Screening for Celiac Disease in Rheumatology: HLA First?

Hakim Rahmoune, Nada Boutrid, Mounira Amrane, Belkacem Bioud

International Journal of Celiac Disease

Screening for Celiac Disease in Rheumatology: HLA First?

Hakim Rahmoune1,, Nada Boutrid1, Mounira Amrane2, Belkacem Bioud1

1Pediatrics Department, Setif University Hospital; Setif-1 University, Algeria

2Biochemistry Department, Setif University Hospital; Setif-1 University, Algeria


HLA genes have been shown to be strongly associated with a large repertoir of autoimmune diseases including Rheumatoid Arthritis (RA), Juvenile idiopathic arthritis (JIA) and Celiac Disease (CD). The present article will discuss what is the place of performing celiac disease associated serology in face of a rheumatologic patient, when gluten enteropaty is suspected. More specifically, should HLA be done prior to the serology? Unnecessary serial serological CD screening in such rheumatology patients could be avoided by performing an HLA typing, as a long-life marker of genetically CD-susceptible patients.

Cite this article:

  • Hakim Rahmoune, Nada Boutrid, Mounira Amrane, Belkacem Bioud. Screening for Celiac Disease in Rheumatology: HLA First?. International Journal of Celiac Disease. Vol. 5, No. 1, 2017, pp 30-32.
  • Rahmoune, Hakim, et al. "Screening for Celiac Disease in Rheumatology: HLA First?." International Journal of Celiac Disease 5.1 (2017): 30-32.
  • Rahmoune, H. , Boutrid, N. , Amrane, M. , & Bioud, B. (2017). Screening for Celiac Disease in Rheumatology: HLA First?. International Journal of Celiac Disease, 5(1), 30-32.
  • Rahmoune, Hakim, Nada Boutrid, Mounira Amrane, and Belkacem Bioud. "Screening for Celiac Disease in Rheumatology: HLA First?." International Journal of Celiac Disease 5, no. 1 (2017): 30-32.

Import into BibTeX Import into EndNote Import into RefMan Import into RefWorks

1. Introduction

During the past decades, an accumulating evidence shows a dramatic rise in the frequency of autoimmune diseases, including Rheumatic (i.e. Rheumatoid Arthritis, RA) and gastrointestinal (i.e.Celiac Disease, CD) conditions [1].

Celiac disease, as an example of a well-described pathophysiological autoimmunity, is diagnosed via a myriad of laboratory tests discussed in recent guidelines from the European Society for Pediatric Gastroenterology, Hepatology and Nutrition, the American College of Gastroenterology and the World Gastroenterology Organisation: Immunoglobulin A anti-tissue transglutaminase (IgA-TTG) serology is thus considered as first-line test (as IgA-TTG greater than 10 times the upper limit of normal has a specificity and positive predictive value of 100%), while omiting intestinal biopsy for diagnosis is still controversial. The decreasing cost of HLA-typing may increase its use as a genetic background screening tool [2].

HLA genes are, in fact linked to a panel of autoimmune conditions by proven causative effects, the best known descriptions are CD and RA as well as Type 1 Diabetes [3].

Genes encoding human leukocyte antigen (HLA) are located in the major histocompatibility complex (MHC) on chromosome 6. Particualrly, HLA class II genomic region encodes the HLA-DR, HLA-DQ and HLA-DP proteins involved in presentation of peptides to HLA-class II-restricted CD4+ T-helper cells., and this region is associated with a large panel of autoimmune conditions [4].

2. HLA invlovment in Rheuamtoid Arthritis, Juvenile Idiopathic Arthritis and Celiac Disease

In both CD and RA, immune responses to modified protein antigens induce a loss of tolerance. In these two conditions, the antigen specific interaction between B and T cells is likely to drive an amplification loop, and lead to both T and B cell responses towards the target proteins involved [5]

RA and CD are also autoimmune diseases sharing a strong association with class II HLAs: individuals carrying HLA-DQ2.5 and/or HLA-DQ8 alleles present an increased risk of developing coeliac disease, whereas those carrying HLA-DR alleles have an increased risk of developing RA [6].

Juvenile idiopathic arthritis (JIA) are quite different and form a complex genetic trait influenced by both genetic and environmental factors. The International League of Associations for Rheumatology (ILAR) defined seven categories of JIA based on various clinical and laboratory findings, as JIA could be regarded as a myriad of autoimmune and non autoimmunes diseases appearing in pediatric ages: some children diagnosed as JIA do exhibit a non-autoimmune systemic form; namely the Still Disease or Systemic Onset JIA best classified as an auto-inflammatory syndrome [7] while the other subtypes of JIA seem to be effectively of autoimmune origine. [4, 6]

Polyarticular Rheumatoid Factor- positive JIA, which can considered the childhood onset of seropositive adult rheumatoid arthritis, represents about 10% of all cases of JIA, HLA DRB1 gene playing a major role in shaping RF-positive JIA in childhood similar to that seen in adults with RA. [4]

3. A Step Wised Serology/Genetic Appraoch

CD patients negative for any of these HLA alleles are very rare. Therefore, the absence of both HLA-DQ2 and HLA-DQ8 heterodimer makes diagnosis of celiac disease very unlikely (sensitivity >96 %). HLA typing of patients has been included as a useful test to exclude celiac disease in the ESPGHAN guidelines for CD diagnosis. [8, 9]

HLA typing confers a high negative predictive value: patients with a negative HLA (i.e. neither DQ2 nor DQ8) will not develop CD; and a suggested strategy to avoid repeated CD screening would be to first perform an HLA test. [10]

Targetting the HLA risk first, rather than tracking positive serology, would be a rasonable step-up appraoch, probably cost efective and time saving: in the past, HLA typing has been expensive and time-consuming, but new single nucleotide polymorphisms techniques [11].

and other combined home-made procedures [12] have recently been reported as very cost-effective and work-time saving for HLA-DQ2 and DQ8 genotyping in CD screening.

In fact, a scottish study concluded that HLA typing would cost as high as £30,198, compared to a system of TTG IgA 3 yearly that costs £609 [13], but recent protocols decreased HLA typing prices from 2397.33 $ to 352.27$; and appear largely cost- effective versus serial serology [11, 12].

In general population, the preferred test to screen for CD is the measurement of IgA TTG along with total serum IgA to avoid false-negative results due to selective IgA deficiency. Positive serology would lead to endoscopic small intestinal biopsies [14]. These serological tests, based on TTG associated to endomysial and deamidated gliadin peptides antibodies are recognized as performant screening tools. [15]

However, in asymptomatic members of a high-risk group, like those presenting RA, it seems reasonable to test first for negative result of HLA-DQ2/DQ8 in order to exclude CD, so that further serologic testing would be unnecessary [16]. Performing HLA genetic typings seems cost effective and could avoid subsequent fibroscopies and biopises [17]

Availability and health insurance coverage of such HLA analysis is questionable, specially in developing world; but recent studies emerging from the South Hemisphere confer solid arguments to such strategies [18] as CD is reported to be strongly associated with HLA-DQ2 in these regions [19].

4. Conclusion

HLA loci are long-life markers of genetically CD-susceptible patients before any clinical or serological signs, and thus increasingly considered to assess CD diagnosis.

Serogenetic screening without the requirement for follow-up small bowel biopsies provides a flexible, cost-effective methodology that could be widely applied to obtain accurate estimates of the prevalence of CD in large cohort studies

Conflict of Interest



[1]  Lerner A, Jeremias P, Matthias T. The World Incidence and Prevalence of Autoimmune Diseases is Increasing. International Journal of Celiac Disease. 2015 Nov 16; 3(4): 151-5.
In article      View Article
[2]  Barakauskas VE, Lam GY, Estey MP. Digesting all the options: Laboratory testing for celiac disease. Critical reviews in clinical laboratory sciences. 2014 Dec 1; 51(6): 358-78.
In article      View Article  PubMed
[3]  Howell WM. HLA and disease: guilt by association. International journal of immunogenetics. 2014 Feb 1; 41(1): 1-2.
In article      View Article  PubMed
[4]  Hersh AO, Prahalad S. Immunogenetics of juvenile idiopathic arthritis: A comprehensive review. Journal of autoimmunity. 2015 Nov 30; 64: 113-24.
In article      View Article  PubMed
[5]  Koning F. Recent insight in the pathophysiology of coeliac disease: relevance to rheumatoid arthritis. Clin Exp Rheumatol. 2015 Jul 1; 33(4 Suppl 92): 8-10.
In article      
[6]  Koning F, Thomas R, Rossjohn J, Toes RE. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nature Reviews Rheumatology. 2015 Aug 1; 11(8): 450-61.
In article      View Article  PubMed
[7]  Rossi-Semerano L, Koné-Paut I. Is Still's disease an autoinflammatory syndrome? International journal of inflammation. 2012 Apr 26; 2012.
In article      
[8]  Fasano ME, Dametto E, D’Alfonso S. HLA Genotyping: Methods for the Identification of the HLA-DQ2,-DQ8 Heterodimers Implicated in Celiac Disease (CD) Susceptibility. Celiac Disease: Methods and Protocols. 2015: 79-92.
In article      
[9]  Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. Journal of pediatric gastroenterology and nutrition. 2012 Jan 1; 54(1): 136-60.
In article      View Article  PubMed
[10]  Anderson RP, Henry MJ, Taylor R, Duncan EL, Danoy P, Costa MJ, Addison K, Tye-Din JA, Kotowicz MA, Knight RE, Pollock W. A novel serogenetic approach determines the community prevalence of celiac disease and informs improved diagnostic pathways. BMC medicine. 2013 Aug 28; 11(1): 1.
In article      View Article  PubMed
[11]  Lund F, Hermansen MN, Pedersen MF, Hillig T, Toft–Hansen H, Sölétormos G. Mapping of HLA–DQ haplotypes in a group of Danish patients with celiac disease. Scandinavian journal of clinical and laboratory investigation. 2015 Aug 18; 75(6): 519-22.
In article      View Article  PubMed
[12]  Aguayo-Patrón S, Beltrán-Sauceda L, Calderón de la Barca AM. A population-wide applicable HLA-DQ2 and DQ8 genotyping using DNA from dried blood spots and duplex allele-specific qPCR amplification. Scandinavian Journal of Clinical and Laboratory Investigation. 2016 Oct 2; 76(7): 581-7.
In article      View Article  PubMed
[13]  Mitchell RT, Sun A, Mayo A, et al. Coeliac screening in a Scottish cohort of children with type 1 diabetes mellitus: is DQ typing the way forward? Arch Dis Child 2016; 101: 230-3.
In article      View Article  PubMed
[14]  Rashid M, Lee J. Serologic testing in celiac disease Practical guide for clinicians. Canadian Family Physician. 2016 Jan 1; 62(1): 38-43.
In article      PubMed
[15]  Samaşca G, Sur G, Lupan I. Current trends and investigative developments in celiac disease. Immunological investigations. 2013 May 1; 42(4): 273-84.
In article      View Article  PubMed
[16]  Snyder J, Butzner JD, DeFelice AR, et al. Evidence-Informed Expert Recommendations for the Management of Celiac Disease in Children. Pediatrics 2016; 138.
In article      View Article
[17]  Ludvigsson JF, Card TR, Kaukinen K, Bai J, Zingone F, Sanders DS, Murray JA. Screening for celiac disease in the general population and in high-risk groups. United European gastroenterology journal. 2015 Apr 1; 3(2): 106-20.
In article      View Article  PubMed
[18]  Crovella S, Brandao L, Guimaraes R, de Lima Filho JL, Arraes LC, Ventura A, Not T. Speeding up coeliac disease diagnosis in the developing countries. Digestive and Liver Disease. 2007 Oct 31; 39(10): 900-2.
In article      View Article  PubMed
[19]  Barada K, Daya HA, Rostami K, Catassi C. Celiac disease in the developing world. Gastrointestinal endoscopy clinics of North America. 2012 Oct 31; 22(4): 773-96.
In article      View Article  PubMed
  • CiteULikeCiteULike
  • MendeleyMendeley
  • StumbleUponStumbleUpon
  • Add to DeliciousDelicious
  • FacebookFacebook
  • TwitterTwitter
  • LinkedInLinkedIn