1
Long- e m Follow-up in Adul s wi h Coeliac Disease: P edic o s and E ec on Heal h
Ou comes
Henna Pekki1,2, Ka i Kaukinen1-3, Tui e Ilus1,4, Ma kku Mäki5, Heini Huh ala6, Kaija Lau ila5,
Kalle Ku ppa2,5
1Celiac Disease Resea ch Cen e, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al,
Tampe e, Finland
2Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland
3Depa men o In e nal Medicine, Tampe e Uni e si y Hospi al, Tampe e, Finland
4Depa men o Gas oen e ology and Alimen a y T ac Su ge y, Tampe e Uni e si y Hospi al,
Tampe e, Finland
5Tampe e Cen e o Child Heal h Resea ch, Uni e si y o Tampe e and Tampe e Uni e si y
Hospi al, Tampe e, Finland
6Facul y o Social Sciences, Uni e si y o Tampe e, Tampe e, Finland
Co espondence o Kalle Ku ppa, MD, PhD
Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, FIN-33014, Tampe e, Finland.
E-mail: kalle.ku ppa@u a. i
The au ho s epo no con lic o in e es
Wo d coun : 2981
Abb e ia ions: EmA, Endomysium an ibodies, GSRS, Gas oin es inal Symp om Ra ing Scale;
PGWB, Psychological Well-Being Index; SF-36, Sho -Fo m 36; TG2ab, ansglu aminase 2
an ibodies
This is he accep ed manusc ip o he a icle, which has been published in Diges i e and Li e Disease. 2018, 50(11),
1189-1194. h p://dx.doi.o g/10.1016/j.dld.2018.05.015
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Abs ac
In oduc ion: Cu en guidelines ecommend egula ollow-up in coeliac disease, bu e ec o
his on long- e m heal h ou comes emains unclea .
Aims: To e alua e p edic o s and signi icance o long- e m ollow-up
Me hods: Al oge he 677 p e iously diagnosed coeliac disease pa ien s we e ec ui ed o a
na ionwide heal h su ey. Medical da a we e ga he ed h ough in e iews and pa ien eco ds.
Cu en symp oms and quali y o li e we e assessed by alida ed ques ionnai es and blood
samples we e d awn o se ology. All a iables we e compa ed be ween pa ien s wi h and
wi hou long- e m (>2 yea s) ollow-up.
Resul s: Only 15% had long- e m ollow-up, median du a ion 10 yea s. P edic o s (p<0.05) o
he ollow-up we e immunological (35% s. 24%) and ci cula o y (20% s. 12%)
como bidi ies, whe eas i was less common in subjec s wi h musculoskele al (23% s. 34%)
como bidi y and hose no belonging o any a - isk g oup (16% s. 27%). Pa ien s wi h o
wi hou ollow-up had compa able age, adhe ence and abili y o manage a glu en- ee die and
equency o se oposi i i y. Also ques ionnai e sco es pa alleled, bu hose wi hou ollow-up
epo ed mo e o e all symp oms (16% s. 26%). Mos pa ien s in bo h g oups wished o
ollow-up.
Conclusion: Only a mino i y o pa ien s had egula ollow-up. Howe e , pa ien s wi h and
wi hou he ollow-up we e compa able in mos long- e m ou comes, indica ing ha i migh
no be always necessa y. The esul s call o mo e pe sonalized ollow-up policies in coeliac
disease.
Key wo ds: Glu en- ee die ; T ea men , Quali y o li e; Symp oms; Complica ions
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In oduc ion
Coeliac disease is a li elong glu en-induced au oimmune en e opa hy wi h a p e alence up o
2% in Caucasian popula ions (1). The only ea men is a s ic glu en- ee die , he ini ia ion o
which usually elici s a clea clinical and his ological esponse and disappea ance o he disease-
speci ic au oan ibodies (2). Un o una ely, he high cos and es ic i e na u e o he glu en- ee
die p edisposes o poo adhe ence and subsequen ly o pe sis en en e opa hy and an inc eased
isk o se ious complica ions such as os eopo o ic ac u es and malignancy (3-6). Mo eo e ,
he e is a subg oup o pa ien s wi h a condi ion called e ac o y coeliac disease, who do no
a ain adequa e clinical and his ological eco e y despi e a s ic die and hus ha e pa icula ly
poo p ognosis (7).
In o de o ensu e p ope adhe ence and esponse o he glu en- ee die and o de ec
possible complica ions, mos cu en guidelines ecommend egula long- e m ollow-up in
coeliac disease e en as o en as annually (2, 8). Howe e , he e is a pauci y o e idence as o
how he ollow-up is ac ually implemen ed in clinical p ac ice, and whe he he absence o
ollow-up eally a ec s he long- e m coping and heal h o he pa ien s (9-15). In e es ingly, in
a 15-yea ollow-up we ecen ly ound ha he lack o a epea biopsy one yea a e coeliac
disease diagnosis is no associa ed wi h an inc eased isk o ad e se ou comes such as educed
well-being o malignancies (16). This would indica e ha he associa ion be ween he p esence
o ollow-up and he p ognosis o coeliac disease is mo e complex han one migh expec .
To u he elucida e he signi icance o egula ollow-up o he ea men success
in coeliac disease, we conduc ed a na ionwide su ey and compa ed a ious pa ien - ela ed and
o he ele an ac o s be ween la ge coho s o coeliac disease pa ien s wi h o wi hou long-
e m ollow-up a e diagnosis.
Ma e ials and Me hods
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Pa ien s and s udy design
A na ionwide c oss-sec ional heal h su ey was conduc ed in Tampe e Uni e si y Hospi al and
he Uni e si y o Tampe e. The su ey was c ea ed o in es iga e a iable aspec s o coeliac
disease, no jus ac o s associa ed wi h he long- e m ollow-up. The pa icipan s we e
ec ui ed h ough newspape ad e isemen s and wi h he aid o coeliac disease socie ies.
Inclusion c i e ia we e age ≥18 yea s and a biopsy-p o en diagnosis a leas wo yea s be o e
en olmen . All pa icipan s illed alida ed ques ionnai es on cu en symp oms and quali y o
li e and we e in e iewed sys ema ically by a physician o a s udy nu se wi h expe ise in
coeliac disease. Pa ien s unable o a ain he s udy cen e we e in e iewed by phone and
ques ionnai es we e sen by mail. Pa ien eco ds we e e iewed in o de o con i m he
diagnosis and o complemen medical da a. In addi ion, blood samples we e d awn o
se ological measu emen s, in case o phone in e iews his was done a he nea es labo a o y.
Subjec s wi h de ma i is he pe i o mis we e excluded owing o hei di e en diagnos ic and
ollow-up p o ocol, as well as pa ien s wi h an unclea diagnosis o subs an ially incomple e
medical in o ma ion. Al oge he 677 pa icipan s, ep esen ing app oxima ely 2% o he whole
Finnish coeliac popula ion (4), we e en olled o u he analyses.
A e da a collec ion he esul s we e analyzed be ween subg oups o pa icipan s
who ei he had o had no been sys ema ically and egula ly assessed o a leas wo yea s a e
he diagnosis by heal h ca e o die a y compliance and ea men success. This so ing was
based on he pa ien s´ own epo ing and medical eco d da a. Also possible coeliac disease
con ols ca ied ou du ing heal h ca e isi s o o he condi ions we e included. Subg oup
analyses we e ca ied ou in pa ien s wi h only a sho - e m ollow-up (<2 yea s) and hose
wi hou any ollow-up. The indings we e compa ed wi h ou na ional ecommenda ions. In
Finland, he ollow-up o coeliac disease is decen alized o p ima y ca e, wi h he gene al
p ac i ione s in cha ge. I needed, he pa ien can be e e ed o a specialis in a easonable ime
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ame. To uni y diagnos ics and ea men , he e a e na ional Cu en Ca e Guidelines, which
ecommend a epea biopsy one yea a e diagnosis and egula clinical and se ological ollow-
up a 2-3-yea in e als (Collin 2010).
Pa ien en olmen and collec ion o s udy da a we e conduc ed wi h he
pe mission and acco ding o he guidelines o he E hical Commi ee o he Pi kanmaa Hospi al
Dis ic . All pa icipan s ga e w i en in o med consen .
Clinical cha ac e is ics
The clinical in o ma ion collec ed included demog aphic da a, he ype and he se e i y o
clinical p esen a ion be o e diagnosis, du a ion o symp oms and hei cu en sel -expe ienced
pe sis ence. Family his o y o coeliac disease, p esence o coeliac disease-associa ed and o he
signi ican ch onic como bidi ies we e also inqui ed. The la e included pa icula ly
immunological (e.g. as hma, alle gies), ci cula o y (e.g. hype ension, co ona y a e y disease)
and musculoskele al (e.g. a h i is, ib omyalgia) condi ions. Cu en o p e ious smoking and
whe he he coeliac disease diagnosis was made in p ima y, seconda y o e ia y public ca e o
in p i a e ca e we e also inqui ed. The sel -pe cei ed se e i y o clinical p esen a ion was asked
o es ima e he bu den o symp oms. These we e u he classi ied in o 1) no symp oms; 2) mild
symp oms such as occasionally dis u bing gas oin es inal o ex a-in es inal symp oms o a
combina ion o hem and 3) se e e symp oms se iously dis u bing daily li e, such as ecu en
awakenings because o pain o symp oms equi ing acu e inpa ien ca e (17).
Small-bowel mucosal biopsies
Da a on small-bowel mucosal biopsies we e collec ed om he pa ien eco ds. Ou na ional
diagnos ic guidelines o coeliac disease ecommend a leas ou duodenal biopsies o be aken
ou inely om each pa ien upon coeliac disease suspicion and du ing he possible epea

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endoscopy a e one yea on a glu en- ee die . The his ological specimens a e o wa ded o he
hospi als’ pa hology depa men , whe e he se e i y o mucosal damage is e alua ed in
ep esen a i e and co ec ly o ien a ed biopsy cu ings. Demons a ion o duodenal illous
a ophy is equi ed o celiac disease diagnosis. The deg ee o mucosal lesion has o decades
been g aded as pa ial, sub o al o o al illous a ophy, hese co esponding app oxima ely
g ades 3a, 3b and 3c in Ma sh-Obe hube classi ica ion.
Celiac disease se ology
Values o se um endomysial an ibodies (EmA) a diagnosis we e ga he ed om pa ien
eco ds. Fu he mo e, EmA and ansglu aminase 2 an ibodies (TG2ab) we e measu ed in all
pa ien s a he ime o he cu en s udy. Indi ec immuno luo escence was used o EmA
measu emen s as p e iously desc ibed (18). Ti e s 1: ≥5 we e conside ed posi i e and dilu ed
un il nega i e o 1:50, 1:100, 1:200, 1:500, 1:1000, 1:2000 and 1:4000. These we e u he
classi ied as low (1:5-1:200) and high posi i e (1:500-1:4000). TG2ab we e es ed by
comme cial ELISA (QUANTA Li e h- TG IgA, INOVA Diagnos ics, San Diego, CA),
conside ing a cu -o >30.0 U/l posi i e. Co esponding IgG-class an ibodies we e measu ed in
cases o selec i e IgA de iciency.
Adhe ence o he glu en- ee die
P o ision o die a y ad ice a coeliac disease diagnosis was e i ied by pa ien in e iew and
om pa ien eco ds. Cu en long- e m die a y adhe ence was also inqui ed by an expe ienced
s udy nu se/physician wi h an expe ise in coeliac disease and classi ied as “s ic ” (mino
inad e en lapses less han a ew imes a yea ), “occasional lapses” (lapses less o en han once
pe mon h) and “no mal die ”.Long- e m adhe ence was u he es ima ed on he basis o
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coeliac an ibody posi i i y a he ime o he p esen s udy. Alongside adhe ence, pa ien ’s
o e all compe ency in managing he die and he possible use o pu i ied oa s was asked.
Ques ionnai es
Sho Fo m 36 Heal h Su ey (SF-36) and Psychological Gene al Well-Being ques ionnai es
(PGWB) we e used o assess pa ien s’ cu en sel -pe cei ed quali y o li e and gas oin es inal
symp oms a ime o s udy.
SF-36 comp ises 36 sepa a e ques ions, di ided in o eigh sub-dimensions as
ollows; physical unc ioning, ole limi a ions due o physical p oblems, bodily pain, gene al
heal h, i ali y, social unc ioning, ole limi a ions due o emo ional p oblems and men al heal h
(19-23). I ems a e e-sco ed om 0 o 100, highe sco es indica ing be e heal h and quali y o
li e.
PGWB is a well- alida ed and widely used ques ionnai e bo h in coeliac disease
and in gene al (18, 20, 22, 23). The 22 sepa a e i ems can be u he di ided in o six sub-
dimensions measu ing anxie y, dep ession, well-being, sel -con ol, gene al heal h and i ali y.
All i ems use a 6-g ade Like scale wi h highe sco es ep esen ing be e well-being and
quali y o li e.
Gas oin es inal symp oms we e e alua ed by he Gas oin es inal Symp om Ra ing
Scale (GSRS) ques ionnai e (18, 24). I includes 15 sepa a e i ems which can be added oge he
as a o al sco e and u he di ided in o 5 sub-dimensions measu ing abdominal pain, gas o-
esophageal e lux, indiges ion, dia hea and cons ipa ion. The sco ing is based on a 7-g ade
Like scale, highe sco es e lec ing mo e se e e gas oin es inal symp om.
S a is ical analysis
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Con inuous a iables a e p esen ed as medians wi h qua iles o anges. Ca ego ical a iables
a e p esen ed as numbe o subjec s and pe cen ages.S a is ical signi icance in di e ences
be ween pa ien s wi h and wi hou long- e m ollow-up was s udied using Mann-Whi ney es .
Binominal and classi ied a iables we e analyzed using Chi-squa e es . A p- alue <0.05 was
conside ed signi ican in all analyses. All analyses we e ca ied ou using SPSS 20.0 (IBM
Co p. A monk, NY).
Resul s
The median age o he whole s udy coho was 44 ( ange 22-89) yea s and 80% we e women.
The median ollow-up ime o he whole s udy g oup was 10 ( ange 2-38) yea s. Ou o he
677 pa icipan s, 99 (15%) had and 578 (85%) had no ecei ed long- e m ollow-up o coeliac
disease.
Fac o s p edic ing long- e m ollow-up
Exis ence o ollow-up was p edic ed by he p esence o immunological (35% s 24%, p=0.020)
and ci cula o y (20% s. 12%, p=0.010) como bidi ies, whe eas i was less common in subjec s
wi h coexis ing musculoskele al disease (23% s. 34%, p=0.045). Those no belonging o any
a - isk g oup, such as pa ien s wi h ype I diabe es and hose wi h amily his o y o coeliac
disease, we e mo e likely o be wi hou ollow-up (Table 1). In con as , ollow-up was no
p edic ed by o he co-mo bidi ies (da a no shown), gende , si e o diagnosis, se oposi i i y o
celiac au oan ibodies o se e i y o his ological lesion a diagnosis, symp oms in childhood,
clinical p esen a ion o du a ion o symp oms be o e diagnosis, amily isk o coeliac disease
o associa ed condi ion and smoking (Table 1). Also age a diagnosis (median 42 s. 44 yea s,
ange 18-75 s. 18-71 yea s, p = 0.117) o a p esen (median 54 s. 54 yea s, ange 22-81 s
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21-89 yea s, p = 0.919) did no signi ican ly di e be ween pa ien s wi h and wi hou ollow-
up.
When looking in o he sho - e m clinical cha ac e is ic one yea a e diagnosis o
hose pa ien s he da a was a ailable, he e was no signi ican associa ion be ween he p esence
coeliac au oan ibody posi i i y (6.3% s. 15.1%, espec i ely p=0.343; n=95) be ween g oups.
Nei he did he g oups di e in he p e alence o his ological eco e y ( ully no malized 53.0%
s. 60.2%, p=0.378; n=398) in he ollow-up and no- ollow up g oups a e one yea on a glu en-
ee die and exis ence o long- e m ollow.
Long- e m ou comes in pa ien s wi h and wi hou ollow-up
Pa icipan s in bo h ollow-up and no- ollow up g oups had simila die a y adhe ence andabili y
o manage he glu en- ee die , as well as use o pu i ied oa s (Table 2). The e was also no
di e ence be ween he g oups in cu en posi i i y o coeliac au oan ibodies (Table 2) o in
any o he ques ionnai e sco es measu ing heal h- ela ed quali y o li e (SF-36, PGWB) and
gas oin es inal symp oms (GSRS) (Table 3). Howe e , pa ien s wi hou egula long- e m
ollow-up su e ed mo e om cu en sel - epo ed o e all symp oms (Table 2). Despi e his
di e ence in signi icance, he e was a co ela ion be ween sel - epo ed symp oms and hose
e alua ed by GSRS. Ne e heless, pa ien s wi h mo e indiges ion, e lux, cons ipa ion and
abdominal pain in GSRS a e mo e likely o epo mo e se e e sel -pe cei ed symp oms. In
con as , he amoun s o dia hea and cons ipa ion we e no associa ed wi h he se e i y o sel -
pe cei ed symp oms (Da a no shown)
Al oge he 98 % o pa ien s wi h egula long- e m ollow-up wished o i also in
he u u e, and his was also seen in o e 80% o he pa ien s o pa ien s no cu en ly unde
ollow-up (Table 2). Mos o hese pa ien s wished he ollow-up o be o ganized in public
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Figu e legends
Figu e 1: Pa ien s’ opinion on whe e he long- e m ollow-up o celiac disease should be
o ganized, di ided on basis o he lack (No ollow-up) o p esence (Follow-up) o cu en
egula ollow-up.
Figu e 2. Pa ien s’ opinion on who should be in cha ge o he long- e m ollow-up o celiac
disease, di ided on basis o he lack (No ollow-up) o p esence (Follow-up) o cu en
egula ollow-up.