RESEARCH Open Access
Reuma.p / asculi is – he Po uguese
asculi is egis y
C is ina Pon e
1,2*
, Niki a Khmelinskii
1,2
, Ví o Teixei a
1,2
, Ka ine Luz
1,3
, Daniela Peixo o
4
, Ma ília Rod igues
5,6
,
Ma iana Luís
5
, Lídia Teixei a
7,8
, Sand a Sousa
7
, Na halie Madei a
9
, Joana A. Aleixo
10,11
, Te esa Ped osa
12,13
,
So ia Se a
12
, Raquel Campanilho-Ma ques
1,2,9
, Wal e Cas elão
12
, Ana Co dei o
7
, Inês Co dei o
1,7
,
Síl ia Fe nandes
1,14
, Ca la Maciei a
1
, Ped o Madu ei a
10
, A mando Malca a
5
, Romana Viei a
10,11
, Fe nando Ma ins
15
,
G aça Sequei a
16
, Jaime C. B anco
12
, Lúcia Cos a
10
, José Vaz Pa o
9
, José Canas da Sil a
7
, José A. Pe ei a da Sil a
5
,
Ca mo A onso
4
, Helena Canhão
15,17
, Ma ia J. San os
2,7,15
, Raashid A. Luqmani
18
and João E. Fonseca
1,2
Abs ac
Backg ound: The asculi ides a e a g oup o a e diseases wi h di e en mani es a ions and ou comes. New
he apeu ic op ions ha e led o he need o long- e m egis ies. The Rheuma ic Diseases Po uguese Regis e ,
Reuma.p , is a web-based elec onic clinical eco d, c ea ed in 2008, which cu en ly includes speci ic modules o
12 diseases and > 20,000 pa ien s egis e ed om 79 heuma ology cen es. On Oc obe 2014, a dedica ed module
o asculi is was c ea ed as pa o he Eu opean Vasculi is Socie y collabo a i e ne wo k, enabling p ospec i e
collec ion and cen al s o age o enc yp ed da a om pa ien s wi h his condi ion. All Po uguese heuma ology
cen es we e in i ed o pa icipa e. Da a ega ding demog aphics, diagnosis, classi ica ion c i e ia, assessmen ools,
and ea men we e collec ed. We aim o desc ibe he s uc u e o Reuma.p / asculi is and cha ac e ize he pa ien s
egis e ed since i s de elopmen .
Resul s: A o al o 687 pa ien s, wi h 1945 isi s, om 13 cen es we e egis e ed; mean age was 53.4 ± 19.3 yea s a
las isi and 68.7% we e emales. The mos common diagnoses we e Behçe ’s disease (BD) (42.5%) and gian cell
a e i is (GCA) (17.8%). Pa ien s wi h BD me he In e na ional S udy G oup c i e ia and he In e na ional C i e ia o
BD in 85.3 and 97.2% o cases, espec i ely. Wi hin he mos common small- and medium- essel asculi ides
egis e ed, median [in e qua ile ange] Bi mingham Vasculi is Ac i i y Sco e (BVAS) a i s isi was highes in
pa ien s wi h ANCA-associa ed asculi is (AAV) (17.0 [12.0]); he e we e no di e ences in he p opo ion o pa ien s
wi h AAV o polya e i is nodosa who elapsed (BVAS≥1) o had a majo elapse (≥1 majo BVAS i em) du ing
p ospec i e assessmen (p= 1.00, p= 0.479). Biologic ea men was p esc ibed in 0.8% o pa ien s wi h GCA, 26.7%
o pa ien s wi h AAV, and 7.6% o pa ien s wi h BD. The e we e 34 (4.9%) dea hs epo ed.
(Con inued on nex page)
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* Co espondence: [email p o ec ed]
1
Rheuma ology Depa men , Hospi al de San a Ma ia - Cen o Hospi ala
Uni e si á io Lisboa No e, Cen o Académico de Medicina de Lisboa, Lisbon,
Po ugal
2
Unidade de In es igação em Reuma ologia, Ins i u o de Medicina Molecula ,
Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal
Full lis o au ho in o ma ion is a ailable a he end o he a icle
Pon e e al. O phane Jou nal o Ra e Diseases (2020) 15:110
h ps://doi.o g/10.1186/s13023-020-01381-0
(Con inued om p e ious page)
Conclusions: Reuma.p / asculi is is a bespoke web-based egis y adap ed o ou ine ca e o pa ien s wi h his
o m o a e and complex diseases, allowing an e icien da a- eposi o y a a na ional le el wi h he po en ial o link
wi h o he in e na ional da abases. I acili a es esea ch, ials ec ui men , se ice planning and benchma king.
Keywo ds: Ra e diseases, Vasculi is, Pa ien egis ies, Da abase managemen sys ems, Pa ien epo ed ou come
measu es
In oduc ion
The asculi ides a e a g oup o ela i ely uncommon
and complex diseases. The inc eased clinical ial ac i i y
and new he apeu ic op ions o pa ien s wi h asculi is
ha e led o he de elopmen o long- e m speci ic egis-
ies o his condi ion [1,2].
The Rheuma ic Diseases Po uguese Regis e , Reu-
ma.p , was c ea ed in June 2008 wi h he aim o p o-
spec i ely eco d clinical da a and ea men ad e se
e ec s o pa ien s om all Po uguese heuma ology de-
pa men s [3–5]. I has been a ailable as a web based
online sys em since 2012 (www. euma.p ) and cu en ly
includes speci ic modules o wel e di e en g oups o
heuma ic diseases (au oin lamma o y synd omes, ea ly
a h i is, ju enile idiopa hic a h i is, myosi is, os eoa h-
i is, pso ia ic a h i is, heuma oid a h i is, scle o-
de ma, Sjög en’s synd ome, spondyloa h i is, sys emic
lupus e y hema osus and asculi is) in Po uguese and
English language. O e 20,000 pa ien s and 170,000 isi s
ha e been egis e ed, up o Decembe 2018, by 79
na ional and in e na ional heuma ology cen es. On
Oc obe 2014, Reuma.p launched a dedica ed module
o egis e pa ien s wi h asculi is. The a iables in-
cluded we e chosen based on o he p e-exis ing Eu o-
pean egis ies, pa icula ly UKIVAS (UK and I eland
Vasculi is Regis y) [6], as pa o he Eu opean Vascu-
li is Socie y (EUVAS) collabo a i e ne wo k wi h he
long- e m goal o ha ing compa ible egis ies capable o
analysing impo an ou comes in a la ge scale [7,8].
Ou aim is o desc ibe he s uc u e o Reuma.p / as-
culi is and gi e a b ie o e iew on he cha ac e is ics o
pa ien s egis e ed since i s de elopmen .
Me hods
Desc ip ion and con en s
Reuma.p wo ks as an elec onic medical eco d, which
enables p ospec i e collec ion and cen al s o age o
enc yp ed da a. The da abase in o ma ion secu i y was
app o ed by he Po uguese Na ional Commission o
Da a P o ec ion and he e hics commi ees o he pa ici-
pa ing ins i u ions. Regis e ed pa ien s a e equi ed o
sign an in o med consen . All iden i iable da a is
enc yp ed, only accessible h ough an indi idual pass-
wo d a ibu ed o clinicians, who can only isualize da a
ela ed o hei cen e. Reuma.p is managed by he
Po uguese Socie y o Rheuma ology and has simila
s uc u ed modules o each disease. Reuma.p use s can
wo k indi e en ly in Po uguese and English, as he all
sys em is bilingual. A de ailed desc ip ion o i s gene al
design and da a managemen has been published else-
whe e [3].
The Reuma.p / asculi is displays a ee o ma able o
con en s on he le hand side (Fig. 1) whe e s anda d
i ems, equal o all Reuma.p modules, and disease spe-
ci ic i ems a e collec ed. All sec ions highligh ed in ed
a e manda o y o comple ion a each pa ien isi .
S anda d i ems include pa ien iden i ica ion, biobank
code o linkage, in o med consen s a us, demog aphics
(da e o bi h, gende , e hnici y, ma i al s a us, educa ion
and wo king s a us), da e o disease onse and diagnosis,
pas medical his o y, p e ious su ge ies, smoking and al-
cohol habi s, accina ion, sc eening o ube culosis,
diagnos ic es esul s, quali y o li e assessmen s (Sho
o m 36 [SF-36], Eu oQol-5D [EQ-5D], Func ional As-
sessmen o Ch onic Illness The apy [FACIT] Fa igue
Scale, and Hospi al Anxie y and Dep ession Scale
[HADS]), ea men his o y and epo o ad e se
ad en s (which is elec onically linked o he Na ional
Au ho i y o Medicines and Heal h P oduc s -
INFARMED). In addi ion, pa ien s ha e hei own dedi-
ca ed a ea ha can also be accessed online o comple e
he pa ien epo ed ou comes be o e he medical isi .
Wi hin he disease speci ic i ems, he 2012 Re ised
In e na ional Chapel Hill Consensus Con e ence
Nomencla u e o Vasculi ides [9] is used o selec he
diagnosis sub ype (Fig. 1,sec ion 1), acco ding o which
a possible classi ica ion c i e ia se is a ailable o com-
ple ion: he 1990 Ame ican College o Rheuma ology
(ACR) classi ica ion c i e ia o gian cell a e i is (GCA,
o me empo al a e i is) [10], Takayasu’s a e i is
(TAK) [11], polya e i is nodosa (PAN) [12], g anuloma-
osis wi h polyangii is (GPA, o me Wegene ’s g anulo-
ma osis) [13], eosinophilic g anuloma osis wi h
polyangii is (EGPA, o me Chu g-S auss Synd ome)
[14] and IgA asculi is (IgAV, o me Henoch–Schönlein
pu pu a) [15]; he 1984 Lanham c i e ia also o EGPA
[16]; he 2004 Ame ican Hea Associa ion Diagnos ic
C i e ia o Kawasaki disease (KD) [17]; he 1990 In e -
na ional S udy G oup c i e ia and he 2006 and 2013
In e na ional C i e ia o Behçe ’s disease (BD) [18–20]
Pon e e al. O phane Jou nal o Ra e Diseases (2020) 15:110 Page 2 o 12
and he 2011 p elimina y classi ica ion c i e ia o c yo-
globulinaemic asculi is (CV) [21]. A e he comple ion
o he c i e ia an au oma ic sen ence appea s a he bo -
om o he sc een in o ming he submi ing physician i
he pa ien s mee s he c i e ia (example o GCA in Sup-
plemen a y Fig 1). We expec o upda e hese c i e ia
a e he esul s om he DCVAS s udy (Diagnos ic and
Classi ica ion C i e ia o Vasculi is) [22] a e published.
Addi ional in o ma ion ega ding symp oms and signs,
which may ha e no been collec ed in he classi ica ion
c i e ia, a e a ailable o comple ion in a di e en sec-
ion - clinical ea u es sec ion - wi h au oma ic expo -
a ion o da a o equi alen i ems in he i s Bi mingham
Vasculi is Ac i i y Sco e (BVAS) assessmen (Fig. 1, sec-
ion 6). Mo eo e , in he gene al clinical da a sec ion
(Fig. 1, sec ion 2), speci ic medica ions and illici d ugs
known o be associa ed wi h he de elopmen o ascu-
li is, we e ex ac ed om he DCVAS case epo o m
(CRF) and a e inqui ed in his egis y. Gi en he i ems
collec ed in he DCVAS CRF we e e ised and ag eed
upon in a EUVAS mee ing in 2010, hey wo k as
e e ences o da a collec ion in some Eu opean egis-
ies (e.g. UKIVAS). Da a on speci ic asculi is immun-
ology es s (an i-neu ophil cy oplasmic an ibodies
[ANCA], an i–glome ula basemen memb ane [an i-
GBM] and c yoglobulins), gene ics (human leukocy e
an igen [HLA]-B51) (Fig. 1,sec ion 3) and biopsy ea-
u es (based on he DCVAS CRF) a e also collec ed. Re-
ga ding speci ic disease assessmen s: o p ognosis he
Fi e Fac o sco e (FFS) - o iginal and e ised - is col-
lec ed o ANCA-associa ed asculi ides (AAV) and
PAN (Fig. 1,sec ion 4) [23,24] and he ca dio ascula
isk sco e is a ailable o es ima e isk in GPA and mic o-
scopic polyangii is (MPA) [25] (Fig. 1,sec ion 5); o dis-
ease ac i i y he BVAS ( e sion 3) [26] is used and o
damage he Vasculi is Damage Index (VDI) [27] (Fig. 1,
sec ion 6). The disease e olu ion is p esen ed in he
o m o g aphics and cha s and includes all measu e-
men s a ailable du ing isi s o e y h ocy e sedimen a-
ion a e (ESR), C- eac i e p o ein (CRP), c ea inine,
eosinophil coun , BVAS, VDI and ANCA i es (Fig. 1,
sec ion 7).
Fig. 1 B ie summa y o he Reuma.p / asculi is con en s. ACR Ame ican College o Rheuma ology, AHA Ame ican Hea Associa ion, ANCA an i-
neu ophil cy oplasmic an ibody, BVAS Bi mingham Vasculi is Ac i i y Sco e, CNS Cen al Ne ous Sys em, CRP C- eac i e p o ein, eGFR (MDRD)
es ima ed glome ula il a ion a e by he modi ica ion o die in enal disease s udy equa ion, EGPA eosinophilic g anuloma osis wi h
polyangii is, ELISA Enzyme-Linked Immunoso ben Assay, EQ-5D Eu oQol-5D, ESR e y h ocy e sedimen a ion a e, FACIT Func ional Assessmen o
Ch onic Illness The apy Fa igue Scale, FFS Fi e Fac o Sco e, GBM glome ula basemen memb ane, GPA g anuloma osis wi h polyangii is, HADS
Hospi al Anxie y and Dep ession Scale, HLA human leukocy e an igen, ICBD In e na ional C i e ia o Behçe ’s disease, IF immuno luo escence, ISG
In e na ional S udy G oup, MPO myelope oxidase, PR3 P o einase 3, SF-36 Sho o m 36, UNK unknown, VDI Vasculi is Damage Index
Pon e e al. O phane Jou nal o Ra e Diseases (2020) 15:110 Page 3 o 12
Eligibili y
Eligible pa ien s include all pa ien s wi h a diagnosis o
asculi is. Al hough he s uc u e o Reuma.p / asculi is
is cu en ly be e sui ed o collec da a om adul pa-
ien s, we a e also including pa ien s aged below 18
yea s. A speci ic module o Paedia ic asculi is, includ-
ing he EULAR/PRINTO/PRES c i e ia [28] and disease
speci ic assessmen sco es ( o e.g. he Paedia ic Vascu-
li is Ac i i y Sco e [29] and he Paedia ic Vasculi is
Damage Index [30]), is p esen ly being de eloped. I will
wo k as a “sub-module”wi hin he gene al Reuma.p /
asculi is p o ocol, in o which all paedia ic asculi ic
pa ien s will “mig a e”a e being ope a ional. O in e -
es , Reuma.p cu en ly has modules o Ju enile Idio-
pa hic A h i is and o he Paedia ic heuma ic
condi ions and so has al eady ex ensi e unc ionali ies
applied o Paedia ic heuma ology. In addi ion, pa ien s
wi h asculi is seconda y o a connec i e issue disease
a e no included in Reuma.p / asculi is i hei main
diagnosis is a disease ha al eady has a Reuma.p spe-
ci ic module (e.g. sys emic lupus e y hema osus,
heuma oid a h i is and Sjög en’s synd ome). In hose
cases, he clinical ea u e “ asculi is”is a ailable o se-
lec ion in he di e en modules, allowing u u e iden i i-
ca ion and easy ex ac ion o da a i needed. Howe e ,
only pa ien s egis e ed in Reuma.p / asculi is could be
e alua ed using asculi is speci ic assessmen ools such
as BVAS o VDI. Pa ien s can be egis e ed ei he a dis-
ease p esen a ion o du ing ollow-up, in which case
da a ela ed o disease onse was egis e ed
e ospec i ely.
Implemen a ion and ec ui men
All cen es ha wo k wi h Reuma.p a e allowed o
egis e pa ien s in o Reuma.p / asculi is. Be o e i s o i-
cial launch, all Po uguese Rheuma ology cen es we e
in i ed o pa icipa e in he ac i e egis y o pa ien s
wi h asculi is unde he ca e o hei depa men . On
he 31s o Janua y 2015, a asculi is wo kshop was held
in which he i s esul s we e p esen ed and s a egies
o imp o e he egis y o pa ien s we e discussed.
T aining and ce i ica ion in pe o ming BVAS and VDI
was also gi en a he wo kshop o ensu e co ec collec-
ion o p ospec i e da a.
Analysis
We analysed all pa ien s egis e ed in Reuma.p / asculi is,
up o July 2018, wi h desc ip i e analysis o he demo-
g aphics; numbe o isi s pe pa ien ; disease du a ion;
diagnosis acco ding o he Chapel Hill nomencla u e; clas-
si ica ion c i e ia o he wo mos common ypes o ascu-
li is egis e ed; ype o o gan in ol emen ; immunology
and gene ics; imaging and biopsies esul s (when applic-
able); immunosupp essi e ea men ; ad e se e en s;
disease speci ic assessmen ools; pa ien epo ed ou -
comes; and ollow-up. Rega ding he disease speci ic as-
sessmen ools, we assessed he p opo ion o pa ien s
wi h AAV and PAN who had a FFS o 0, 1 and ≥2, and
calcula ed he median and in e qua ile ange (IQR) BVAS
a i s isi and VDI a las isi o pa ien s wi h he mos
common small- and medium- essel asculi ides eco ded.
Di e ences in median BVAS and VDI be ween asculi -
ides we e compa ed using Mann Whi ney U es s. Pa ien s
who had longi udinal da a on BVAS eco ded, we e
assessed o he occu ence o any elapses (BVAS ≥1) as
well as o majo elapses (≥1 majo BVAS i em) [31]. The
numbe o pa ien s who elapsed wi hin each sub ype o
asculi is was compa ed using chi-squa e analyses. An ad-
jus ed Cox p opo ional haza d model was used o iden i y
a iables a ec ing su i al. S a is ical signi icance was se
a p<0.05.
Resul s
Gene al da a
A o al o 687 pa ien s om 13 di e en Po uguese cen-
es we e egis e ed in o Reuma.p / asculi is. The num-
be o pa icipa ing cen es inc eased wi h ime, bu
a ound hal he pa ien s egis e ed came om an unique
cen e ha has a dedica ed asculi is ou pa ien clinic
[32]. Da a was p ospec i ely collec ed a each isi and
in o al he e we e 1945 isi s egis e ed (2.8 isi s/pa-
ien ). The mean age was 53.4 ± 19.3 yea s a las isi ;
68.7% we e emales. The diagnoses egis e ed acco ding
o he 2012 Chapel Hill Consensus nomencla u e a e
p esen ed in Table 1. The main ea u es o he mos
common sub ypes o asculi is egis e ed (n ≥20) a e
p esen ed in Table 2.A longe delay in diagnosis was
mos commonly seen in pa ien s wi h Behçe ’s disease
(BD), wi h an a e age o 82.5 ± 110.1 (0–672) mon hs
om disease onse o diagnosis (disease onse was com-
monly conside ed by he physicians as he i s disease
mani es a ion a ibu able o asculi is); he sub ype o
asculi is wi h less ime aken o diagnose since disease
onse was GCA wi h an a e age o 4 ± 10.9 (0–84)
mon hs.
Classi ica ion c i e ia and diagnos ic modali ies
The mos common diagnoses we e Behçe ’s disease (BD)
(n= 298; 42.5%) and gian cell a e i is (GCA) (n= 125;
17.8%). All diagnoses eco ded we e based on physician’s
clinical judgemen . Fo BD, 216 pa ien s had enough
da a o assess he In e na ional S udy G oup (ISG) 1990
c i e ia and o 251 pa ien s, we could apply he In e -
na ional C i e ia o BD (ICBD) (mos o he emaining
pa ien s we e lacking e idence o he esul s o he
pa he gy es ); 85.3% me he 1990 ISG c i e ia, 97.2%
he 2006 ICBD, and 97.2% he 2013 ICBD. HLA-B51
yping was a ailable in a ound hal he BD cases (n=
Pon e e al. O phane Jou nal o Ra e Diseases (2020) 15:110 Page 4 o 12
131), wi h posi i e esul s in 45% (n= 59). Fo GCA, 118
pa ien s had enough da a o assess he 1990 Ame ican
College o Rheuma ology classi ica ion c i e ia (mos o
he emaining pa ien s we e lacking biopsy); 97.5% o
118 cases me he c i e ia. A biopsy o he empo al a -
e y was pe o med in a ound hal he cases (n= 72),
compa ible wi h asculi is in 65% (n= 47). Resul s o
ul asound o he empo al ± axilla y a e ies we e a ail-
able in 94 cases, 87% showing a non-comp essible halo
compa ible wi h GCA (n= 82). A o al o 52 pa ien s
wi h he diagnosis o GCA unde ook bo h exams: 56%
(n= 29) had posi i e biopsy and ul asound; 21% (n= 11)
had posi i e ul asound and nega i e biopsy; 8% (n=4)
had posi i e biopsy and nega i e ul asound; and 15%
(n= 8) had nega i e biopsy and ul asound. Recen ly, a
endency has been obse ed o pe o ming ul asound,
a he han biopsy, o diagnose pa ien s wi h GCA, as
well as o complemen he ul asound assessmen o
empo al a e ies wi h he e alua ion o axilla y a e ies.
De ailed desc ip ion on axilla y assessmen was a ailable
in 36/94 ul asound epo s, wi h 11/36 (30.5%) cases
compa ible wi h la ge essel-GCA (LV-GCA). Mo eo e ,
a posi on emission omog aphy (PET) was pe o med
o diagnose asculi is in i e pa ien s, e ealing LV-GCA
in all o hem, a compu ed omog aphy angiog aphy
(CTA) was pe o med in six pa ien s, compa ible wi h
LV-GCA in only wo cases, and no pa ien wi h GCA
was epo ed o unde go magne ic esonance angiog-
aphy (MRA). In o al, imaging assessmen o la ge
essel in ol emen o he disease was epo ed in 41/125
pa ien s wi h GCA, 16/42 (38.1%) compa ible wi h LV-
GCA. In TAK, 36 de ailed imaging epo s we e a ail-
able o 22/29 pa ien s (79%) wi h his diagnosis. Resul s
we e compa ible wi h asculi is in 16/16 CTAs, 8/12
PETs, 4/4 ca he e -based dye angiog ams, 3/3 ul a-
sounds, and 1/1 MRA. All 22 pa ien s had a leas one
imaging modali y wi h epo ed asculi is.
In o he less common sub ypes o asculi is egis-
e ed, pa icula ly in small essel asculi is, he diag-
nosis was mos ly based on immunology and biopsy
esul s. ANCA es ing was a ailable in 87.0% o pa-
ien s wi h AAV and 80.8% o pa ien s wi h PAN;
Table 2shows espec i e ANCA s a us and sub ype.
Biopsy esul s we e a ailable in 84.6, 58.5, 37.9 and
36.4% o pa ien s wi h PAN, GPA, EGPA and MPA,
espec i ely. Table 3shows he numbe o biopsies
ob ained om di e en si es and pe cen age o cases
compa ible wi h asculi is. In pa ien s wi h he diag-
nosis o c yoglobulinaemic asculi is, he c yoglobu-
lins sub ype was a ailable in 60% o cases (n= 12):
ype II was he mos common sub ype (58.3%),
ollowed by ype I (25.0%) and ype III (16.7%). In pa-
ien s wi h associa ed hepa i is C in ec ion, 80% we e
ype II (n= 4) and 20% we e ype I (n=1).
Table 1 Diagnosis acco ding he 2012 Re ised In e na ional
Chapel Hill Consensus Con e ence Nomencla u e o Vasculi ides
Sub- ype o asculi is N (%)
La ge essel asculi is
Takayasu’s a e i is 28 (4)
Gian cell a e i is 125 (17.8)
Non-classi iable la ge essel asculi is 10 (1.4)
Medium essel asculi is
Polya e i is nodosa
b
26 (3.7)
Kawasaki disease 1 (0.1)
Non-classi iable medium essel asculi is 2 (0.3)
Small essel asculi is
An i-neu ophil cy oplasmic an ibody (ANCA)-associa ed asculi is
Mic oscopic polyangii is 22 (3.1)
G anuloma osis wi h polyangii is 41 (5.8)
Eosinophilic g anuloma osis wi h polyangii is 29 (4.1)
Non-classi iable ANCA-associa ed asculi is 11 (1.6)
Immune complex small essel asculi is
C yoglobulinaemic asculi is 20 (2.9)
IgA asculi is 16 (2.3)
Va iable essel asculi is
Behçe ’s disease 298 (42.5)
Cogan’s synd ome 12 (1.7)
Single-o gan asculi is
Cu aneous leukocy oclas ic angii is 16 (2.3)
Cu aneous a e i is
b
4 (0.6)
P ima y cen al ne ous sys em asculi is 3 (0.4)
O he 10 (1.4)
Vasculi is associa ed wi h sys emic disease
Rheuma oid asculi is 2 (0.3)
O he 11 (1.6)
Vasculi is associa ed wi h p obable e iology
Hepa i is C i us-associa ed c yoglobulinaemic asculi is 5 (0.7)
Hepa i is B i us-associa ed asculi is 1 (0.1)
D ug-associa ed immune complex asculi is 1 (0.1)
Cance -associa ed asculi is 2 (0.3)
O he 5 (0.7)
TOTAL
a
701 (100)
a
The numbe o diagnoses is highe han he numbe o pa ien s, gi en
ha in 14 cases mo e han one diagnosis was selec ed: six pa ien s wi h
c yoglobulinaemic asculi is and hepa i is C i us-associa ed
c yoglobulinaemic asculi is (n= 5) o o he asculi is associa ed wi h
sys emic disease (n= 1); h ee pa ien s wi h cu aneous leukocy oclas ic
angii is and o he asculi is associa ed wi h sys emic disease (n=2)o
non-classi iable la ge essel asculi is (n= 1); wo pa ien s wi h single-
o gan asculi is and g anuloma osis wi h polyangii is (n= 1) o o he
asculi is associa ed wi h sys emic disease (n= 1); wo pa ien s wi h o he
asculi is associa ed wi h sys emic disease and polya e i is nodosa (n=
1) o non-classi iable ANCA-associa ed asculi is (n= 1); and one pa ien
wi h Takayasu‘s a e i is and Hepa i is B i us-associa ed asculi is
b
All pa ien s wi h polya e i is nodosa had sys emic in ol emen o he
disease; all pa ien s wi h cu aneous a e i is had limi ed o ms o
polya e i is nodosa
Pon e e al. O phane Jou nal o Ra e Diseases (2020) 15:110 Page 5 o 12

Table 2 Demog aphics, o gan in ol emen , disease assessmen s and ea men o he mos common sub ypes o asculi is
egis e ed in Reuma.p / asculi is
TAK GCA PAN MPA GPA EGPA CV BD
Numbe o pa ien s (N) 28 125 26 22 41 29 20 298
Demog aphics
Female/male a io 6 1.8 0.9 3.4 1.6 2.2 4 3
Mean age a onse , yea s (SD) 32.1 74.4 40.4 59.8 47.6 48.1 57.8 27
(13.8) (8) (20.5) (12.5) (14.8) (16.3) (12.8) (12.7)
Mean age a diagnosis, yea s (SD) 34.5 74.7 42.5 60.7 50 51.7 58.7 33.8
(14.6) (7.8) (18.9) (12.3) (14.1) (14.9) (13.6) (12.1)
Mean age a las isi , yea s (SD) 40 77.6 55.8 62.3 56.4 57.6 59.4 43.9
(15.8) (7.9) (18.1) (15.2) (12.1) (15.5) (15.3) (14.9)
O gan in ol emen (%)
Cons i u ional symp oms 56.5 59.5 62.5 60.0 69.4 45.8 47.1 26.6
Musculoskele al 34.8 60.7 79.2 70.0 65.7 54.2 76.5 60.2
Skin 4.5 1.7 75.0 30.0 47.2 60.0 75.0 74.3
Eyes 21.7 47.1 12.5 10.0 31.4 16.7 11.8 36.8
ENT 8.7 50.0 8.7 30.0 82.9 62.5 11.8 4.5
Ches / pulmona y 9.1 1.7 20.8 45.0 58.3 100 –4.5
Ca dio ascula 87.5 69.7 50.0 10.0 8.6 29.2 17.6 17.3
Gas oin es inal 29.2 4.9 20.8 20.0 17.1 16.7 11.8 98.5
O al ulce a ion 4.2 ––15.0 8.6 8.3 –98.5
O he symp oms 25.0 4.9 20.8 5.0 8.6 8.3 11.8 16.4
Geni ou ina y 52.2 3.3 33.3 80.0 58.3 12.5 5.9 83.6
Geni al ulce a ion 4.3 ––––––83.6
O he symp oms 47.8 3.3 33.3 80.0 58.3 12.5 5.9 4.0
Neu ologic 54.4 88.6 45.8 40.0 42.9 66.7 47.1 19.0
Diagnos ic es s
c-ANCA o ANCA-PR3 posi i i y
N/N o pa ien s (%)
0/14 0/36 0/21 4/21 26/36 3/23 0/15 0/93
(0.0) (0.0) (0.0) (19.0) (72.2) (13.0) (0.0) (0.0)
p-ANCA o ANCA-MPO posi i i y
N/N o pa ien s (%)
0/14 0/36 0/21 16/21 6/36 10/23 0/15 1/92
(0.0) (0.0) (0.0) (76.2) (16.7) (43.5) (0.0) (1.1)
Vascula imaging wi h asculi is
a
N/N o pa ien s (%)
22/22 85/95 4/5 −/−−/−−/−−/−5/8
(100) (89.5) (80.0) (62.5)
Biopsy compa ible wi h asculi is
b
N/N o pa ien s (%)
2/3 47/72 16/22 6/8 7/21 6/11 1/1 −/−
(66.6) (65.3) (72.3) (75.0) (33.3) (54.5) (100)
Disease assessmen s
FFS 1996
N/N o pa ien s (%)
FFS = 0 ––16/23 7/20 –17/23 ––
(69.6) (35.0) (73.9)
FFS = 1 5/23 5/20 6/23
(21.7) (25.0) (26.1)
FFS ≥2 2/23 8/20 0/23
(8.7) (40.0) (0.0)
FFS 2011
N/N o pa ien s (%)
FFS = 0 ––18/23 6/20 18/36 10/24 ––
(78.3) (30.0) (50.0) (41.7)
FFS = 1 4/23 9/20 13/36 13/24
Pon e e al. O phane Jou nal o Ra e Diseases (2020) 15:110 Page 6 o 12
Disease assessmen , ea men , and ollow-up
Disease assessmen in pa ien s wi h asculi is a ge s
ou main domains - ac i i y, damage, p ognosis and
quali y o li e - and i is based on he combina ion o
physical examina ion, labo a o y bioma ke s, imaging
modali ies and assessmen ools. In la ge- essel ascu-
li is, gi en he e a e no speci ic moni o ing ools, disease
assessmen is mos ly based on clinical symp oms, con-
en ional acu e phase ma ke s (e y h ocy e sedimen a-
ion a e [ESR] and C- eac i e p o ein [CRP]), and
imaging. A o al o 63 ul asounds we e pe o med in 35
pa ien s wi h an es ablished diagnosis o GCA o moni-
o ing pu poses.
In small- and medium- essel asculi is disease ac i i y
is assessed by BVAS and damage by VDI. Al hough high
BVAS and VDI sco es ha e been associa ed wi h in-
c eased mo ali y in hese pa ien s [33,34], p ognosis is
usually assessed using he FFS (FFS 1996 o MPA,
EGPA and PAN; and e ised FFS 2009 o all AAV and
PAN, bu no ye alida ed on non-F ench pa ien s).
Table 2shows a FFS o ≤1 o mos o he AAV and
PAN, sugges ing ha mos pa ien s egis e ed a e
Table 2 Demog aphics, o gan in ol emen , disease assessmen s and ea men o he mos common sub ypes o asculi is
egis e ed in Reuma.p / asculi is (Con inued)
TAK GCA PAN MPA GPA EGPA CV BD
(17.4) (45.0) (36.1) (54.2)
FFS ≥2 1/23 5/20 5/36 1/24
(4.3) (25.0) (13.9) (4.1)
Median BVAS 3 a i s isi (IQR) ––12.0 17.5 17.0 15.0 8.0 –
(6.0) (9.0) (15.5) (12.0) (10.5)
Median VDI a i s isi (IQR) ––3.0 3.0 1.5 3.0 1.0 –
(3.0) (3.0) (2.8) (3.0) (3.0)
T ea men wi h DMARDs (%)
Syn he ic DMARDs
Aza hiop ine 16.0 0.8 70.8 68.4 41.0 39.3 22.2 30.3
Colchicine ––––.–5.6 75.3
Cyclophosphamide o al ––8.3 5.3 23.1 –5.6 0.8
Cyclophosphamide IV 16.0 0.8 41.7 42.1 41.0 17.9 11.1 5.2
Cyclospo ine –––5.3 2.6 –16.7 12.7
Hyd oxychlo oquine ––4.2 –5.1 –16.7 2.0
Le lunomide ––––––5.6 –
Me ho exa e 64.0 36.1 33.3 10.5 43.6 17.9 16.7 10.0
Mycophenola e mo e il ––8.3 21.1 5.1 3.6 5.6 0.8
Sul asalazine –––––––4.8
Biological DMARDs
Adalimumab –––––––2.4
E ane cep –––––––1.2
In liximab 4.0 –8.3 ––––5.6
Mepolizumab –––––3.6 ––
Ri uximab ––8.3 26.3 41.0 3.6 16.7 –
Tocilizumab 12.0 0.8 –––––0.4
ANCA An i-neu ophil cy oplasmic an ibody, BD Behçe ’s disease, BVAS 3 Bi mingham Vasculi is Ac i i y Sco e e sion 3, c-ANCA Cy oplasmic ANCA:CV
C yoglobulinaemic asculi is, DMARDs Disease-modi ying an i- heuma ic d ugs, EGPA Eosinophilic g anuloma osis wi h polyangii is, ENT Ea nose and h oa , FFS
Fi e Fac o Sco e, GCA Gian cell a e i is, GPA G anuloma osis wi h polyangii is, IQR In e qua ile ange, IV In a enous, LVV La ge essel asculi is, MPA
Mic oscopic polyangii is, MPO Myelope oxidase, PAN Polya e i is nodosa, p-ANCA Pe inuclea ANCA, PR3 P o einase 3, SD S anda d de ia ion, TAK Takayasu’s
a e i is, VDI Vasculi is Damage Index
a
In LVV, ul asound showing halo sign, angiog aphy showing ascula wall hickening, enhancemen , s enosis, occlusion, o aneu ysms, o PET showing FDG
up ake o he ao a o i s majo b anches. In PAN, angiog aphy showing mul iple mic oaneu ysms. In BD, angiog aphy showing h ombosis, ascula wall
hickening, enhancemen , s enosis, occlusion, o aneu ysms
b
In LVV, p esence o a e i is, o en g anuloma ous, a ec ing he ao a o i s majo b anches. In PAN, nec o izing a e i is o medium o small a e ies. In AAV,
nec o izing asculi is p edominan ly a ec ing small essels: in EGPA eosinophil- ich and nec o izing g anuloma ous in lamma ion, in GPA nec o izing
g anuloma ous in lamma ion, and in MPA nec o izing in lamma ion wi h absence o g anulomas. In CV, asculi is a ec ing small essels wi h c yoglobulin
immune deposi s
Pon e e al. O phane Jou nal o Ra e Diseases (2020) 15:110 Page 7 o 12
expec ed o ha e a good chance o su i al a 5 yea s.
Disease ac i i y a i s e alua ion was highe in pa ien s
wi h AAV, wi h a median [IQR] BVAS o 17.0 [12.0], in
compa ison o PAN (BVAS 12.0 [6.0]; p= 0.025) and
c yoglobulinaemic asculi is (BVAS 8.0 [10.5]; p= 0.002).
The e we e no di e ences in cumula i e damage a las
isi be ween pa ien s wi h AAV and PAN (median
[IQR] VDI 2.0 [3.0] s. 3.0 [3.0], p= 0.847); howe e , me-
dian [IQR] VDI o pa ien s wi h c yoglobulinaemic as-
culi is (1.0 [3.0]) was signi ican ly lowe in compa ison
o PAN (p= 0.001) and AAV (p< 0.001). In addi ion, no
di e ences in disease ac i i y a i s isi and cumula i e
damage a las assessmen we e ound amongs each
sub ype o AAV (p> 0.05). P ospec i e BVAS assessmen
was a ailable o 12 pa ien s wi h PAN (collec ed in 74
isi s), 36 pa ien s wi h AAV (collec ed in 125 isi s) and
2 pa ien s wi h CV (collec ed in 5 isi s). In PAN, 6/12
(50%) pa ien s had a leas one disease elapse eco ded
(1/6 wi h a majo elapse), in AAV, 18/36 (50%) pa ien s
had a leas one elapse eco ded (7/18 wi h a majo e-
lapse); and in CV, 1/2 (50%) pa ien s had a leas one e-
lapse eco ded (co esponding o a majo elapse). No
di e ences we e ound in he p opo ion o pa ien s wi h
a diagnosis o PAN o AAV who elapsed (p= 1.00) o
had a majo elapse (p= 0.479). Mo eo e , amongs each
sub ype o AAV, he e we e no di e ences ound in he
numbe o pa ien s who elapsed (MPA 4/10, GPA 8/17,
and EGPA 6/9; p> 0.05) o who had a majo disease e-
lapse (MPA 2/4, GPA 2/8, and EGPA 2/6; p> 0.05). In
all asculi ides quali y o li e has been assessed by gen-
e ic measu es such as he SF-36, cu en ly included in
he AAV co e se measu es o assessmen endo sed by
he Ou come Measu es in Rheuma ology (OMERACT)
Vasculi is Wo king G oup [35] and used in ials o
la ge- essel asculi is (LVV) [36]. Howe e , he a e o
i s comple ion in Reuma.p / asculi is was e y low; only
9.6% (n= 66) o pa ien s had a leas one SF-36 com-
ple ed in he e alua ion o hei disease ( o al o 97
isi s), mos commonly assessed in BD (n= 55), ollowed
by AAV (n= 4) and LVV (n= 4). O he pa ien epo ed
ou comes we e also e alua ed in less hen 10% o pa-
ien s: 67 pa ien s (9.8%) comple ed FACIT in 89 isi s;
64 pa ien s (9.3%) comple ed HADS in 87 isi s; and 43
pa ien s (6.3%) comple ed EQ-5D in 69 isi s.
Da a on ea men wi h disease-modi ying an i heu-
ma ic d ugs (DMARDs) o he mos common asculi -
ides egis e ed is de ailed in Table 2.A o al o 59
biologic DMARDs, mos equen ly i uximab (n= 27;
45.7%), we e p esc ibed o 53 pa ien s. The ollowing
p opo ion o pa ien s wi hin each sub ype o asculi is,
in whom de ailed he apy was egis e ed, we e ea ed
wi h biologic DMARDs: 4/25 (16.0%) pa ien s wi h TAK;
1/122 (0.8%) pa ien s wi h GCA; 3/24 (12.5%) pa ien s
wi h PAN; 5/19 (26.3%) pa ien s wi h MPA; 16/39
(41.0%) pa ien s wi h GPA; 2/28 (7.1%) pa ien s wi h
EGPA; 3/18 (16.7%) pa ien s wi h CV; and 19/251 (7.6%)
wi h BD. Mo eo e , 77 ad e se ad en s ela ed o ea -
men (in a ound ¼ o cases conside ed se e e) we e e-
po ed in 53 pa ien s, mos commonly due o
p ednisolone (n= 18; 23%), ollowed by me ho exa e
(n= 15; 19%) and aza hiop ine (n= 10; 13%).
Dea hs we e epo ed in 34 (4.9%) pa ien s (20 emales
and 14 males), a a mean age o 72.6 ± 15.5 [30–98] yea s
and mean disease du a ion o 4.9 ± 5.7 [0–22] yea s;
howe e , speci ic cause o dea h was a ailable in only 10
cases, none o which di ec ly ela ed o ea men . In ec-
ion was he mos common cause o dea h (n= 4; e-
spi a o y in ec ion in h ee cases and u osepsis in one
case), ollowed by ca dio ascula e en s (n= 3; s oke,
hea a ack, and pulmona y embolism), complica ions
o he disease (n= 2; ischaemic coli is in a pa ien wi h
PAN and complica ion o an ao ic aneu ysm su ge y in
a pa ien wi h TAK) and acu e kidney inju y (n= 1).
Dea hs we e mos commonly epo ed in pa ien s wi h
he diagnosis o GCA (n= 11), ollowed by AAV (n= 6),
CV (n= 5), PAN (n= 2), TAK (n= 2), BD (n= 2), and
Table 3 Biopsies compa ible wi h asculi is pe o med in pa ien s wi h he diagnosis o polya e i is nodosa o ANCA-associa ed
asculi ides pe si e o in ol emen
PAN GPA EGPA MPA
Pa ien s who unde wen biopsy (N) 22 21 11 8
Posi i e biopsies pe si e
a
(N/N o al pe o med) (%)
•Ea , nose and h oa (ENT) –2/12 (16.7) 1/3 (33.3) 1/3 (33.3)
•Kidney –3/8 (37.5) –6/8 (75.0)
•Lung –0/6 (0.0) 1/2 (50.0) –
•Skin 13/16 (81.3) 1/2 (50.0) 3/8 (37.5) –
•Pe iphe al ne e 1/1 (100) 1/3 (33.3) 2/2 (100) 2/2 (100)
•In es ine 1/1 (100) –––
•O he 2/7 (28.6) 0/1 (0.0) 0/1 (0.0) –
a
Compa ible wi h asculi is
EGPA Eosinophilic g anuloma osis wi h polyangii is, GPA G anuloma osis wi h polyangii is, MPA Mic oscopic polyangii is, PAN Polya e i is nodosa
Pon e e al. O phane Jou nal o Ra e Diseases (2020) 15:110 Page 8 o 12
o he sub ypes o asculi is (n= 6). Howe e , an adjus ed
Cox p opo ional haza d model o age and sex, demon-
s a ed ha he e was no s a is ically signi ican di e ence
in e ms o su i al be ween pa ien s wi h he diagnosis o
GCA and o he asculi ides (HR 0.53, 95% CI: 0.21–1.36),
and AAV and o he asculi ides (HR 1.08, 95% CI: 0.42–
2.79). Pa ien s wi h AAV who unde wen biologic
DMARDs p esen ed an inc eased a e o 5-yea mo ali y
(HR 16.44, 95% CI 1.71–157.65), bu no di e ences in su -
i al we e ound be ween AAV pa ien s wi h a FFS o 0
and a FFS o ≥1 (1996 FFS: HR 5.51, 95% CI 0.22–140.17;
2009 FFS: HR 0.69, 95% CI 0.42–11.29). The e we e h ee
pa ien s discha ged om hospi al ca e in o gene al p ac-
ice due o disease emission (GCA [n= 1], BD [n=1],
and cu aneous leukocy oclas ic angii is [n= 1]) and 43
cases o los o ollow-up (mos equen ly in pa ien s wi h
BD [n= 17] and GCA [n=8]).
Discussion
Reuma.p / asculi is is an e icien elec onic clinical ec-
o d and online egis y o pa ien s wi h he diagnosis o
asculi is, designed o eco d all ele an da a in clinical
p ac ice ollowing a s anda dised app oach. I p o ides
an oppo uni y o imp o e he quali y o clinical ca e in
his g oup o a e diseases and cha ac e ize he na u al
his o y o asculi is cap u ed by di e en Po uguese
Rheuma ology cen es.
Reuma.p / asculi is wo ks as a da a eposi o y a a na-
ional le el wi h he po en ial o link wi h o he in e -
na ional da abases. To ou knowledge, he e a e eigh
o he Eu opean coun ies wi h an es ablished asculi is
egis y: Uni ed Kingdom and I eland (UKIVAS) [6,37];
F ance (FVSG egis y) [38]; Spain (REVAS) [39]; Poland
(POLVAS egis y) [7,40]; No way (No Vas) [41]; Czech
Republic (Czech Regis y o AAV) [42]; and G eece
(G eek Regis y o AAV) [43]. In addi ion, in many o he
Eu opean coun ies he de elopmen o a asculi is
egis y is on hei esea ch agendas (e.g. Ge many,
Swi ze land, he Ne he lands and I aly) [8]. Reuma.p /
asculi is was de eloped based on local expe ise and
adap ions om o he p e-exis ing Eu opean egis ies
(mainly UKIVAS) and he DCVAS CRF ( he la ges
in e na ional s udy in asculi is) [22]. The e o e, i al-
lows o compa ible u u e join expo s as pa o he
EUVAS long- e m s a egy o aligning he Eu opean as-
culi is egis ies and es ablish ag eed co e-se i ems
p esen in all egis ies [8]. This capabili y is also an es-
sen ial equi emen o he cu en Eu opean Re e ence
Ne wo k ini ia i e o imp o e ca e o pa ien s wi h a e
diseases, including asculi is [44].
Reuma.p / asculi is comp ises a g oup o a ious sub-
ypes o asculi is, wi h di e en clinical mani es a ions,
classi ica ion c i e ia and disease speci ic assessmen s
and ou comes o in e es . In addi ion, he egis y o da a
by he physicians is done on an en i ely olun a y basis.
The e o e, balancing g anula i y and easibili y o da a
collec ion, when cons uc ing he da abase, posed a chal-
lenge. Al hough we encoun e ed missing da a in ou
analysis, mainly on he p ospec i e disease assessmen s
and cause o dea h, o e all ou da a was obus and
allowed us o ob ain eliable in o ma ion on many o ou
pa ien s’cha ac e is ics. Mo e han 1/3 o pa ien s had
he diagnosis o BD (n= 298), la gely ollowed by GCA
(n= 125). Al hough Reuma.p / asculi is is a egis y
e lec ing he eali y o he Po uguese Rheuma ology
cen es and is gene ally no in ended o epidemiologic
s udies, he numbe o pa ien s wi h BD egis e ed
(97.2% and 85.3% ul illing he ICBD and he ISG c i-
e ia, espec i ely) exceeded he p e iously epo ed
p e alence o 1.5 pe 100,000 in 1991 [45] and o 2.4 pe
100,000 in 1997 [46], highligh ing he need o new epi-
demiologic s udies on his disease in Po ugal. Ano he
in e es ing ac is ha he e we e mo e pa ien s diag-
nosed wi h GCA ha unde ook ul asound in compa i-
son o TAB (n= 94 s. n= 72), e lec ing mode n
p ac ice and he inco po a ion o ul asound as an es-
sen ial diagnos ic ool in he Rheuma ology se ing [47].
The immunosupp essi e ea men used in hese pa-
ien s is in line wi h cu en Eu opean League Agains
Rheuma ism (EULAR) ecommenda ions o he man-
agemen o AAV, LVV and BD [48–50]; he ac ha
only one pa ien wi h GCA (0.8%) was ea ed wi h oci-
lizumab e lec s he low na ional accessibili y o his
DMARD in he con ex o his indica ion, which is ex-
pec ed o change in he nea u u e.
The e we e some limi a ions ound in Reuma.p / as-
culi is. Besides he expec ed missing da a and unde e-
po ing (e.g. imaging esul s in LVV and PAN, biopsy
esul s and ANCA s a us in AAV, de ailed ea men ,
e c.), e y equen ly encoun e ed in his so o egis y,
he diagnosis o each sub ype o asculi is was pu ely
based on he submi ing physician’s clinical knowledge
and expe ience, he e o e lacking ex e nal alida ion. In
addi ion, mos o he classi ica ion c i e ia used a e cu -
en ly ou da ed and wai ing o he DCVAS esul s o
ensu e p ope upda e [22]. Mo eo e , no all physicians
who egis e ed pa ien s a e ei he ce i ied on he BVAS
and VDI assessmen s, o ha e p ope p ac ice in e alua -
ing pa ien s wi h asculi is using hese assessmen ools.
Al hough we p o ided ini ial aining we ecommend
mo e p ac ice and ce i ica ion sessions in he u u e o
gua an ee da a quali y and co ec assessmen o disease
ac i i y and damage, pa icula ly in pa ien s unde bio-
logic DMARDs.
We expec his egis y o con inue expanding, includ-
ing mo e cen es, di e en special ies (e.g. Neph ology)
and o he da a i ems. We aim o include he new AAV
pa ien - epo ed ou comes (AAV-PRO) [51]; a speci ic
Pon e e al. O phane Jou nal o Ra e Diseases (2020) 15:110 Page 9 o 12