Original Article

United European Gastroenterology Journal

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Case-finding in primary care for coeliac ! Author(s) 2018

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disease: Accuracy and cost-effectiveness DOI: 10.1177/2050640618761700
journals.sagepub.com/home/ueg
of a rapid point-of-care test

Maria Esteve1,2, Mercè Rosinach1,2, Montserrat Llordés3, Judit Calpe3,

Glòria Montserrat3, Mar Pujals1, Abel Cela3, Anna Carrasco1,2,
Montserrat Ibarra1, Pablo Ruiz-Ramirez1, Eva Tristán1,2,
Beatriz Arau1, Carme Ferrer3, Meritxell Mariné1,2, Josepa Ribes4 and
Fernando Fernández-Bañares1,2; on behalf of the Primary
Care Coeliac Disease Study Group (Appendix 1)

Abstract
Background: An on-site, rapid, fingertip, whole-blood point-of-care test (POCT) is attractive for active case-finding of coeliac
disease (CD) in primary care because of its simplicity.
Aim: The aim of this article is to assess the usefulness and cost-effectiveness of adult case-finding using a POCT based on
deamidated gliadin peptide antibodies (IgA/IgG-DGP) in primary care for CD diagnosis.
Methods: A case-finding study for CD was conducted by using an easy-to-use, on-site, whole-blood for IgA/IgG-DGP-based
fingertip POCT compared with tTG2 in 350 individuals. Sample size was calculated based on 0.28% prevalence in the
reference population. Duodenal biopsies for histology, intraepithelial lymphocytes and in situ deposition of tTG2 were
obtained if tTG2 and/or POCT were positive. Accuracy and cost-effectiveness of strategies using serology or POCT were
calculated.
Results: Prevalence of CD was 1.14% (95% CI, 0.3–3.4), almost double what was previously observed. Four patients were
diagnosed with CD. tTG2 was positive in three (0.85%) and POCT in 29 (8.2%). Sensitivity of POCT for CD was 100%,
specificity 93%, PPV 14%, and NPV 100%. POCT followed by duodenal biopsy was the most cost-effective approach in our
setting (standard diagnosis: E13,033/case; POCT þ duodenal biopsy: E7360/case).
Conclusions: A negative POCT allows ruling out CD in primary care, making it suitable for case-finding. POCT strategy was
the most cost effective.

Keywords
Coeliac disease, diagnosis, serology, point-of-care test

Received: 24 December 2017; accepted: 31 January 2018

4
Cancer Plan of the Catalan Government, L’Hospitalet de Llobregat,
Catalonia, Spain; Department of Clinical Sciences, School of Medicine,
1
Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Universitat de Barcelona; Cancer Epidemiology, Bellvitge Biomedical
Barcelona, Spain Research Institute-IDIBELL, L’Hospitalet de Llobregat, Spain
2
Centro de Investigación Biomédica en Red de enfermedades hepáticas y Corresponding author:
digestivas (CIBEREHD), Madrid, Spain Maria Esteve, Department of Gastroenterology, Hospital Universitari Mútua
3
Sud, Oest and Rambla Primary Care Centers, Hospital Universitari Mutua Terrassa, University of Barcelona, Pl. Dr. Robert 5, 08221, Terrassa, Spain.
Terrassa, Barcelona, Spain Email: mariaesteve@mutuaterrassa.cat
2 United European Gastroenterology Journal 0(0)

Key summary
Established knowledge on this subject
. Active case-finding is useful to detect new coeliac disease (CD) patients in primary care.
. Standard serology has been used for CD case-finding.
. A rapid point-of-care test (POCT) based on deamidated gliadin peptide antibodies (immunoglobulin
(Ig)A/IgG-DGP) was shown to be cost effective at pre-endoscopy in patients assessed with anaemia.

What are the significant and/or new findings of this study?

. A point-of-care test (POCT) based on immunoglobulin (Ig)A/IgG deamidated gliadin peptide (DGP) has
never been used as a diagnostic screening tool in a case-finding strategy in primary care, compared to
standard serology.
. A POCT based on IgA/IgG-DGP detection was demonstrated to be suitable for coeliac disease (CD)
screening in primary care identifying all seropositive CD patients while a negative test ruled out CD.
. The economic impact of this strategy has never been evaluated in this setting and showed to be cost
effective compared with the standard approach using serology.

The aims were to assess: (a) the effectiveness of a

Introduction strategy of adult case-finding using a POCT in primary
The prevalence of coeliac disease (CD) using serological care for CD diagnosis compared with serology, and
mass screening is around 0.2% to 1%1–4 but the (b) whether this strategy was cost effective.
number of CD patients diagnosed in clinical practice
is much lower and CD remains under-diagnosed.
Active case-finding is useful in terms of an increase in
Patients and methods
the number of newly detected CD patients in primary A cross-sectional study was carried out in the health
care.5–9 This approach relies on an active role being area of the Hospital Universitari Mutua Terrassa,
played by primary care physicians (PCPs) in selecting from April 2014 to September 2015. Three primary
the individuals to be tested for CD. Standard serology care centres (PCCs) providing health assistance to
(endomysial (AEA) or anti-transglutaminase 2 antibo- 100,000 inhabitants participated in the study. The first
dies (tTG2)) has generally been used for this purpose.10 step consisted in setting up an educational programme
In symptomatic patients the prevalence of CD is higher designed to go beyond updated notions on CD. All 58
than in the general population, ranging from 2% to PCPs of the three PCCs were invited to complete a pre-
10%.5–9 A number of studies have demonstrated that study questionnaire to assess their knowledge about
CD-related complications are reversed by a gluten- CD. Thirty-four of them (58.6%) chose to participate.
free diet (GFD). Thus, case-finding has to be Consecutive adult patients following a gluten-
encouraged.11,12 containing diet with clinical manifestations of CD
An easy-to-use, on-site, whole-blood, deamidated were included (Table 1).
gliadin peptide (DGP)-based, fingertip, point-of-care
test (POCT) provides rapid results,13 making it particu-
larly attractive for use in primary care. The SimtomaxÕ
Study procedures
assay detects CD with a combination of immunoglobu- POCT (SymtomaxÕ ) and tTG2 testing were conducted
lin A (IgA) and immunoglobulin G (IgG) antibodies in parallel on patients meeting the enrolment criteria.
against DGP, allowing the detection of CD in IgA-defi- Individuals with positive POCT and/or tTG2 testing
cient patients. It has been recently demonstrated that were referred for duodenal biopsy to assess histopath-
SimtomaxÕ has a similar accuracy to standard serology ology, intraepithelial lymphocyte (IEL) flow cytometry,
for biopsy-proven CD and is more reliable than and in situ deposition of tTG2 antibodies. A blood
another commercially available POCT based on sample was obtained for confirmatory tTG2 and
tTG2.14 AEA and CD genetic markers (human leucocyte anti-
The costs of different diagnostic approaches applied gen (HLA)-DQ2.5, HLA-DQ2.2, and/or HLA-DQ8).
to large populations may be highly variable, having an Patients with negative POCT and standard serology
impact on the public health system. A recent study but with persistent severe symptoms were also referred
demonstrated that the performance of a POCT for duodenal biopsy (Figure 1). A detailed description
(SimtomaxÕ -IgA/IgG-DGP) pre-endoscopy in patients of these techniques has been previously described in
assessed with anaemia was cost effective.15 detail16–20 (Appendix 2).
Esteve et al. 3

Table 1. Clinical enrolment criteria.

Unexplained anaemia (Hb <11.5 g/dl for women and <12 g/dl for men) or iron deficiency (serum ferritin <20 mg/l)a
Unexplained recurrent abdominal pain with bloating or flatulence (longer than four weeks)a
Unexplained isolated frequent abdominal bloating with flatulence (longer than four weeks)a
‘Irritable bowel syndrome – Rome III criteria’
Chronic or recurrent frequent diarrhoea (longer than four weeks)a
Unexplained weight loss (>10% of weight) (in the last six months)a
Unexplained isolated and persistent hypertransaminasemia (ALT/AST levels two times the normal range for at least six months)b
Thyroid disorders with positive autoantibodies
Autoimmune disorders (insulin-dependent type 1 diabetes, autoimmune hepatitis, Sjögren’s syndrome) with confirmed diagnosis at
secondary- or tertiary-level hospital
Total IgA deficiency (<0.3 mg/l)
Epilepsies resistant to pharmacological treatment or epilepsies with intracranial calcifications
Dermatitis herpetiformis
Unexplained osteopenia (Z score <2 SD)
Down syndrome and Turner syndrome
Family history positive for CD (first- and second-degree relatives)
a
An initial diagnostic work-up was conducted to rule out other, potentially more severe diseases responsible for symptoms such as colon cancer or
inflammatory bowel disease.
b
Viral, metabolic, neoplastic and autoimmune liver diseases were previously ruled out.
ALT: alanine transaminase; AST: aspartate transaminase; CD: coeliac disease; Hb: haemoglobin; IgA: immunoglobulin A.

PCP visit
Evaluation of a
possible CD patient

Nurse visit
Questionnaire (Likert scale)*
POCT reading
Blood extraction
(Standard serology)
n =350 patients

POCT and/or standard POCT and standard

serology (+) serology (–)
n = 29 patients n =321 patients

ENDOSCOPIC UNIT Follow-up:

Blood ananlysis: Yes Persistent symptoms No
Confirmatory standard serology
CD genetic markers
Biopsy:
Histopathological analysis ENDOSCOPIC UNIT Stop follow-up
IEL flow cytometry n =296 patients
CD genetic markers
duodenal anti-tTG2 IgA Biopsy:
Histopathological analysis
IEL flow cytometry
* Likert scales (from 0 to 5) about the duodenal anti-tTG2 IgA
presence of all the enrolment criteria n =25 patients

Figure 1. Flowchart of the study procedures.

CD: coeliac disease; IEL: intraepithelial lymphocyte; IgA: immunoglobulin A; PCP: primary care physician; POCT: point-of-care test;
anti-tTG2: anti-transglutaminase 2 antibodies.
4 United European Gastroenterology Journal 0(0)

POCT seropositive patients, and (c) POCT followed by endos-

IgA anti-DGP, IgG anti-DGP, and total IgA analyses copy in positive patients (Table A.1 in Appendix 3).
are embedded in SimtomaxÕ (Augurix SA,
Switzerland). A detailed description of the development
Statistical analysis
of the device has been previously described.14,15 In the
test, secondary gold-conjugated antibodies bind to the The prevalence of CD in the general adult population
patient’s antibodies to form detectable complexes that detected by serological screening in our area is 0.28%
are captured by the test in lines A and B. The CT is the (1:357).22 CD prevalence in symptomatic patients and
control line. A CD-positive result is indicated by detec- in risk groups is estimated at 3% to 10%.5–9,22,23 If the
tion of both the CT and A lines (Figure 2(a)). IgA prevalence of CD was around 3%, a sample size of 350
deficiency is indicated by absence of the B line. patients would enable us to obtain a 95% confidence
interval (CI) with a precision of 1.8%.24
In order to ascertain whether the ‘educational pro-
Definition of CD
gramme’ had an impact on the number of diagnoses, we
CD was considered in patients with (a) positive IgA/ performed a post hoc analysis to compare the CD cases
IgG tTG2/AEA and duodenal changes of the CD spec- in the study period with those diagnosed during the
trum (from lymphocytic enteritis to atrophy), and previous 18 months and cases diagnosed by the non-
(b) negative IgA/IgG tTG2/AEA but duodenal atrophy participant PCPs in the study period. The Z test was
together with CD cytometric pattern plus positive used to compare proportions. Prevalence of CD (95%
immunofluorescence (IF) staining of tTG2 IgA CI) in different periods was calculated. The diagnostic
deposits.19,21 accuracy of the POCT was assessed by means of sensi-
tivity, specificity, positive predictive value (PPV), and
negative predictive value (NPV), and their 95% CIs,
Calculation of the costs taking CD cases as the gold standard.
Costs of three diagnostic approaches based on POCT or
serology as screening for CD were calculated as follows:
(a) standard diagnosis: serology followed by endoscopy
Ethical considerations
in positive patients, (b) POCT followed by confirmatory This study was conducted according to the ethical
serology in positive POCT and endoscopy in guidelines of the 1975 Declaration of Helsinki.

(a)

Wait 30 seconds 5 droplets

Results in 10´

(b)
A A A A
B B B B
CT CT CT CT

CD negative CD negative CD positive CD positive

Normal IgA IgA deficiency Normal IgA IgA deficiency

Results of the
present study 299 patients 22 patients 28 patients 1 patient

Figure 2. (a) Point-of-care test (SimtomaxÕ ). CT: control line; line A: IgA/IgG deamidated gliadin peptide; line B: total IgA. (b) Results of
the present study.
CD: coeliac disease; IgA: immunoglobulin A; IgG: immunoglobulin G.
Esteve et al. 5

Ethical approval was obtained from the Hospital Accuracy of the DGP antibody POCT compared
Universitari Mutua Terrassa Ethical Committee on 25
February 2014, and all patients signed the informed
with standard serology
consent. The four patients fulfilling the criteria of CD had a
positive POCT, but only three of them had positive
standard serology (tTG2 and AEA). None of the
Results patients with negative POCT fulfilled the diagnostic
A total of 350 patients (266 women; 42.1  0.9 years) criteria of CD. This resulted in a sensitivity of POCT
were consecutively recruited. Of these, 210 patients detecting CD of 100% (95% CI: 40–100%), a specifi-
(60%) had only one clinical manifestation of CD, city of 93% (95% CI: 89–95%), NPV 100% (95% CI:
gastrointestinal symptoms being the most frequent, 98.5–100%) and PPV 14% (95% CI: 4.5–33%).
accounting for more than 60% (Figure A.1 in
Appendix 4). The SimtomaxÕ POCT was positive in
Cost-effectiveness analysis
29 patients (8.2%) (Figure 2(a) and (b)). In 23 cases,
the B line was lacking but IgA deficiency was ruled out The total costs of the three diagnostic strategies, the
in all cases (lowest value ¼ 0.41 g/l). Four of the 29 detailed procedures and the number of cases diagnosed
patients positive for SimtomaxÕ fulfilled the criteria with each diagnostic strategy are detailed in Figure 3.
for CD. Three of them had atrophy and the remaining The use of POCT followed by endoscopy and duodenal
patient had a Marsh 1 lesion. All of them had a com- biopsy in positive patients demonstrated the best cost-
plete cytometric CD pattern, tTG2 IgA duodenal effective result with a total cost of E7360.63 per diag-
deposits and good clinical, serological, and histological nosed case (n ¼ 4).
response to a GFD (Table 2). Of the 25 patients with
false-positive POCT (7.1%, n ¼ 350 patients), 10 (40%) Prevalence of CD in the ‘case-finding’ and control
had some duodenal markers of potential CD. A cohorts. The prevalence of CD in the case-finding
detailed description of these patients is shown in cohort was 1.14% (95% CI: 0.44–2.90), which repre-
Table 3. sents 1:87. This figure is 3.8 times higher than that
In 25 additional patients with both negative POCT observed in the general adult population in the same
and standard serology, a duodenal biopsy was per- geographical area by using a mass screening serological
formed due to persistent symptoms (Figure 1). Five of strategy.21 During the previous 18 months before the
these patients (Table 4) had some duodenal markers of initiation of the case-finding programme (1 October
potential CD. 2012 to 31 March 2014), 1050 serum IgA tTG2 deter-
No differences were found in the percentage of minations were performed and seven patients fulfilled
potential CD markers between patients with negative the diagnostic criteria of CD, disclosing a prevalence of
and positive POCTs, not fulfilling the criteria of CD (10 0.67% (95% CI: 0.33–1.37), which represents 1:149. Six
of 25 patients – 40% – with positive POCT and five of patients had atrophy and one patient had a Marsh 1
25 patients – 20% – with negative POCT; p ¼ 0.216). lesion. In the case-finding study using POCT, CD was

Table 2. Serological, genetic and duodenal markers of the four patients fulfilling the diagnostic criteria of coeliac disease.

POCT Genetics Serology Histology Cytometric pattern tTG2 IgA deposits Outcome

þ HLA-DQ2.5 þ tTG2 > 80 Marsh 3c Coeliac þþþ Good clinical/serological/

AEA > 1/5 TCRgd 58.2 histological response to GFD
CD3– 2.2
þ HLA-DQ2.2 þ tTG2 > 80 Marsh 3c Coeliac þþþ Good clinical/serological/
AEA>1/5 TCRgd 39 histological response to GFD
CD3– 3.5
þ HLA-DQ2.2 þ tTG2 1.0 Marsh 3b Coeliac þþþ Good clinical/histological
AEA– TCRgd 39 response to GFD
CD3– 5.3
þ HLA-DQ2.5 þ tTG2 34 Marsh 1 Coeliac þþþ Good clinical/serological/
AEAþ TCRgd 24.7 histological response to GFD
CD3– 3.3
t
TG2: anti-transglutaminase 2 antibodies; AEA: endomysial antibodies; GFD: gluten-free diet; HLA: human leucocyte antigen; TCR: T cell receptor.
Complete coeliac cytometric pattern: TCRgd > 8.5% and CD3– <10%.
6 United European Gastroenterology Journal 0(0)

Table 3. Genetic and duodenal markers of the 10 patients with positive POCT and negative standard serology (t-TG2, AEA) with duodenal
markers of potential CD.

POCT Genetics Serology Histology Cytometric pattern tTG2 IgA deposits Outcome

þ Negative tTG2 – Marsh 1 Normal þþþ Good clinicala and histological

AEA- TCRgd 0.97 response to GFD
CD3– 6.31
þ Negative tTG2 – Marsh 0 Complete þþþ Good clinicala response to GFD
AEA- TCRgd 12.19
CD3– 3.89
þ HLA-DQ2.2þ tTG2 – Marsh 0 Incomplete – Fructose/sorbitol intolerance
AEA– TCRgd 10.11
CD3– 25.3
þ HLA-DQ2.2þ tTG2 – Marsh 0 Incomplete – Fructose/sorbitol intolerance
AEA– TCRgd 16.08
CD3– 24.63
þ HLA-DQ2.5þ tTG2 – Marsh 0 Incomplete – Erosive gastritis
AEA– TCRgd 28.49 H. pylori þ
CD3– 9.76
þ HLA-DQ8þ tTG2 – Marsh 0 Complete – Non-response to GFD
AEA– TCRgd 10.14 Irritable bowel syndrome
CD3– 3.7
þ HLA-DQ8þ tTG2 – Marsh 0 Normal þþ Crohn’s disease of the
AEA– TCRgd 3.34 small bowel
CD3– 15.89
þ HLA-DQ2.5þ tTG2 – Marsh 1 Normal þþ Bile acid malabsorption
AEA– TCRgd 5.61
CD3– 13.74
þ Negative tTG2 – Marsh 0 Normal þþ Fructose/sorbitol/lactose
AEA– TCRgd 5.57 intolerance
CD3– 29
þ HLA-DQ2.5þ tTG2 – Marsh 0 Normal þþ Lactose intolerance
AEA– TCRgd 4.24
CD3– 20.89
tAEA: endomysial antibodies; CD: coeliac disease; GFD: gluten-free diet; HLA: human leucocyte antigen; POCT: point-of-care test; TCR: T cell receptor;
TG2: anti-transglutaminase 2 antibodies.
Complete coeliac cytometric pattern: TCRgd > 8.5% and CD3–<10.
Incomplete coeliac cytometric pattern: selective increase of TCRgd > 8.5%.
a
Chronic relapsing diarrhoea.

diagnosed 1.7 times more often than in the previous standard serology for CD diagnosis. However, the
period of time; however, differences were not statistic- low prevalence of CD in this case-finding cohort
ally significant. means that the difference in favour of POCT was due
In addition, 24 PCPs that did not participate in the only to a single case diagnosed with POCT and not
study requested 624 standard serology tests to rule out with standard serology. Thus, it can be considered
CD during the study period. Six out of the 624 patients that both serum IgA tTG2 and DGP-based POCTs
fulfilled the diagnostic criteria of CD (two with atro- are good diagnostic tools for CD screening in primary
phy, four with Marsh 1). The prevalence of CD in this care. Similar diagnostic accuracy of both tests was
cohort attended by PCPs not participating in the case- demonstrated in the pre-endoscopy setting.14,15
finding study was 0.96% (95% CI: 0.44–2.08), repre- The low PPV (14%) of the POCT SimtomaxÕ was
senting 1:104. due to the detection of 7% false-positive patients for
both CD diagnosis and IgA deficiency, suggesting that
the cut-off for IgA/IgG-DGP detection is very low,
Discussion
ensuring that no cases of CD are missed. To ascertain
The present study showed better diagnostic accuracy whether this false-positive IgA/IgG-DGP detected by
for a POCT based on IgA/IgG-DGP detection than POCT could reflect a potential CD, the duodenal
Esteve et al. 7

Table 4. Genetic and duodenal markers of potential CD of the five patients with negative POCT and negative standard serology (t-TG2,
AEA).

POCT Genetics Serology Histology Cytometric pattern tTG2 IgA deposits Outcome

– HLA-DQ2.5þ tTG2 – Marsh 1 Complete – Good clinicala/histological response to GFD

AEA– TCRgd 14.57
CD3– 7.5
– HLA-DQ8þ tTG2 – Marsh 1 Complete – Good clinicalb/histological response to GFD
HLA-DQ2.2þ AEA- TCRgd 35.11
CD3– 1.56
– Negative tTG2 – Marsh 0 Incomplete – Lactose intolerance
AEA– TCRgd 11.55
CD3– 10.43
– HLA-DQ2.5þ tTG2 – Marsh 0 Normal þþ Non-response to GFD Fructose/
HLA-DQ8þ AEA– TCRgd 3.77 sorbitol intolerance
CD3– 29.49
– HLA-DQ2.5þ tTG2 – Marsh 0 Normal þþ Non-response to GFD
AEA– TCRgd 2.53 Bile acid malabsorption
CD3– 33.23
AEA: endomysial antibodies; CD: coeliac disease; GFD: gluten-free diet; HLA: human leucocyte antigen; POCT: point-of-care test; TCR: T cell receptor; tTG2:
anti-transglutaminase 2 antibodies.
Complete coeliac cytometric pattern: TCRgd > 8.5% and CD3– <10.
Incomplete coeliac cytometric pattern: selective increase of TCRgd > 8.5%.
a
Relapsing diarrhoea. bRelapsing diarrhoea þ iron-deficient anaemia.

STANDARD DIAGNOSIS POCT+t-TG2 + BIOPSY POCT + BIOPSY

t-TG2 + BIOPSY

First visit physician First visit physician First visit physician

(n =350) (n =350) (n =350)

Blood analysis Simtomax ® Simtomax ®

(n=350) (n =350) (n =350)

Second visit physician Blood analysis Endoscopy+biopsy

(n=350) (n =29) (n =29)

Endoscopy+biopsy Second visit physician Second visit physician

(n=3) (n=29) (n =29)

Third visit physician Endoscopy + biopsy Blood analysis

(n=3) (n =3) (n =4)

Third visit physician Third visit physician

(n =3) (n =4)

€13,033.33/case €8,929.84/case €7,360.63/case

Figure 3. Total costs and detailed procedures of the three diagnostic strategies.
anti-tTG2: anti-transglutaminase 2 antibodies; POCT: point-of-care test. Tariffs of the National Health Services of the Catalan Government
are provided in Table A.1 (Appendix 3).
8 United European Gastroenterology Journal 0(0)

biopsy was analysed not only for histopathology but The 0.96% prevalence of CD in the cohort attended
also for IEL subsets (T cell receptor (TCR) gdþ and by PCPs not participating in the case-finding study
CD3–) and tTG2 IgA deposits.19 Though the majority (using tTG2 for screening) was intermediate between
of false-positive patients had normal duodenal mucosa, those found in the POCT study (1.14%) and in the
40% of them had duodenal markers of potential CD. previous period (0.67%). Therefore, it seems that
However, similar results were obtained in a subgroup of PCPs’ declining participation was also influenced by
25 patients with negative POCTs and persistent symp- the ‘educational programme’ and by the active CD
toms in whom a duodenal biopsy was performed. findings developed by their colleagues. A similar posi-
Therefore, we realized that the majority of these tive influence of an active CD case-finding environment
patients did not have CD. was previously demonstrated by an Italian case-finding
It is remarkable that some symptomatic patients study in primary care.6
may have a seronegative ‘coeliac-lite’ disease and may The prevalence of CD in other case-finding studies
benefit from a GFD.25 This was the case for two using standard serology for CD screening ranged from
patients in the POCT-negative and two more in the 2% to 10%, a figure higher than in our study. However,
POCT-positive group showing a good response to a in these geographical areas the prevalence of CD in the
GFD. In seronegative patients with a doubtful diagno- general population was 1:100, which is clearly higher
sis of CD, the performance of a duodenal biopsy is than that reported in our country.5–9,16 Thus, the preva-
mandatory. In these cases, the presence of duodenal lence of CD in high-risk groups essentially depends on
CD markers together with positive genetic predispos- the prevalence of CD in a specific geographical area, as
ition and histological lesion of the CD spectrum (either well as on the type of risk group included. In this sense,
lymphocytic enteritis or atrophy) could be of help in first-degree relatives have the highest risk of CD10,23
deciding whether to start a GFD.19,25 Regardless, while patients with only one digestive symptom have
POCT based on IgA/IgG-DGP has no more accuracy the lowest CD risk.9 In our study, the most frequent
for ‘coeliac-lite’ diagnosis than IgA tTG2. inclusion criteria were digestive symptoms, which
The strategy of using the SimtomaxÕ POCT for CD accounted for 60% of the total cohort; the majority
screening was more cost effective than a strategy based of them had only one digestive symptom.
on tTG2 according to the tariffs of the National Health The present study has some limitations. The most
Services of the Catalan government. The immediate important is the use of tTGA as the main parameter
referral of the patients with positive POCT to the for CD diagnosis. The availability of duodenal histo-
Endoscopic Unit for duodenal biopsy allowed us to pathology in all the patients would be desirable in
reduce the time delay from the visit of the PCP to future studies. This would provide valuable informa-
CD diagnosis. In addition, the POCT strategy allowed tion deeper in the CD iceberg in seronegative patients.
us to reduce the cost per patient to almost half com- Another limitation is the number of included patients,
pared with the cost using standard serology, even which precluded establishing firm conclusions regard-
though 7% more patients in the POCT group than in ing the impact of the ‘educational programme’ on the
the standard diagnosis had to undergo duodenal number of new CD diagnoses between periods. At any
biopsy. However, it should be taken into account that rate, a POCT detection was demonstrated to be suitable
prices may vary among countries, organisation of for CD screening in primary care. POCT identified all
healthcare institutions and/or insurance companies. seropositive patients while a negative test ruled out CD.
The study also demonstrated that the case-finding It is easy to use, allows early diagnosis, and is cost
strategy using a IgA/IgG-DGP POCT in patients at effective compared with the standard approach using
risk for CD is suitable for CD diagnosis in primary serology.
care since it allowed for the detection of four times as
many cases of CD (1:87 (1.14%)) than that found in the Acknowledgements
general population of the same area (1:357 (0.28%)).22 ME is the guarantor of this work.
The post hoc analysis to assess the impact of the Author contributions are as follows: ME, MR and FFB:
‘educational programme’ on the number of diagnoses design of the study, coordination, acquisition of data, statis-
showed that PCPs participating in the POCT study tical analysis and interpretation of data, manuscript writing,
diagnosed 1.7 more CD cases than those diagnosed in critical revision and approval of the final draft. MLl, JC, GM,
the previous 18-month period. Differences were not MP, AC, AC, MI, PRR, ET, BA, CF, MM and JR: acquisi-
statistically significant but the sample size was not cal- tion of data and approval of the final draft.
culated to find differences between the two periods. In
fact, taking into account the CD prevalence in our geo- Declaration of conflicts of interest
graphical area, more than 2000 patients per group ME has received funding from Tillotts Pharma Spain S.L.U.
would be needed to find differences. The other authors have nothing to declare.
Esteve et al. 9

Funding 13. Mooney PD, Kurien M and Sanders DS. Simtomax, a

This work was supported by a research grant from Tillotts novel point of care test for coeliac disease. Expert Opin
Pharma Spain S.L.U., which had no input in the study design, Med Diagn 2013; 7: 645–651.
access to the study data, or interpretation of results. 14. Mooney PD, Wong SH, Johnston AJ, et al. Increased
detection of celiac disease with measurement of deami-
dated gliadin peptide antibody before endoscopy. Clin
Informed consent Gastroenterol Hepatol 2015; 13: 1278–1284.
15. Lau MS, Mooney P, White W, et al. Pre-endoscopy point
All patients signed informed consent to participate in this
of care test (Simtomax- IgA/IgG-deamidated gliadin pep-
study.
tide) for coeliac disease in iron deficiency anaemia:
Diagnostic accuracy and a cost saving economic model.
Ethics approval BMC Gastroenterol 2016; 16: 115.
16. Rostami K, Kerckhaert JP6, Tiemessen R, et al. The rela-
This study was conducted according to the ethical guidelines
tionship between anti-endomysium antibodies and villous
of the 1975 Declaration of Helsinki. Ethical approval was
atrophy in coeliac disease using both monkey and human
obtained from the Hospital Universitari Mutua Terrassa
substrate. Eur J Gastroenterol Hepatol 1999; 11: 439–442.
Ethical Committee on 25 February 2014.
17. Walker MM and Murray JA. An update in the diagnosis
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Gastroenterol Hepatol 2011; 9: 118–123. Primary Care Coeliac Disease Study Group
12. Evans KE, Hadjivassiliou M and Sanders DS. Is it time
to screen for adult coeliac disease? Eur J Gastroenterol Francisco Javier Avilésa, Javier Martı́neza, Nuria
Hepatol 2011; 23: 833–838. Portaa, Mercé Villaróa, Immaculada Vazqueza,
10 United European Gastroenterology Journal 0(0)

Mariona Sanmartı́a, Gemma Bonfilla, Elba Zurdoa, microscope. Both the complete cytometric pattern and
Encarna Romeroa, Alba Rodrı́gueza, Sandra the sum of an incomplete cytometric pattern with posi-
Sabaricha, Judith Novoa, Montserrat Rocaa, Maite tive tTG2 IgA deposits have 100% specificity for CD
Noguéa, Laura Lopez Canoa, Miriam Pozoa, Mireia diagnosis.19
Martı́nez Ortegab, Marı́a Diez-Caballerob, Marı́a José
Lorenzob, Luis O Pastranab, Dámaris Gascónb, Jorge CD genetic markers. Genomic DNA from whole blood
Hidalgob, Maria Concepció Rocab, Gloria Carbonellb, was purified using a commercial QiampDNABlood
Silvia Cárcelesc, Olga Casadoc, Mercè Custalc, Eva Mini kit (Qiagen, Düsseldorf, Germany). A commercial
Dı́az-Lópezc, Inma Falcónc, Silvia Giménez-Magañac, reverse hybridisation kit for the detection of CD het-
Lidia González-Gilc, Rosa Larac, Jesús López-Vivóc, erodimers HLA-DQ2 (A1*0501/*0505, B1*0201/
Daniel Pañartc, Noemı́ Quesadac, Angel Francoc and *0202) and HLA-DQ8 (A1*0301, B1*0302) was used
Montserrat Garridoc. (GenID, GmbH, Strasburg, Germany). HLA-DQ2/
a
Sud Primary Care Center. DQ8 haplotypes are present in 97% of CD patients in
b
Oest Primary Care Center. our geographical area.20 Positive coeliac genetics indi-
c
Rambla Primary Care Center. cates the presence of HLA-DQ2.5, HLA-DQ2.2 and/ or
HLA-DQ8.

Appendix 2
Appendix 3
Analytical methods
Table A.1 Tariffs of the National Health Services
Serology. Serology was analysed in the laboratory of the
of the Catalan government
health area (CATLAB, Terrassa). IgA tTG2 (or IgG
tTG2 in IgA deficiency) were assessed by enzyme-
linked immunosorbent assay detection (kit EliA
CelikeyTM, Phadia AB, Freiburg, Germany). AEA Primary care physician visit 41.00 E
was performed by indirect immunofluorescence assay Blood analysis (total) 27,88 E
in serum samples at 1:5 dilution (commercial sections - IgA tTG2 12.43 E
of monkey distal oesophagus; BioMedical Diagnostics, - IgA 6.45 E
Marne-la-Vallée, France) in all patients with positive
- Blood collection (nurse þ expendables) 9.00 E
POCT and/or positive tTG2.
AEA (confirmatory serology) 13.88 E
Histopathological assessment. Four endoscopic biopsies Esophagogastroduodenoscopy þ biopsy þ sedationa 130.3 E
from the duodenum were processed with hematoxylin/ Histopathological analysis (2 to 10 paraffin blocks) 43.00 E
eosin staining and CD3 immunophenotyping. POCT procedure 28.00 E
Histopathological findings were classified following the - SimtomaxÕ device 20.00E
revised Marsh criteria.16 Lymphocytic enteritis (Marsh - Nurse reading 8.00 E
1) was defined as 25 IEL per 100 epithelial nuclei.17,18
tAEA: endomysial antibodies; IgA: immunoglobulin A; IgG: immunoglobu-
lin G; POCT: point-of-care test; TCR: Toll cell receptor;TG2: anti-transgluta-
Flow cytometry and intestinal deposits of anti-TG2 IgA minase 2 antibodies.
antibodies. A description of both techniques has pre- National Health Services of the Catalan government (DOGC núm. 6079
viously been presented in detail by our research 2-3-2012. Review 2013-Resolution SLT/353/2013).
a
Recommended tariffs of the Official College of Physicians of Barcelona.
group.19 The incomplete CD pattern consists of a selec-
tive increase of TCRgdþ >8.5%. IgA tTG2 deposits
were analysed with IF staining using a confocal
Esteve et al. 11

Appendix 4

Figure A1. Frequency of the clinical enrollment criteria.