Celiac disease (CD) affects the small intestine, leading to a progressive disappearance of intestinal villi, and can be found in association with several other autoimmune and inflammatory conditions. The main objective of this study was to determine the prevalence and the clinical significance of anti-transglutaminase and anti-endomysium antibodies in patients diagnosed with early rheumatoid arthritis (RA) and spondyloarthritis (SpA).
Methods
We measured anti-transglutaminase and anti-endomysium antibodies in biobanked serum samples at inclusion in two French prospective multicenter cohorts of patients with suspected early rheumatoid arthritis (ESPOIR, n = 713) and spondyloarthritis (DESIR, n = 709). Results were compared with the clinical, laboratory, and radiographic findings obtained in patients during a 10-year follow-up period.
Results
In the DESIR cohort, anti-transglutaminase antibodies were evidenced at low levels (less than three times the upper limit of normal) in 2/709 (0.42%) patients and anti-endomysium antibodies in 0/709 (0%). In the ESPOIR cohort, anti-transglutaminase antibodies were evidenced in 6/713 (0.84%) patients and anti-endomysium antibodies in 1/713 (0.14%). Only the latter patient was confirmed to have celiac disease. Interestingly, this patient was ultimately diagnosed with Sjögren’s disease, an autoimmune condition known to be associated with an increased risk of celiac disease.
Conclusion
The very low identified prevalence of anti-transglutaminase and anti-endomysium antibodies suggests a negligible risk of celiac disease in patients with early-stage RA or SpA, which are among the most common inflammatory rheumatic conditions. Consequently, routine screening for celiac disease via these antibodies in patients presenting with early inflammatory rheumatic conditions should not be performed except in case of clinical suspicion of celiac disease.
Key Summary Points
Why carry out this study?
In Western countries, an increasing number of patients with rheumatoid arthritis or spondyloarthritis are inclined to try a gluten-free diet for several months, often influenced by information encountered on the internet and other media sources.
This trend persists despite the lack of concrete evidence supporting the efficacy of such dietary changes for individuals without a confirmed diagnosis of celiac disease.
Patients with rheumatoid arthritis or spondyloarthritis need data about the relevance of a systematic screening of celiac disease.
What was learned from this study?
Anti-transglutaminase immunoglobulin A antibodies were detected in only 0.84% of patients with rheumatoid arthritis and 0.42% of patients with spondyloarthritis.
Systematic screening of celiac disease antibodies is not recommended in patients with inflammatory rheumatic conditions without clinical suspicion.
Celiac disease screening in patients with inflammatory rheumatic conditions should focus on symptomatic patients and those with additional risk factors.
Introduction
Rheumatoid arthritis (RA) [1] and spondyloarthritis (SpA) [2] are inflammatory chronic diseases affecting nearly 1% of the global population [3]. RA impacts approximately 0.5% to 1% of individuals worldwide, primarily women aged 40 to 60 [1]. This disease is characterized by symmetrical polyarthritis, synovial inflammation, progressive destruction of articular cartilage and bone, systemic inflammation, and specific autoantibodies like rheumatoid factor and anti-citrullinated protein antibodies. SpA affects around 0.5% of the adult population [4], with a male predominance and symptoms typically manifesting between ages 20 and 40. SpA is characterized by axial skeleton inflammation, peripheral arthritis, enthesitis, dactylitis, along with possible extra-articular features like uveitis. The strong association with HLA-B27 indicates a significant immunogenetic predisposition. Both RA and SpA may coexist with other immune-related disorders, such as Sjögren’s syndrome [5]; or inflammatory bowel disease (IBD) and psoriasis [2], respectively.
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Celiac disease (CD) [6], affecting about 1% of the population, is a chronic immune-mediated intestinal disorder triggered by dietary gluten leading to villous atrophy and malabsorption. It presents with a wide range of symptoms, from gastrointestinal manifestations like diarrhea and bloating to systemic effects including anemia, or osteoporosis, often due to nutrient deficiencies. Some patients may present atypical forms of CD leading to non-specific manifestations such as arthritis. These atypical forms are often misdiagnosed and found in adults [6]. Additionally, CD is associated with an increased risk of numerous autoimmune diseases such as type 1 diabetes, thyroiditis, vitiligo, or autoimmune liver diseases [6]. Serological tests, particularly anti-transglutaminase immunoglobobulin A (IgA) autoantibodies and anti-endomysium IgA autoantibodies, play a crucial role in the initial non-invasive screening. Indeed, these serological markers, owing to their high sensitivity, are good preliminary assessments for diagnosis, while intestinal biopsy remains the definitive diagnostic method especially in adults [6].
Emerging data suggests a varied prevalence of CD among individuals with inflammatory rheumatic diseases. In juvenile idiopathic arthritis, the prevalence of CD has been estimated at 0.4% in Germany [7] and 2.4% in Italy [8]. Similarly, in adults, 3% of patients with inflammatory rheumatism due to systemic autoimmune diseases in Italy have anti-transglutaminase antibodies [9]. Regarding SpA, only scarce data are available and are contradictory [10, 11], and no reports have been made yet regarding RA. The prevalence and the significance of anti-transglutaminase and anti-endomysium IgA testing in patients with these inflammatory rheumatic conditions at early stages thus remain unclear, despite shared autoimmune backgrounds of these conditions and the potential overlap in clinical manifestations [12].
In France, as well as in other Western countries, an increasing number of patients with RA or SpA are inclined to experiment with a gluten-free diet for several months, often influenced by information encountered on the internet and other media sources. This trend persists despite the lack of concrete evidence supporting the efficacy of such dietary changes for individuals without a confirmed diagnosis of CD [13].
Aligned with these observations, this study aims to investigate the prevalence and clinical significance of CD-specific antibodies in patients with suspected early forms of RA and SpA from the DESIR and ESPOIR cohorts, respectively.
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Methods
ESPOIR Cohort
The ESPOIR cohort (NCT03666091) is a French multicenter prospective study on early arthritis consistent with RA, which enrolled 813 adults aged 18 to 70 suspected of having early RA for inclusion across 14 centers between 2003 and 2005. The main inclusion criteria were at least two inflammatory joints for at least 6 weeks but no more than 6 months, a definite or probable clinical diagnosis of RA, and no previous DMARD or glucocorticoid therapy. Exclusion was based on definitive diagnoses of other inflammatory or connective-tissue diseases. The cohort followed standard care without specific treatment protocols, with visits every 6 months for 2 years, then annually. A detailed description of the study protocol is available on the ESPOIR website (https://www.lacohorteespoir.fr). Baseline assessments notably included rheumatoid factor (RF) and anti-CCP2 antibodies, and the Disease Activity Score 28 (DAS28) was completed at each visit. A decade later, assessments were repeated along with radiographs for van der Heijde-modified total Sharp score (mTSS) analysis. The main outcomes of this cohort after 10 years are available elsewhere [14].
DESIR Cohort
The DESIR cohort is a French prospective multicenter cohort of patients with early arthritis consistent with SpA (NCT01648907). Individuals aged 18 to 50 experiencing inflammatory back pain lasting between 3 months and 3 years were included in 25 centers in France on the basis of a rheumatologist’s opinion. Between December 2007 and April 2010, 709 patients were included. Throughout the initial 2 years, all willing patients were retained within the study. From the second year onwards and up until 10 years, patients could be withdrawn if subsequent evaluations led investigators to attribute symptoms to diagnoses other than SpA. A detailed description of the study protocol is available on the DESIR website (http://www.lacohortedesir.fr/desir-in-english/). Among the main collected parameters, ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score using C-Reactive Protein), HLA-B27 status, BASFI (Bath Ankylosing Spondylitis Functional Index), presence of sacroiliitis, and axial SpA score were assessed at inclusion. The main outcomes of this cohort after 10 years are also available elsewhere [15] and access to data up to 5 years was obtained for this study.
Ethical Approval
The ESPOIR cohort study protocol was approved by the local ethics committee (No. 020307). All patients gave their signed informed consent before inclusion. The DESIR cohort study protocol was approved by the local ethics committee (EUDRACT#2007-A00608-45). All patients gave their signed informed consent before inclusion. Both studies (ESPOIR and DESIR) were performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
Laboratory Measurements
Anti-endomysium IgA autoantibodies were assessed by indirect immunofluorescence on monkey esophagus using INOVA Werfen reagents. Results were systematically assessed by two readers.
Anti-transglutaminase IgA autoantibodies were determined using a chemiluminescent assay on the Isys-IDS immune-analyzer. The cutoff was set at 10 AU/ml based on the manufacturer’s recommendations and internal validation. The sensitivity of anti-transglutaminase IgA is extremely high (over 95%), and its diagnostic accuracy is increased by the concomitant presence of anti-endomysium IgA autoantibodies [6].
In case of an anti-transglutaminase IgA value under 0.8 IU/ml, a total IgA deficiency may be suspected in patients. Such cases were further explored by immunoturbidimetry on the Atellica CH 930 (Siemens Healthineers, Erlangen, Germany) according to the manufacturer’s instructions. All tests were performed using samples from the first visit (inclusion) of the DESIR cohort and from the second visit (6 months after inclusion) of the ESPOIR cohort.
Statistical Analysis
We planned to evaluate the prevalence of anti-transglutaminase and endomysium antibodies (after verification of IGA deficiency) in patients with early inflammatory rheumatism (ESPOIR cohort and DESIR cohort) and to do exploratory analysis to compare patients with and without antibodies in each cohort using chi-square and Mann–Whitney tests. The sample size was calculated on the basis of the confidence interval of the prevalence. For an expected threshold of 2%, with 800 patients included, the accuracy is of the order of 1%.
Results
Characteristics and Serological Markers of CD in Patients from the ESPOIR Cohort
In the ESPOIR cohort, sera were available for 713/813 patients. Anti-transglutaminase antibodies were evidenced in 6/713 (0.84%) patients and anti-endomysium antibodies in 1/713 (0.14%). Anti-transglutaminase IgA antibodies ranged from 10.5 to 11.6 AU/ml (normal range, < 10 AU/ml) in five patients and one result was over 200 AU/ml. Anti-endomysium IgA antibodies were positive only in the latter case (Fig. 1). Two patients had anti-transglutaminase IgA titers under 0.8 IU/ml which prompted a total IgA measurement. For both patients, a complete IgA deficiency was confirmed. Figure 2b shows the values of antibodies and the Table 1 characteristics of patients with antibodies.
Fig. 1
Comparison of anti-endomysium autoantibody fluorescence: negative test result (a) and positive test result in a patient from the ESPOIR cohort (b). Anti-endomysium IgA were assessed by indirect immunofluorescence on monkey esophagus using INOVA Werfen reagents. The patient testing positive (b) exhibits a continuous, linear fluorescence that distinctly outlines the periphery of the smooth muscle fibers, revealing a typical “network” pattern within the muscularis mucosa, a hallmark of anti-endomysium antibody positivity. IgA immunoglobobulin A
Fig. 2
Anti-transglutaminase IgA autoantibody measurements in patients from the a ESPOIR and b DESIR cohorts. IgA immunoglobobulin A. Dotted line at 10 AU/ml indicates the cutoff value for positivity
Table 1
Main characteristics of patients with positive antibodies in the ESPOIR and DESIR cohorts
No.
Characteristics at inclusion
CD serological and clinical signs
Outcome at 5 years
Age range
Sex
Concomitant disease
DAS in RA
or ASDAS-CRP in SpA
Sharp score in RA or BASFI in SpA
ACR/EULAR RA criteria or axial SpA criteria
RF/anti-CCP in RA or HLA B27 status in Spa
Anti-transglutaminase IgA (AU/ml)
Anti-endomysium IgA
Signs and/or diagnosis of CD
Signs and/or diagnosis of CD
1a
50–55
M
No
1.45
6.7
+
+/+
11.4
−
No
No
2a
45–50
F
No
6.85
1.3
+
−/+
11.6
−
No
No
3a
30–35
F
No
6.98
0
+
+/+
10.3
−
No
No
4a
55–60
F
No
5.06
0
+
+/+
11.1
−
No
No
5a
30–35
F
Sjögren’s disease
5.65
UNK
+
−/−
> 200
+
No
Yes
6a
60–65
F
No
4.54
UNK
+
−/−
10.5
−
No
UNK
7b
25–30
M
No
2.79
33
+
+
16.5
−
No
No
8b
40–45
F
No
2.82
13
−
−
26.6
−
No
No
ACR/EULAR European League Against Rheumatism/American College of Rheumatology, ASDAS Ankylosing Spondylitis Disease Activity Score using C-Reactive Protein, BASFI Bath Ankylosing Spondylitis Functional Index, CD celiac disease, DAS Disease Activity Score, RA rheumatoid arthritis, SpA spondyloarthritis, UNK unknown
aPatients with RA from the ESPOIR cohort
bPatients with SpA from the DESIR cohort
×
×
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Only the one patient with anti-transglutaminase IgA over 200 AU/ml and positive anti-endomysium IgA antibodies had a diagnosis of CD 5 years after inclusion. This patient had a seronegative polyarthritis considered at inclusion as RA associated with Sjögren’s disease. The definitive CD diagnosis was confirmed after a biopsy prompted by the occurrence of a small bowel cancer.
Characteristics and Serological Markers of CD in Patients from the DESIR Cohort
In the DESIR cohort, sera were available for 702/709 patients. Anti-transglutaminase IgA antibodies were evidenced at low levels in 2/702 (0.42%) patients and anti-endomysium IgA antibodies in 0/708 (i.e., none). Figure 2a shows the values of antibodies and Table 1 shows the characteristics of the two patients with positive antibodies. Presence of antibodies was just above the cutoff, only for anti-transglutaminase IgA, and not ascribed to digestive symptoms. After 5 years of follow-up, no CD was retrieved in the entire DESIR cohort. Five patients also presented an anti-Tg IgA titer below 0.8 AU/ml, and were confirmed to have a complete IgA deficiency.
Discussion
The prevalence of anti-transglutaminase antibodies was 0.84% in the ESPOIR cohort and 0.42% in the DESIR cohort. These are below the majority of rates (between 0.4% and 3%) seen in other inflammatory rheumatic conditions in the literature [7‐10]. Given that CD affects approximately 1% of the general population [6], the observed rates suggest at least a similar or even a lower prevalence of CD among our cohorts than initially expected. A significant proportion of gastrointestinal symptoms was nevertheless observed among the cohort participants (8.5% in the ESPOIR cohort and 10% in the DESIR cohort) [14, 15], most often due to IBD for patients with SpA, indicating that CD is unlikely to be the underlying cause of gastrointestinal symptoms occurring in patients with SpA or RA.
Among the seven patients presenting positive anti-transglutaminase IgA autoantibodies, only one patient was confirmed with the concomitant anti-endomysium IgA autoantibody test, and clinically with CD. Anti-transglutaminase IgA are known for their increased sensitivity and slightly lower specificity as compared to anti-endomysium IgA, which can explain these low false positives [6].
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Only one female patient from the ESPOIR cohort was discovered to have highly positive anti-transglutaminase IgA. She was diagnosed with definite CD 5 years after her inclusion in the cohort. Initially diagnosed with RA and associated Sjögren’s disease, the patient showed no apparent symptoms of CD for several years. It was the discovery of a small bowel tumor 5 years post enrollment that led to an incidental yet confirmed diagnosis of CD following the biopsy. This case underscores the challenges of suspecting CD in patients already diagnosed with inflammatory rheumatic diseases, particularly in the absence of gastrointestinal symptoms. Notably, this patient was presenting Sjögren’s disease associated with RA, and an increased risk of CD has already been described in Sjögren’s disease [5]. In this individual, the Sjögren condition may have influenced the development of CD. This case may suggest a need for targeted surveillance only in patients with additional CD risk factors such as Sjögren’s disease.
The lower-than-expected antibody positivity rate within these cohorts suggests a lack of association between early inflammatory rheumatic diseases in adults and the presence of CD antibodies. Screening for CD should then be reserved for patients presenting with symptomatic evidence of the disease or with an additional risk factor for CD. Similarly, a gluten-free diet is therefore not universally recommended for patients with early inflammatory rheumatism [13]. This highlights the importance of symptom-driven diagnostics over broad-spectrum screening in the management of patients with rheumatic conditions.
While this study provides valuable insights into the prevalence of CD and related autoantibodies in patients with early inflammatory rheumatic diseases, it has several limitations. There is a risk of incomplete clinical information, potentially leading to missed CD cases. We attempted to mitigate this through data interrogation from clinicians involved in the DESIR and ESPOIR protocols. Additionally, the adherence to a gluten-free diet by patients was not directly assessed, potentially causing false-negative autoantibody results. However, no patients at the start of ESPOIR and DESIR were known to have CD, and CD was not a criterion for exclusion. Lastly, as an observational study, the generalization of our findings may be limited to similar cohorts and may not extend to broader populations with differing demographic and healthcare characteristics. Despite these constraints, this study provides important insights into CD autoantibody prevalence in early inflammatory rheumatic diseases.
Conclusions
This study identifies the lack of association between anti-transglutaminase and anti-endomysium antibodies and the onset of early inflammatory rheumatic conditions such as RA or SpA. Consequently, systematic screening for CD in patients with these conditions is not recommended.
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Acknowledgements
We thank the participants of the study.
Acknowledgements ESPOIR: An unrestricted grant from Merck Sharp and Dohme (MSD) was allocated for the first 5 years. Two additional grants from INSERM were obtained to support part of the biological database. The French Society of Rheumatology, Pfizer, Abbvie, Lilly, and more recently Fresenius and Galapagos also supported the ESPOIR cohort study. We also wish to thank Nathalie Rincheval (Montpellier) who did expert monitoring and data management and all the investigators who recruited and followed the patients (F. Berenbaum, Paris-Saint Antoine, MC. Boissier, Paris-Bobigny, A. Cantagrel, Toulouse, B. Combe , Montpellier, M. Dougados, Paris-Cochin, P. Fardellone and P. Boumier Amiens, B. Fautrel, Paris-La Pitié, RM. Flipo, Lille , Ph. Goupille, Tours, F. Liote, Paris- Lariboisière, O. Vittecoq, Rouen, X. Mariette, Paris Bicetre, P. Dieude, Paris Bichat, A. Saraux, Brest, T. Schaeverbeke, Bordeaux, J. Sibilia, Strasbourg). One biological resources centre (Sarah Tubiana, Paris-Bichat) was in charge of centralising and managing biological data collection.
Acknowledgements DESIR: The DESIR cohort is conducted with Assistance Publique-Hopitaux de Paris (AP-HP, Paris France) as the sponsor and under the umbrella of the French Society of Rheumatology. The DESIR cohort is run with the support of unrestricted grants from (in order of decreasing support) Pfizer France, Biogen, AbbVie, UCB, Lilly, Galapagos, Novartis, MSD, Fresenius and Celltrion HealthCare. We thank the Clinical Research Unit Paris Centre (AP-HP, Paris France), and the Institut national de la sante et de la recherche medicale (Inserm). We also thank the investigators: Pr Maxime Dougados, Pr André Kahan, Dr Julien Wipff and Dr Anna Molto (Paris-Cochin), Pr Olivier Meyer, Pr Philippe Dieudé (Paris-Bichat), Pr Pierre Bourgeois, Pr Laure Gossec (Paris-La Pitie-Salpétriere), Pr Francis Berenbaum (Paris-Saint-Antoine), Pr Pascal Claudepierre (Creteil), Pr Maxime Breban, Pr Maria-Antonietta D’Agostino, Pr Félicie Costantino (Boulogne-Billancourt), Pr Michel De Bandt, Dr Bernadette Saint-Marcoux (Aulnay-sous-Bois), Pr Philippe Goupille (Tours), Pr Jean-Françis Maillefert (Dijon), Pr Xavier Puechal, Dr Emmanuelle Dernis (Le Mans), Pr Daniel Wendling, Pr Clément Prati (Besançon), Pr Bernard Combe, Pr Cédric Lukas (Montpellier), Pr Liana Euller-Ziegler, Pr Véronique Breuil (Nice), Pr Pascal Richette (Paris Lariboisière), Pr Pierre Lafforgue, Pr Thao Pham (Marseille), Pr Patrice Fardellone, Dr Patrick Boumier, Dr Pauline Lasselin (Amiens), Pr Jean-Michel Ristori, Pr Martin Soubrier, Pr Anne Tournadre (Clermont-Ferrand), Dr Nadia Mehsen (Bordeaux), Pr Damien Loeuille (Nancy), Pr Rene-Marc Flipo (Lille), Pr Alain Saraux (Brest), Pr Corinne Miceli, Dr Stephan Pavy (Le Kremlin-Bicêtre), Pr Alain Cantagrel, Pr Adeline Ruyssen-Witrand (Toulouse), Pr Olivier Vittecoq, Pr Thierry Lequerre (Rouen). The biological resources center (Paris, Bichat Hospital Claude Bernard – CRB BCB, Certificate number 34457, S. Tubiana) was in charge of centralizing and managing biological data collection. We thank the Biological Resource Center of Bichat Hospital (Paris France).
Declarations
Conflict of Interest
None of the authors (Eléonore Bettacchioli, Divi Cornec, Pauline Gardien, Lucille Quenehervé, Dewi Guellec, Alice Tison, Arnaud Constantin, Thierry Lequerre, Clothilde Bideau, Anne Lise André, Clément Capaldo, Valérie Devauchelle-Pensec, Maryvonne Dueymes, Alain Saraux) has any conflicts of interest to declare. Alain Saraux is an Editorial Board member of Rheumatology and Therapy. Alain Saraux was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.
Ethical Approval
The ESPOIR cohort study protocol was approved by the local ethics committee (No. 020307). All patients gave their signed informed consent before inclusion. The DESIR cohort study protocol was approved by the local ethics committee (EUDRACT#2007-A00608-45). All patients gave their signed informed consent before inclusion. Both studies (ESPOIR and DESIR) were performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
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Prevalence and Significance of the Presence of Anti-transglutaminase and Anti-endomysium Antibodies in Patients with Early Inflammatory Joint Disease
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