is based on s udies
o PsO, and e y ecen ly in HLA- B*27- posi i e SpA and AU
pa ien s.29 30 Skin lesional CD8+T cells in PsO can ecognise an
HLA- C06:02- es ic ed au oan igen epi ope om ADAMTSL5
highly exp essed in skin melanocy es.30 31 ADAMTSL5- speci ic
CD8+T cells sec e e PsO- p omo ing cy okines (eg, IL- 17)
speci ically a e ecognising melanocy e- pep ide p ocessed by
ERAP1 and p esen ed by he disease- associa ed MHC- I HLA-
C06:02.30–32 He e, he immunogenici y o melanocy es o
sel - eac i e CD8+T cell esponses was inc eased by disease-
associa ed ERAP1 haplo ypes h ough g ea e supply o he
pep ide au oan igen.30 I has, he e o e, been sugges ed ha
pha macological modula ion o ERAP ac i i y owa ds p ecu so
pep ides speci ically p esen ed by MHC- I alleles could e e se
in lamma ion in MHC- I- associa ed diseases.143 144
Resea che s ecen ly ound ha issue- in il a ing CD8+T
cells sha ed TCRs in eye liquid as well as syno ial luid o HLA-
B*27- posi i e pa ien s wi h AS and AU.29 These CD8+T cells
speci ically ecognise mic obial (eg, YEIH p o ein om eac i e
a h i is- igge ing pa hogens) and sel - an igens (eg, pep ides
om GPER1 o PRPF3 p o eins) speci ically wi hin he con ex
o HLA- B27. Acco ding o hese indings, en i onmen al pa ho-
gens may igge au oimmuni y ia CD8+T cell ac i a ion in
MHC- I- opa hies, hus suppo ing he p ima y hypo hesis o
he MHC- I- opa hy pa hogenesis. Fu u e esea ch migh explo e
whe he HLA- B27 p esen a ions o hese pep ides a e a ec ed by
isk allo ypes o ERAP1 and whe he pha macological a ge ing
o ERAPs in e e es wi h hese esponses.
I emains unclea why o he housands o sel - pep ides in
he immunopep idome only a mino i y become immunogenic,
while he majo i y emain ole able. Howe e , T cell au oan i-
gens o en ha e pos - ansla ional modi ica ions o show al e ed
binding con o ma ion.145–147
Wha igge s CD8+T cell sel - eac i i y in MHC- I- opa hies
emains unknown. The classical iew is ha nega i e selec ion
in he hymus elimina es au o eac i e T cells. Some sel - eac i e
CD8+T cells manage o escape his il e ing p ocess and a e
ein oduced in o he ci cula ion (some imes a high equencies)
bu kep in check by ole ance mechanisms.148–150
In e es ingly, ecen wo k sugges s ha hymic egula-
o y T- cells, a he han nega i e selec ion o au o eac i e T
cells, en o ce p o ec ion agains au oimmuni y.148 151 He e,
he cy okine IL- 23 elimina es hymic egula o y T cells in an
IL23R- dependen manne ,152 while selec i ely en iching IL23R-
exp essing CD8+T cells.153 Mo eo e , he e is no sha p a ini y
h eshold o he ecogni ion o MHC- pep ide complex by
TCRs, and CD8+T cells wi h o he wise low a ini y TCRs can be
ac i a ed by a la ge inc ease in p esen ed au oan igen.154 155 This
also i s wi h he ecen ly p oposed ‘au oimmune su eillance o
hype sec e ing mu an s’ heo y ha links high au oan igen le els
o T- cell au oimmuni y.156 C oss- p esen a ion o ex acellula
an igens in dend i ic cells can also lead o he en y o ex a-
cellula an igens in o he MHC class I pa hway, he eby g ea ly
expanding he po en ial pool o immunogenic pep ides. Concep-
ually, his in eg a es he possibili y o mic obial agen s causing
disease, as demons a ed o SpA, and AU.29 Vi us- igge ed
Box 1 The aims o he EULAR s udy g oup on "MHC- I-
opa hy"
1. Mul idisciplina y collabo a ion be ween heuma ologis s,
de ma ologis s and oph halmologis s o consensus and
s anda dised anno a ion o disease symp oms.
2. De ailed pheno ypic e alua ion by pa ien - epo ed
symp oms/ou comes.
3. In eg a ion o GWAS da a o MHC- I- opa hy- ela ed diseases,
ac oss a la ge numbe o exis ing coho s, o acili a e ine
mapping o he gene ic basis.
4. Ha monisa ion o he nomencla u e (eg, ERAP allo ypes) and
p o ide expe syn hesis o cu en bes p ac ice o he s udy
o key aspec s o he biology in MHC- I- opa hies.
5. Es ablishmen o a pan- Eu opean conso ium wi h
s anda dised clinicopa hological disease pheno ypes om
aim 1 and 2, (complemen ed by molecula da a on ERAP
and MHC- I haplo ypes and possibly o he biological da a
such as me agenomics o assess mic obiome in ol emen
and TCR- epe oi e da a) o imp o ed disease classi ica ion,
diagnos ic c i e ia and p ognos ic bioma ke s o p edic ion o
disease p og ession and e icacy o ( ype o ) he apy.
6. E alua ion o MHC- I- opa hies in di e en e hnic backg ounds,
gi en he massi e he e ogenei y wi hin class- 1 an igens.
7. Pa ien pa icipa ion: in ol emen o pa ien esea ch
pa ne s.
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892 Kuipe JJW, e al. Ann Rheum Dis 2023;82:887–896. doi:10.1136/ann heumdis-2022-222852
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clonal CD8+T cell esponses a e p ocessed h ough MHC class
I, and some o hese esponses a e con olled by ERAP1.157
Recen echnological ad ancemen s which ha e inc eased he
sensi i i y and scale o analysing immunopep idomes o p ima y
pa ien issues (ideally sampled a he a ec ed o gans) as- well
as high- h oughpu p o iling o (au o)an igen- speci ic T- cell
epe oi es (ie, single- cell TCR sequencing) may help iden i y
CD8+T cell- media ed disease mechanisms in MHC- I- opa hies
in g ea e de ail.158–161
Towa ds MHC-I pa hway he apy
This s udy g oup’s ul ima e goal is o imp o e disease ou come
o MHC- I- opa hies. Al hough de ini e disease mechanisms need
o be es ablished, a ailable clinical and molecula e idence
allow us o ou line se e al po en ial s a egies. Gi en ha
MHC- I is conside ed a oo cause o MHC- I- opa hies, he a-
peu ic a ge ing o an igen p ocessing and p esen a ion seems
sel - e iden . This may be achie ed by in e en ions aimed a
dis up ing cy okine signalling (see sec ion IL23R and T cells) o
s a egies ha acili a e es o a ion o he mic obiome.48 Pa ien s
wi h MHC- I- opa hies may ha e an al e ed mic obio a,162–164
bu heal hy indi iduals may also show mic obio a composi ions
ha clus e acco ding o hei HLA alleles (eg, HLA- B*27, HLA-
A*29).165 Eme ging T cell- an igen disco e y app oaches wi hin
he mic obiome may p o ide an exci ing ield o upcoming
s udies.166 In case o au oan igen- media ed pa hology, i may be
possible o speci ically nega e T cell in e ac ion by an ibodies
o small compounds ha speci ically block access o MHC- I-
pep ide complexes. T- cell engagemen may also be blocked
by p e en ing o changing he abundance o a ge pep ide
p esen a ion by manipula ion ups eam o MHC- I, including
he cellula p o eome (eg, chemo he apy), o pha macological
inhibi ion o modula ion o he p o easome, TAP o he an igen
loading complex,167–171 al hough wi h limi a ions in speci ici y a
he cos o po en ial ad e se e ec s.
Inhibi ing o , depending on he disease, enhancing he ac ion
o ERAP1 and ERAP2 may be a p omising app oach, since hese
enzymes a e highly specialised o an igen p esen a ion, and much is
known abou hei s uc u e and unc ion o allow he de elopmen
o inhibi o s o enhance s.143 144 172 The ac ha hei impac on
an igen p esen a ion may be limi ed o a pa o he immunopep-
idome,173 may cons i u e a middle g ound be ween single an igen
s a egies (an ibodies o MHC/pep ide complex) and gene al
supp ession o he MHC- I pa hway. Mos o hese he apeu ic
‘op ions’ a e s ill in hei in ancy and equi e ansla ional s udies
in sui able p eclinical models. Al hough he HLA- B*27- ansgenic
oden models,174 ha e p o ided aluable insigh s in o he disease
mechanisms o MHC- I- opa hies, he e emains an unme need o
addi ional ansgenic MHC- I models. To de e mine i i is possible o
a ge he MHC- I pa hway he apeu ically in pa ien s, hese models
should be ‘ ully’ humanised and cap u e a b oade spec um o clin-
ical and molecula cha ac e is ics.
Mission o he EULAR s udy g oup on MHC-I-opa hies
As a esul o he complexi y o he clinical pheno ypes and he
lack o knowledge abou he unde lying mechanisms o MHC- I-
opa hies, in e na ional c oss- disciplina y collabo a ions and comple-
men a y scien i ic expe ise a e u gen ly needed. The EULAR s udy
g oup on MHC- I- opa hies p o ides an in e na ional ne wo k ha
b ings medical specialis s, ansla ional and undamen al scien is s
unde one umb ella wi h he aim o coope a i ely o e coming long-
s anding unme needs in he disease managemen and unde s anding
o he biology o MHC- I- opa hies.
The s udy g oup (cu en ly >50 pa icipan s: de ma ologis s,
oph halmologis s, heuma ologis , scien is s and pa ien ep e-
sen a i es om >15 coun ies) was ounded in 2020 amids he
COVID- 19 pandemic. The global pandemic es ic ed ini ial discus-
sion o online mee ings. An inaugu al mee ing ook place in May
2022, in Ams e dam, ollowed by a mee ing du ing EULAR in June
2022 in Copenhagen. S udy g oup esea ch and collabo a ions will
ocus on he pa hophysiology o MHC- I pa hway in hese condi-
ions. B ie ly, he s udy g oup aims a e summa ised in box 1 and he
objec i e is o ha monise, acili a e and imp o e esea ch me hod-
ology and e minology, s udy disease mechanisms mo e collec i ely;
os e basic and ansla ional knowledge exchange in an in e disci-
plina y ashion h ough mee ings ia symposia du ing EULAR mee -
ings(h ps://www.eula .ch/myUploadDa a/ iles/s udy_g oup_aims_
mhc_i_opa hy_ o _web.pd ) and dissemina e p og ess ia social
media (eg, an open Linked- in page o in e es ed colleagues, h ps://
www.linkedin.com/g oups/12722534/). To accomplish hese objec-
i es, he S udy G oup o med se e al mul idisciplina y ask o ces
composed o clinicians, biologis s and pa ien ep esen a i es o
p io i ise unme esea ch needs ha would equi e c oss- Eu opean
collabo a ion. Fo example, one o he ask o ces aims o conduc
me a- analysis o GWAS da a o he MHC- I- opa hies o ine map
he MHC and iden i y no el isk loci in ela ion o clinical ea u es.
Ano he ask o ce cu en ly wo ks on e alua ion o a pa ien -
epo ed symp om in as uc u e, which has al eady been success-
ully employed in COVID- 19 s udies.175 Al hough cu en ly all wo k
wi hin he s udy g oup is con ibu ed in kind by i s membe s, he
apidly g owing s udy g oup aims o apply o ex e nal unding o
esea ch. This will also be equi ed o achie e mo e ambi ious goals,
such as he collec ion o bioma e ials o os e inno a i e esea ch
by deep immunop o iling (eg, T- cell epe oi es, MHC- I immu-
nopep idomes) and ansla ional s udies (eg, ERAP modula ion in
pa ien issues). The EULAR s udy g oup will complemen hei
scien i ic objec i es wi h he o ganisa ion o in e ac i e wo kshops
and symposia connec ed o EULAR o exchange basic, ansla ional
and clinical knowledge in an in e disciplina y ashion and u he
acili a e he g ow h o he s udy g oup by inclusion o physicians
and scien is s ac i e in his ield.
In conclusion, he EULAR s udy g oup on MHC- I- opa hies
b idges a a ie y o medical scien i ic disciplines wi h he ambi-
ious join objec i e o conduc an in eg a ed in es iga ion o
MHC- I- opa hies o disco e he cause and cu e o a a ie y o
complex in lamma o y condi ions.
Au ho a ilia ions
1Depa men o Oph halmology, Cen e o T ansla ional Immunology, Uni e si y
Medical Cen e U ech , U ech , The Ne he lands
2Uni e si y Hospi al, depa men o De ma ology and Alle gy, Ludwig Maximilians
Uni e si y Munich, Munchen, Ge many
3Labo a o y o Biochemis y, Depa men o Chemis y, Na ional and Kapodis ian
Uni e si y o A hens, A hens, G eece
4Labo a o y o Immunogene ics and Tissue Immunology, Ins i u e o Immunology
and Expe imen al The apy Ludwik Hi sz eld Polish Academy o Sciences, W oclaw,
Poland
5School o Science, Cons uc o Uni e si y B emen gGmbH, B emen, Ge many
6Depa men o De ma ology, Ma e Dei Hospi al, Msida, Mal a
7Depa men o Pa hology, Uni e si y o Mal a Facul y o Medicine and Su ge y,
Msida, Mal a
8Di ision o Clinical Immunology and Rheuma ology, Uni e si y Hospi al Cen e
Zag eb Depa men o In e nal Medicine, Zag eb, C oa ia
9Uni e si y o Zag eb School o Medicine, Zag eb, C oa ia
10Clinic o Rheuma ology, Depa men o Rheuma ology, Medical Uni e si y o So ia,
So ia, Bulga ia
11School o Medicine, Depa men o De ma ology, Koç Uni e si y, Is anbul, Tu key
12Clinic o Rheuma ology and Immunology, Bad B amds ed Hospi al, Bad B ams ed ,
Ge many
13Di ision o Rheuma ology and Sys emic In lamma o y Diseases, Uni e si y Medical
Cen e Hambu g- Eppendo , Hambu g, Ge many
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14Uni e si y o Ams e dam, Depa men o Rheuma ology & Clinical Immunology
and Depa men o Expe imen al Immunology, Ams e dam Ins i u e o In ec ion &
Immuni y, Ams e dam UMC Loca ion AMC, Ams e dam, The Ne he lands
15Ams e dam Rheuma ology and Immunology Cen e (ARC) | Ams e dam UMC,
Uni e si y o Ams e dam, Ams e dam, The Ne he lands
16Depa men o De ma ology, Anka a Uni e si y Facul y o Medicine, Anka a, Tu key
17Depa men o Rheuma ology and Clinical Immunology, Uni e si y o C e e School
o Medicine, I aklio, G eece
18Labo a o y o Au oimmuni y- In lamma ion, Ins i u e o Molecula Biology and
Bio echnology, He aklion, G eece
19Ams e dam Rheuma ology and immunology Cen e (ARC)| Reade, Ams e dam, The
Ne he lands
20Depa men o Rheuma ology, Reade Hoo dloca ie D Jan an B eemens aa ,
Ams e dam, The Ne he lands
21Depa men o Oph halmology, Hospi al de San a Ma ia, Cen o Hospi ala
Uni e si á io Lisboa No e EPE, Lisboa, Po ugal
22Cen o de Es udeos das Ciencias da Visão, Uni e sidade de Lisboa Faculdade de
Medicina, Lisboa, Po ugal
23Uni e si y Eye Clinic, Uni e si y Medical Cen e Ljubljana, Ljubljana, Slo enia
24Facul y o medicine, Uni e si y o Ljubljana, Ljubljana, Slo enia
25Depa men o Oph halmology, Is anbul Uni e si y Is anbul Facul y o Medicine,
Is anbul, Tu key
26Depa emen o Oph halmology, Ams e dam UMC Loca ion AMC, Ams e dam, The
Ne he lands
27Depa men o Oph halmology, Onze Lie e V ouwe Gas huis, Ams e dam, The
Ne he lands
28Se ice de Rheuma ology, Hospi al Amb oise- Pa e, Boulogne- Billancou , F ance
29In ec ion & In lamma ion, UMR 1173, Inse m, UVSQ, Uni e si y Pa is- Saclay,
Mon igny- le- B e onneux, F ance
30In ec ion & In lamma ion, UMR 1173, Inse m, UVSQ/Uni e si é Pa is Saclay,
Mon igny- le- B e onneux, F ance
31Labo a oi e d’Excellence In lamex, Pa is, F ance
32Depa men o Oph halmology, Uni e si y Hospi al Cen e Zag eb, Zag eb, C oa ia
33Depa men o Rheuma ology and Immunology, Inselspi al Uni e si y Hospi al
Be n, Uni e si y o Be n, Be n, Swi ze land
34Rheuma ology Resea ch Uni Molecula João Lobo An unes, Uni e si y o Lisbon
Medical Facul y, Lisboa, Po ugal
35Rheuma ology Depa men San a Ma ia Cen o Hospi al, Academic Medical Cen e
o Lisbon, Lisboa, Po ugal
36Pa ien pa ne , Ge man League agains Rheuma ism, Bonn, Ge many
37Pa ien pa ne , Na ionale Ve eniging ReumaZo g, Nijmegen, The Ne he lands
38T ansla ional Resea ch Ins i u e, Queensland Uni e si y o Technology, B isbane,
Queensland, Aus alia
39School o Medicine, Uni e si y o S And ews School o Medicine, S And ews, UK
40Di ision o Rheuma ology, Is anbul Uni e si y Is anbul Facul y o Medicine, Is anbul,
Tu key
41Cen e o Gene ics and Genomics Ve sus A h i is, Cen e o Musculoskele al
Resea ch, Facul y o Biology, Medicine and Heal h, Manches e Academic Heal h
Science Cen e , The Uni e si y o Manches e , Manches e , UK
42NIHR Manches e Musculoskele al Biomedical Resea ch Uni , Manches e
Uni e si y NHS Founda ion T us , Manches e , UK
43Depa men o Rheuma ology, KU Leu en Uni e si y Hospi als Leu en, Leu en,
Belgium
44Skele al Biology and Enginee ing Resea ch Cen e , Depa men o De elopmen
and Regene a ion, KU Leu en, Leu en, Belgium
45Depa men o Medicine, Di ision o Rheuma ology, NYU Langone Behçe ’s
Disease P og am, NYU Langone Ocula Rheuma ology P og am, New Yo k Uni e si y
G ossman School o Medicine, New Yo k Uni e si y, New Yo k, New Yo k, USA
46Depa men o Pa hology, New Yo k Uni e si y G ossman School o Medicine, New
Yo k, New Yo k, USA
47Depa men Immunopa hology, Sanquin Resea ch, Ams e dam, The Ne he lands
48Leeds Ins i u e o Rheuma ic and Musculoskele al Medicine, Uni e si y o Leeds,
Leeds, UK
49NIHR Leeds Biomedical Resea ch Cen e, Leeds Teaching Hospi als NHS T us ,
Leeds, UK
Twi e Jonas JW Kuipe @jonas_kuipe and Tony J Kenna @ onykenna3
Con ibu o s The inal e sion was app o ed by all au ho s.
Funding The au ho s ha e no decla ed a speci ic g an o his esea ch om any
unding agency in he public, comme cial o no - o - p o i sec o s.
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Founda ion g an s PR 241/5- 2Consul ing ees Boeh inge IngelheimPaymen o
hono a ia o lec u es, p esen a ions, speake s bu eaus, manusc ip w i ing o
educa ional e en s paid ac i i ies as a speake o Almi all, Boeh inge Ingelheim,
Janssen- Cilag, No a is and P ize PK Leade ship o iducia y ole in o he
boa d, socie y, commi ee o ad ocacy g oup, paid o unpaid All unpaid: Human
Immunology (Else ie ) Edi o ial Boa d, F on ie s in Immunology Gues associa e,
Edi o and e iew edi o . Edi o ial boa d o In e na ional Jou nal o Immunogene ics
SS: all suppo o he p esen manusc ip (eg, unding, p o ision o s udy ma e ials,
medical w i ing, a icle p ocessing cha ges, e c. Deu sche Fo schungsgemeinscha
(DFG) o Jacobs Uni e si y B emen DM G an s o con ac s om any en i y
Go e nmen o Mal aPaymen o hono a ia o lec u es, p esen a ions, speake s
bu eaus, manusc ip w i ing o educa ional e en s Sano i, U iageSuppo o
a ending mee ings and/o a el A ene, Biode ma, U iageLeade ship o iducia y
ole in o he boa d, socie y, commi ee o ad ocacy g oup, paid o unpaid Mal ese
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lec u es, p esen a ions, speake s bu eaus, manusc ip w i ing o educa ional e en s
No a is, Eli Lilly, P ize , Abb ie, Hono a ia o lec u es, paymen s di ec ly o me RS
Suppo o a ending mee ings and/o a el Abb ie and P ize Ina IK Consul ing
ees Amgen, Boeh inge ,GSK, SobiPaymen o hono a ia o lec u es, p esen a ions,
speake s bu eaus, manusc ip w i ing o educa ional e en s Abb ie, Amgen.
Boeh inge , GSK, Janssen, Lilly, MSD, No a is, P ize , Sobi M dS G an s o con ac s
om any en i y No a is, UCB, EliLillyPaymen o hono a ia o lec u es, p esen a ions,
speake s bu eaus, manusc ip w i ing o educa ional e en s UCBSuppo o
a ending mee ings and/o a el UCBPa icipa ion on a Da a Sa e y Moni o ing
Boa d o Ad iso y Boa d No a is, UCB, Abb ie GB G an s o con ac s om any
en i y GSK, P ize Paymen o hono a ia o lec u es, p esen a ions, speake s bu eaus,
manusc ip w i ing o educa ional e en s GSK, As aZeneca, P ize , Abb ie, Aeno asis,
No a is, Lilly IL Consul ing ees No a is, Alime a lT- T Consul ing ees AbbVie,
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manusc ip w i ing o educa ional e en s AbbVie, Tu key FC Paymen o hono a ia
o lec u es, p esen a ions, speake s bu eaus, manusc ip w i ing o educa ional
e en s LillySuppo o a ending mee ings and/o a el UCB, No a isPa icipa ion
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ole in o he boa d, socie y, commi ee o ad ocacy g oup, paid o unpaid P esiden ,
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LILLYSuppo o a ending mee ings and/o a el BIOGEN, PFIZER, JANSSEN RJUL
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ORCID iDs
Jonas JWKuipe h p://o cid.o g/0000-0002-5370-6395
DillonMin o h p://o cid.o g/0000-0003-3705-0119
Cha lo e LMK ieckae h p://o cid.o g/0000-0001-6591-7838
ElsaVie a Sousa h p://o cid.o g/0000-0002-7170-8802
MaximeB eban h p://o cid.o g/0000-0002-6932-9395
JohnBowes h p://o cid.o g/0000-0003-4659-031X
Rik JULo ies h p://o cid.o g/0000-0002-5986-3092
F ank ienTu ks a h p://o cid.o g/0000-0002-8055-9036
P o ec ed by copy igh . on June 27, 2023 a Facul y o Medicine, Uni e si y o Lisbon.h p://a d.bmj.com/Ann Rheum Dis: i s published as 10.1136/a d-2022-222852 on 27 Ma ch 2023. Downloaded om
894 Kuipe JJW, e al. Ann Rheum Dis 2023;82:887–896. doi:10.1136/ann heumdis-2022-222852
Re iew
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